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WO2024215787A1 - Methods of treating osteosarcoma using lair1 binding agents and pd-1 antagonists - Google Patents

Methods of treating osteosarcoma using lair1 binding agents and pd-1 antagonists Download PDF

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Publication number
WO2024215787A1
WO2024215787A1 PCT/US2024/023913 US2024023913W WO2024215787A1 WO 2024215787 A1 WO2024215787 A1 WO 2024215787A1 US 2024023913 W US2024023913 W US 2024023913W WO 2024215787 A1 WO2024215787 A1 WO 2024215787A1
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WIPO (PCT)
Prior art keywords
seq
amino acid
acid sequence
lair1
antibody
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PCT/US2024/023913
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French (fr)
Inventor
Hung-I Harry CHEN
Igor MIKAELIAN
Lee Benjamin RIVERA
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NGM Biopharmaceuticals Inc
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NGM Biopharmaceuticals Inc
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Publication of WO2024215787A1 publication Critical patent/WO2024215787A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/572—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 cytotoxic response

Definitions

  • the Sequence Listing XML file submitted with this application is entitled “13370-177-228_SEQLISTING.xml”, was created on April 2, 2024 and is 182,313 bytes in size.
  • the present disclosure relates to methods of using a combination of agents that bind leukocyte-associated immunoglobulin-like receptor 1 (LAIR1 or LAIR-1) (e.g., anti-LAIR1 antibodies) and PD-1 antagonists for treating osteosarcoma.
  • LAIR1 or LAIR-1 leukocyte-associated immunoglobulin-like receptor 1
  • PD-1 antagonists for treating osteosarcoma.
  • a majority of cells in the immune system express at least one, and often many, inhibitory receptors.
  • LAIR1 leukocyte-associated immunoglobulin-like receptor-1
  • CD305 leukocyte-associated immunoglobulin-like receptor-1
  • the present disclosure provides a method of disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a subject having osteosarcoma, comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (K D ) of less than NAI-1539756353v1 1 1 ⁇ 10 -9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 ⁇ 10 -8 M; and (b) a PD-1 antagonist.
  • K D dissociation constant
  • the present disclosure provides a method of disrupting, inhibiting, or blocking collagen-induced LAIR1 activity in a subject having osteosarcoma, comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (K D ) of less than 1 ⁇ 10 -9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 ⁇ 10 -8 M; and (b) a PD-1 antagonist.
  • an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (K D ) of less than 1
  • the present disclosure provides a method of disrupting, inhibiting, or blocking LAIR1-induced suppression of an immune cell or immune cell activity in a subject having osteosarcoma, comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 ⁇ 10 -9 M; and/or (iii) binds to cynomolgus LAIR1 with a K D of less than 1 ⁇ 10 -8 M; and (b) a PD-1 antagonist, wherein the immune cell or immune cell activity is a myeloid cell or myeloid cell activity, a natural killer (NK) cell or NK cell activity, a T-cell or T-cell activity, a myeloid-derived suppressor cell (MDSC) or MD
  • NK natural killer
  • the myeloid cell is a monocyte, a macrophage, a dendritic cell, or an APC; and/or (ii) the T-cell is a cytotoxic T-cell (CTL).
  • CTL cytotoxic T-cell
  • the present disclosure provides a method of treating osteosarcoma in a subject, comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 ⁇ 10 -9 M; and/or (iii) binds to cynomolgus LAIR1 with a K D of less than 1 ⁇ 10- 8 M; and (b) a PD-1 antagonist.
  • KD dissociation constant
  • the present disclosure provides a method of (a) inhibiting tumor growth, (b) increasing or enhancing an immune response to a tumor or tumor cells, (c) activating or enhancing a persistent or long-term immune response to a tumor or tumor cells, (d) inhibiting tumor relapse or tumor regrowth, and/or (e) inducing a persistent or long-term immunity that inhibits tumor relapse or tumor regrowth, in a subject having osteosarcoma, the method comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human NAI-1539756353v1 2 LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 ⁇ 10 -9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD
  • the present disclosure provides a method of activating immune cells in the tumor microenvironment in a subject having osteosarcoma, comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 ⁇ 10 -9 M; and/or (iii) binds to cynomolgus LAIR1 with a K D of less than 1 ⁇ 10 -8 M; and (b) a PD-1 antagonist, wherein the immune cells are myeloid cells, NK cells, and/or T-cells.
  • an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR
  • the myeloid cells are monocytes, macrophages, dendritic cells, or antigen presenting cells (APCs); and/or (ii) the T-cells are cytotoxic T-cells (CTLs).
  • APCs antigen presenting cells
  • CTLs cytotoxic T-cells
  • the present disclosure provides use of (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof and (b) a PD-1 antagonist for (a) treatment of osteosarcoma; (b) disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a subject having osteosarcoma; (c) disrupting, inhibiting, or blocking collagen- induced LAIR1 activity in a subject having osteosarcoma; (d) disrupting, inhibiting, or blocking LAIR1-induced suppression of an immune cell or immune cell activity in a subject having osteosarcoma; (e) inhibiting tumor growth, increasing or enhancing an immune response to a tumor or tumor cells, activating or enhancing a persistent or long-term immune response to a tumor or tumor cells, inhibiting tumor relapse or tumor regrowth, and/or inducing a persistent or long-term immunity that inhibits tumor relapse or tumor regrowth, in a subject having osteosarcoma; and/or (f) activ
  • the present disclosure provides use of (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof and (b) a PD-1 antagonist in the manufacture of a medicament (a) treatment of osteosarcoma; (b) disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a subject having osteosarcoma; (c) disrupting, inhibiting, or blocking collagen-induced LAIR1 activity in a subject having osteosarcoma; (d) disrupting, inhibiting, or blocking LAIR1-induced suppression of an immune cell or immune cell activity in a subject having osteosarcoma; (e) inhibiting tumor growth, increasing or NAI-1539756353v1 3 enhancing an immune response to a tumor or tumor cells, activating or enhancing a persistent or long-term immune response to a tumor or tumor cells, inhibiting tumor relapse or tumor regrowth, and/or inducing a persistent or long-term immunity that inhibits tumor relapse or tumor regrowth, in a
  • the present disclosure provides a method of disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a cell mixture comprising osteosarcoma cells to enhance the immune response to the osteosarcoma cells, the method comprising contacting the cell mixture with (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 ⁇ 10 -9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 ⁇ 10 -8 M; and (b) a PD-1 antagonist.
  • an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human
  • the cell mixture comprises at least one of myeloid cells, NK cells, T-cells, cytotoxic T-cells, MDSCs, and T-regs.
  • the myeloid cells comprise at least one of monocytes, macrophages, dendritic cells, and APCs.
  • the present disclosure provides a method of disrupting, inhibiting, or blocking LAIR1-induced suppression of an immune cell or immune cell activity to enhance the immune response to osteosarcoma cells, comprising contacting a cell mixture comprising the osteosarcoma cells and the immune cell with (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (K D ) of less than 1 ⁇ 10 -9 M; and/or (iii) binds to cynomolgus LAIR1 with a K D of less than 1 ⁇ 10 -8 M; and (b) a PD-1 antagonist, wherein the immune cell or immune cell activity is a myeloid cell or myeloid cell activity, a NK cell or NK cell activity, a T-cell or T- cell activity,
  • the myeloid cell is a monocyte, a macrophage, a dendritic cell, or an APC; and/or (ii) the T-cell is a cytotoxic T-cell (CTL).
  • the PD-1 antagonist is an antagonistic anti-PD-1 antibody.
  • the antagonistic anti-PD-1 antibody is selected from the group NAI-1539756353v1 4 consisting of pembrolizumab, pidilizumab, nivolumab, durvalumab, budigalima, cemiplimab, tislelizumab, spartalizumab, and STI-A1110.
  • the antagonistic anti- PD-1 antibody is administered to the subject prior to, concurrently, or subsequent to the administration of the antibody that binds to LAIR1.
  • the antibody comprises: (i) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:119; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:120, (ii) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:117; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:118, (iii) a VH CDR1, a VH
  • the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:25, SEQ ID NO:31, SEQ ID NO:34, or SEQ ID NO:35; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:44, or SEQ ID NO:45; (3) the VH CDR3 comprising NAI-1539756353v1 5 the amino acid sequence of SEQ ID NO:27, or SEQ ID NO:37, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:28 or SEQ ID NO:38; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:42 or SEQ ID NO:39; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:30 or SEQ ID NO:40.
  • the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:41, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27, the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:42, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:31, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:43, the VH CDR3 comprises the amino acid of SEQ ID NO:27; the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:42, and the VL CDR3 comprises the amino acid sequence of SEQ
  • the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:119, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:120.
  • the VH comprises the amino acid sequence of SEQ ID NO:119, and/or the VL comprises the amino acid sequence of SEQ ID NO:120.
  • the antibody comprises a heavy chain having at NAI-1539756353v1 6 least 90% sequence identity to the amino acid sequence of SEQ ID NO:134 and a light chain having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:136.
  • the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:134 and a light chain comprising the amino acid sequence of SEQ ID NO:136.
  • the antibody comprises: (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:25, SEQ ID NO:31, SEQ ID NO:34, or SEQ ID NO:35; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:26, SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:36; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:27 or SEQ ID NO:37, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:28 or SEQ ID NO:38; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:29 or SEQ ID NO:39; (3) the VL CDR3
  • the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:26, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:31, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:32, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL
  • the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:117, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:118. In certain embodiments, the VH comprises the amino acid sequence of SEQ ID NO:117, and/or the VL comprises the amino acid sequence of SEQ ID NO:118.
  • the antibody comprises: (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:9, SEQ ID NO:15, SEQ ID NO:18, or SEQ ID NO:19; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:10, SEQ ID NO:16, SEQ ID NO:17, or SEQ ID NO:20; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:11 or SEQ ID NO:21, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:12 or SEQ ID NO:22; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:13 or SEQ ID NO:23; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:14 or SEQ ID NO:24.
  • the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:9, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:10, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:11; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:12, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:13, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:14; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:15, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:16, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:11; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:12, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:13, and the VL
  • the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:115, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:116. In certain embodiments, the VH comprises the amino acid sequence of SEQ ID NO:115, and/or the VL comprises the amino acid sequence of SEQ ID NO:116.
  • the antibody comprises: (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:46, SEQ ID NO:52, SEQ ID NO:55, or SEQ ID NO:56; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:47, SEQ ID NO:53, SEQ ID NO:54 or SEQ ID NO:57; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:48 or SEQ ID NO:58, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:49 or SEQ ID NO:59; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:50 or SEQ ID NO:60; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:51 or SEQ ID NO:61.
  • the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:46, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:47, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:48; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:49, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:50, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:51; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:52, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:53, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:48; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:49, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:50, and the VL
  • the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:121, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:122. In certain embodiments, the VH comprises the amino acid sequence of SEQ ID NO:121, and/or the VL comprises the amino acid sequence of SEQ ID NO:122.
  • the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:62, SEQ ID NO:68, SEQ ID NO:71, or SEQ ID NO:72; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:63, SEQ ID NO:69, SEQ ID NO:70, or SEQ ID NO:73; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:64 or SEQ ID NO:74, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:65 or SEQ ID NO:75; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:66 or SEQ ID NO:76; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:67 or SEQ ID NO:77.
  • a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:62, SEQ
  • the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:62, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:63, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:64; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:65, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:66, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:67; (ii) the VH CDR1 NAI-1539756353v1 10 comprises the amino acid sequence of SEQ ID NO:68, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:69, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:64; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:65, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:63; and the
  • the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:123, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:124. In certain embodiments, the VH comprises the amino acid sequence of SEQ ID NO:123, and/or the VL comprises the amino acid sequence of SEQ ID NO:124.
  • the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:25, SEQ ID NO:31, SEQ ID NO:34, or SEQ ID NO:35; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:78, SEQ ID NO:82, SEQ ID NO:83, or SEQ ID NO:84; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:79 or SEQ ID NO:85, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:80 or SEQ ID NO:86; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:29 or SEQ ID NO:39; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:81 or SEQ ID NO:87.
  • a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:25, SEQ
  • the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:78, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:79; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:80, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:81; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:31, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:82, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:79; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:80, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:79;
  • the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:125, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:126. In certain embodiments, the VH comprises the amino acid sequence of SEQ ID NO:125, and/or the VL comprises the amino acid sequence of SEQ ID NO:126. [0036] In certain embodiments, the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:127, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:128.
  • the VH comprises the NAI-1539756353v1 12 amino acid sequence of SEQ ID NO:127, and/or the VL comprises the amino acid sequence of SEQ ID NO:128.
  • the antibody comprises a heavy chain having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:138 and a light chain having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:140.
  • the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:138 and a light chain comprising the amino acid sequence of SEQ ID NO:140.
  • the antibody comprises (a) a VH comprising(1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:25, SEQ ID NO:31, SEQ ID NO:34, or SEQ ID NO:35; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:88, SEQ ID NO:32, SEQ ID NO:93, or SEQ ID NO:94; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:89 or SEQ ID NO:95, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:90 or SEQ ID NO:96; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:91 or SEQ ID NO:97; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:92 or SEQ ID NO:98.
  • the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:88, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:89; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:90, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:91, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:92; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:31, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:32, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:89; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:90, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:91, and the VL
  • the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:129, and/or the light chain variable region has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:130.
  • the VH comprises the amino acid sequence of SEQ ID NO:129, and/or the VL comprises the amino acid sequence of SEQ ID NO:130.
  • the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:99, SEQ ID NO:105, SEQ ID NO:108, or SEQ ID NO:109; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:100, SEQ ID NO:106, SEQ ID NO:107 or SEQ ID NO:110; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:101 or SEQ ID NO:111, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:102 or SEQ ID NO:112; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:103 or SEQ ID NO:113; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:104 or SEQ ID NO:114.
  • the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:99, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:100, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:101; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:102, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:103, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:104; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:105, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:106, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:101; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:102, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:103, and the VL
  • the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:131, and/or the light chain variable region has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:132.
  • the VH comprises the amino acid sequence of SEQ ID NO:131, and/or the VL comprises the amino acid sequence of SEQ ID NO:132.
  • the antibody is a recombinant antibody, a monoclonal antibody, a chimeric antibody, a humanized antibody, a bispecific antibody, or a multispecific antibody.
  • the antibody is an IgG1 antibody, an IgG2 antibody, or an IgG4 antibody; optionally wherein the antibody is a human IgG1 antibody, a human IgG2 antibody, or a human IgG4 antibody.
  • the antibody comprises a kappa light chain or a lambda light chain, optionally wherein the antibody comprises a human kappa light chain or a human lambda light chain.
  • the antibody is attached to a half-life extending moiety.
  • the antibody is an antibody fragment.
  • the antibody fragment comprises at least one antigen binding site that binds to LAIR1.
  • the antibody fragment is a Fab, a Fab’, a F(ab’) 2 , a Fv, a scFv, a (scFv)2, a single chain antibody, a dual variable region antibody, a diabody, or a nanobody.
  • the antibody inhibits binding of LAIR-1 to one or more LAIR ligands and optionally has at least one of the following properties: (i) binding human NAI-1539756353v1 15 LAIR1; (ii) binding cyno LAIR1; (iii) not binding mouse LAIR1; (iv) not binding human LAIR-2; (v) being a LAIR1 antagonist; (vi) inhibiting LAIR1 activity; (vii) inhibiting LAIR1 signaling in cells that express LAIR1; (viii) inhibiting binding of LAIR1 to collagen; (ix) inhibiting binding of LAIR1 to MARCO; (x) inhibiting binding of LAIR1 to COLEC12; (xi) inhibiting LAIR1-induced suppression of myeloid cells; (xii) inhibiting LAIR1-induced suppression of myeloid cell activity; (xiii) restoring FcR activation in myeloid cells; (xiv) restoring cytokine and/or chemokine
  • Figures 1A & 1B provide representative images of immunostaining of LAIR1, IBA1 and CD163 in consecutive sections of a human osteosarcoma biopsy sample.
  • Figure 1A shows low magnification images of IBA1 (left panel), LAIR1 (middle panel) and CD163 (right panel).
  • Figure 1B shows high magnification images of LAIR1 (upper panel) and IBA1 (lower panel).
  • Figure 2 provides representative images of OSCAR expression by in situ hybridization in consecutive sections of a human osteosarcoma biopsy sample. PPIB was used as a control.
  • Figures 3A & 3B depict that collagen abundance was assessed in osteosarcoma resection specimens using immunohistochemistry.
  • Figure 3A shows immunostaining of alpha-1 type I collagen (red) in osteosarcoma samples from six patients.
  • Figure 3B shows percentage of area positive for picrosirius red (PSR) or alpha-1 type I collagen (COL1A1) in different cancer indications via immunostaining. Values presented are Mean +/- SD.
  • Figure 4 shows the scores of a 58-gene set associated with cancer stroma shown in different cancer types. 5.
  • LAIR1 binding agents e.g., LAIR1 binding agents disclosed in Section 5.3
  • compositions e.g., pharmaceutical compositions, see Section 5.5
  • LAIR1 binding agents disclosed herein include antibodies (e.g., monospecific or multispecific, including bispecific) and fragments thereof that bind to LAIR1, including antibodies and fragments thereof that bind to human LAIR1.
  • LAIR1 binding agents disclosed herein inhibit the activity of LAIR1 (e.g., inhibit the LAIR1 suppressive activity, inhibit the binding of LAIR1 to at least one LAIR ligand, such as collagen, MARCO, COLEC12, MBL, SPD, and C1 complex).
  • LAIR1 e.g., inhibit the LAIR1 suppressive activity, inhibit the binding of LAIR1 to at least one LAIR ligand, such as collagen, MARCO, COLEC12, MBL, SPD, and C1 complex.
  • binding agent refers to a molecule (e.g., an antibody) that binds an antigen (e.g., LAIR1).
  • a binding agent is an antibody (including an antibody fragment, such as an antigen-binding fragment or an epitope-binding fragment) or other peptide-based molecule as well as a conjugate of an antibody, antibody fragment, or peptide-based molecule (e.g., an antibody-drug conjugate) that binds to an antigen (e.g., LAIR1).
  • a binding agent comprises an alternative protein scaffold or artificial scaffold (e.g., a non-immunoglobulin backbone).
  • a binding agent is a fusion protein comprising an antigen-binding site.
  • a binding agent is a bispecific or multispecific molecule comprising at least one antigen-binding site.
  • antibody immunoglobulin
  • immunoglobulin immunoglobulin
  • Ig immunoglobulin
  • polyclonal antibodies recombinant antibodies
  • monoclonal antibodies including agonist, antagonist, neutralizing antibodies, full-length monoclonal antibodies
  • synthetic antibodies chimeric antibodies
  • humanized antibodies human antibodies
  • monospecific antibodies multispecific antibodies (e.g., bispecific antibodies)
  • antibody compositions having polyepitopic or monoepitopic specificity single domain antibodies (e.g., VHH), or human versions of antibodies having full-length heavy and/or light chains.
  • VHH refers to a domain antibody derived from a variable region of a heavy chain only antibody.
  • Exemplary single domain antibodies include, but are not limited to, antibodies naturally devoid of light chains such as those from Camelidae species (e.g., llama), single domain antibodies derived from conventional 4-chain antibodies, engineered antibodies and single domain scaffolds other than those derived from antibodies.
  • Single domain antibodies may be derived from any species including, but not limited to mouse, human, camel, llama, goat, rabbit, and bovine.
  • VHH can also be derived from other species besides Camelidae that may produce heavy chain antibodies naturally devoid of light chain.
  • Antibodies also include antibody fragments (and/or polypeptides that comprise antibody fragments) that retain antigen (e.g., LAIR1) binding characteristics.
  • Non-limiting examples of antibody fragments include antigen-binding regions and/or effector regions of the antibody, e.g., Fab, Fab’, F(ab’)2, Fv, scFv, (scFv)2, single chain antibody molecule, dual variable domain antibody, single variable domain, linear antibody, V region, a multispecific antibody formed from antibody fragments, F(ab)2, Fd, Fc, diabody, di-diabody, disulfide- linked Fvs (dsFv), single-domain antibody (e.g., nanobody) or other fragments (e.g., fragments consisting of the variable regions of the heavy and light chains that are non- NAI-1539756353v1 18 covalently coupled).
  • a variable (V) region domain may be any suitable arrangement of immunoglobulin heavy (VH) and/or light (VL) variable domains.
  • VH immunoglobulin heavy
  • VL light
  • antibodies also include tetrameric antibodies comprising two heavy chain and two light chain molecules, an antibody light chain monomer, and an antibody heavy chain monomer.
  • the VH and VL may be covalently coupled directly or through a linker to form a single chain Fv (scFv).
  • scFv proteins are included in the category “antibody fragments.”
  • An antibody fragment can also be a peptide comprising one or more complementarity determining regions (CDRs) of an antibody.
  • CDRs can be obtained by constructing polynucleotides that encode one or more CDRs of interest.
  • Such polynucleotides are prepared, for example, by using the polymerase chain reaction to synthesize the variable region using mRNA of antibody-producing cells as a template (see, for example, Larrick et al., Methods: A Companion to Methods in Enzymology, 2:106 (1991); Courtenay-Luck, “Genetic Manipulation of Monoclonal Antibodies,” in Monoclonal Antibodies Production, Engineering and Clinical Application, Ritter et al.
  • Antibody fragments may be incorporated, for example, into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, variable domains of new antigen receptors (v-NAR), and bis-single chain Fv regions (see, e.g., Hollinger and Hudson, Nature Biotechnology, 23(9):1126-1136, 2005).
  • antigen-binding fragment refers to that portion of an antibody, which comprises the amino acid residues that interact with an antigen and confer on the binding fragment, domain, or region its specificity and affinity for the antigen (e.g., the CDRs).
  • Antigen-binding fragment as used herein includes “antibody fragment,” which comprises a portion of an antibody including one or more CDRs, such as the antigen-binding or variable region of the antibody.
  • antibodies comprising a VH and/or VL further contain a light chain and/or a heavy chain constant region, such as one or more constant regions, including one or more IgG1, IgG2, IgG3 and/or IgG4 constant regions.
  • antibodies can include epitope-binding fragments of any of the above.
  • the antibodies disclosed herein can be of any class (e.g., IgG, IgE, IgM, IgD, and IgA) or any subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) of immunoglobulin molecule.
  • the term “monospecific” when used in reference to a binding agent means that the binding agent (e.g., an antibody) having one or more binding sites, each of which binds to the same epitope of the same antigen.
  • the term “multispecific” when used in reference to a binding agent means that the binding agent can specifically bind to at least two distinct epitopes, for example two binding sites each formed by a pair of an antibody heavy chain variable domain (VH) and an antibody light chain variable domain (VL) or each formed by a pair of VHH domains binding to different antigens or to different epitopes on the same antigen.
  • bispecific binding agent e.g., an antibody
  • each may bind to a different epitope.
  • a bispecific binding agent e.g., an antibody
  • the term “monoclonal antibody” as used herein refers to a substantially homogenous antibody population involved in the highly specific recognition and binding of a single antigenic determinant or epitope.
  • “monoclonal antibody” refers to such antibodies made by any kind of techniques, including but not limited to, hybridoma production, phage library display, recombinant expression, and transgenic animals.
  • chimeric antibody refers to an antibody in which a portion of the heavy and/or light chain is derived from a first source or species, while the remainder of the heavy and/or light chain is derived from a different source or species.
  • humanized antibody refers to an antibody that comprises a human heavy chain variable region and a light chain variable region wherein the native CDR amino acid residues are replaced by residues from corresponding CDRs from a non-human antibody (e.g., mouse, rat, rabbit, or non-human primate), and the non-human antibody has the desired specificity, affinity, and/or activity.
  • one or more framework region amino acid residues of the human heavy chain or light chain variable regions are replaced by corresponding residues from the non-human antibody.
  • humanized antibodies can comprise amino acid residues that are not found in the human antibody or non-human antibody. In certain embodiments, these modifications are made to further refine and/or optimize antibody characteristics.
  • the humanized antibody comprises at least a portion of a human immunoglobulin constant region (e.g., CH1, CH2, CH3, Fc, and/or hinge region).
  • human antibody refers to an antibody that possesses an amino acid sequence that corresponds to an antibody produced by a human and/or an antibody that has been made using any of the techniques that are known to those of skill in NAI-1539756353v1 20 the art for making human antibodies. These techniques include, but not limited to, phage display libraries, yeast display libraries, transgenic animals, recombinant protein production, and B-cell hybridoma technology.
  • nucleic acids or polypeptides refer to two or more sequences or subsequences that are the same or have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned (introducing gaps, if necessary) for maximum correspondence, not considering any conservative amino acid substitutions as part of the sequence identity.
  • the percent identity can be measured by sequence comparison software or algorithms, or visual inspection. Algorithms and software known in the art that can align amino acid or nucleotide sequences include, but are not limited to, BLAST, ALIGN, Megalign, BestFit, GCG Wisconsin Package, and variants thereof.
  • two nucleic acids or polypeptides are substantially identical, meaning that they have at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% (e.g., at least 95%, 96%, 97%, 98%, or 99%) nucleotide or amino acid residue identity, when compared and aligned for maximum correspondence, as measured using a sequence comparison algorithm or by visual inspection.
  • identity exists over a region of the amino acid sequences that is at least about 10 residues, at least about 20 residues, at least about 40 residues, at least about 60 residues, or at least about 80 residues in length. In certain embodiments, identity exists over a region longer than 60 residues, such as at least about 100 residues.
  • the sequences are substantially identical over the full length of the sequences being compared, such as the region of a target protein or an antibody.
  • identity exists over a region of the nucleotide sequences that is at least about 100 bases, at least about 200 bases, at least about 400 bases, at least about 600 bases in length, or at least about 800 base in length.
  • identity exists over a longer region than 600 bases, such as at least about 1000 bases or more.
  • sequences are substantially identical over the full-length of the sequences being compared, such as a nucleotide sequence encoding a protein of interest.
  • a “conservative amino acid substitution” is one in which one amino acid residue is replaced with another amino acid residue having a side chain with similar chemical characteristics.
  • Families of amino acid residues having similar side chains include basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, NAI-1539756353v1 21 phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).
  • an “antigen” is a moiety or molecule that contains an epitope to which a binding agent (e.g., an antibody) can bind.
  • a binding agent e.g., an antibody
  • the antigen, to which a binding agent (e.g., an antibody) disclosed herein binds is LAIR1 (e.g., human LAIR1), or a fragment thereof, including a fragment that comprises one or more domains of LAIR1.
  • an “epitope” refers to a localized region of an antigen to which an antibody can bind.
  • An epitope can be a linear epitope or a conformational, non-linear, or discontinuous, epitope.
  • an epitope can be contiguous amino acids of the polypeptide (a “linear” epitope) or an epitope can comprise amino acids from two or more non-contiguous regions of the polypeptide (a “conformational,” “non-linear” or “discontinuous” epitope).
  • an antibody binds to a group of amino acids regardless of whether they are folded in a natural three-dimensional protein structure.
  • an antibody requires amino acid residues making up the epitope to exhibit a particular conformation (e.g., bend, twist, turn, or fold) in order to recognize and bind the epitope.
  • Epitope binning is the process of grouping antibodies based on the epitopes they recognize.
  • epitope binning comprises methods and systems for discriminating the epitope recognition properties of different antibodies, using competition assays combined with computational processes for clustering antibodies based on their epitope recognition properties and identifying antibodies having distinct binding specificities.
  • An antibody binds “an epitope” or “essentially the same epitope” or “the same epitope” as a reference antibody, when the two antibodies recognize identical, overlapping or adjacent epitopes in a three-dimensional space.
  • Competition assays can be used for determining whether two antibodies bind to identical, overlapping or adjacent epitopes in a three-dimensional space, using labeled antigen or labeled antibody.
  • the antigen can immobilized on a 96-well plate, or expressed on a cell surface, and the ability of unlabeled NAI-1539756353v1 22 antibodies to block the binding of labeled antibodies is measured using radioactive, fluorescent, or enzymatic labels.
  • the terms “specifically binds,” “specifically recognizes,” “immunospecifically binds,” “selectively binds,” “immunospecifically recognizes” and “immunospecific” are analogous terms in the context of antibodies and refer to molecules that bind to an antigen (e.g., epitope) as such binding is understood by one skilled in the art.
  • an antibody or antigen-binding domain binds to or specifically binds to an antigen when it binds to the antigen with higher affinity than to any cross-reactive antigen as determined using experimental techniques, such as radioimmunoassays (RIAs) and enzyme linked immunosorbent assays (ELISAs).
  • RIAs radioimmunoassays
  • ELISAs enzyme linked immunosorbent assays
  • a specific or selective reaction will be at least twice background signal or noise and may be more than 10 times background. See, e.g., Fundamental Immunology 332-36 (Paul ed., 2d ed.1989) for a discussion regarding binding specificity.
  • an antibody can, in certain instances, comprise two identical antigen- binding sites, each of which specifically binds the same epitope on two or more proteins.
  • an antibody can be bispecific and comprise at least two antigen-binding sites with differing specificities.
  • binding means “specific binding”.
  • Binding affinity generally refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., a binding agent such as an antibody) and its binding partner (e.g., an antigen such as LAIR1).
  • binding affinity refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen).
  • the affinity of a binding molecule X for its binding partner Y can generally be represented by the dissociation constant (K D ).
  • K D dissociation constant
  • Affinity can be measured by common methods known in the art, including those disclosed herein. Low-affinity antibodies generally bind antigen slowly and tend to dissociate readily, whereas high-affinity antibodies generally bind antigen faster and tend to remain bound longer. A variety of methods of measuring binding affinity are known in the art, any of which can be used for purposes of the present disclosure.
  • the “KD” or “KD value” may be measured by biolayer interferometry (BLI) using, for example, the OctetQK384 system (ForteBio, Menlo Park, CA).
  • the K D may also be measured in a radiolabeled antigen-binding assay (RIA), for example, performed with the Fab version of an antibody of interest and its antigen (Chen, et al., (1999) J. Mol Biol 293:865-881) or using surface plasmon resonance (SPR) assays by BIACORETM, using, for example, a BIACORETM-2000 or a BIACORETM-3000 (BIACORETM, Inc., Piscataway, NJ).
  • RIA radiolabeled antigen-binding assay
  • an “on-rate” or “rate of association” or “association rate” or “k on ,” as well as an “off-rate” or “rate of dissociation” or “dissociation rate” or “koff,” can also be determined with the same SPR or BLI techniques described above using, for example, the OctetQK384 system (ForteBio, Menlo Park, CA) or a BIACORETM-2000 or a BIACORETM- 3000 (BIACORETM, Inc., Piscataway, NJ), respectively.
  • LAIR1 binding agents e.g., antibodies
  • binding agents that compete for the same epitope or binding site on a target, which includes competition between such binding agents as determined by an assay in which the binding agent under study prevents or inhibits the specific binding of a reference molecule (e.g., a reference ligand, or reference antigen- binding protein, such as a reference antibody) to a common antigen (e.g., LAIR1).
  • a reference molecule e.g., a reference ligand, or reference antigen- binding protein, such as a reference antibody
  • Suitable types of competitive binding assays can be used to determine if a test binding agent competes with a reference molecule for binding to LAIR1 (e.g., human LAIR1).
  • assays include solid phase direct or indirect radioimmunoassay (RIA); solid phase direct or indirect enzyme immunoassay (EIA), sandwich competition assay (see, e.g., Stahli et al., (1983) Methods in Enzymology 9:242-253); solid phase direct biotin-avidin EIA (see, e.g., Kirkland et al., (1986) J.
  • RIA solid phase direct or indirect radioimmunoassay
  • EIA enzyme immunoassay
  • sandwich competition assay see, e.g., Stahli et al., (1983) Methods in Enzymology 9:242-253
  • solid phase direct biotin-avidin EIA see, e.g., Kirkland et al., (1986) J.
  • such an assay involves the use of a purified antigen (e.g., LAIR1, such as human LAIR1) bound to a solid surface or cells bearing either of an unlabeled test antigen-binding protein (e.g., test LAIR1 antibody) or a labeled reference antigen-binding protein (e.g., reference LAIR1 antibody).
  • a purified antigen e.g., LAIR1, such as human LAIR1
  • test antigen-binding protein e.g., test LAIR1 antibody
  • a labeled reference antigen-binding protein e.g., reference LAIR1 antibody
  • Antibodies identified by competition assay include antibodies binding to the same epitope as the reference antibody and/or antibodies binding to an adjacent epitope sufficiently proximal to the epitope bound by the reference antibodies for steric hindrance to occur (e.g., similar epitope or overlapping epitope).
  • a competing antibody when present in excess, it will inhibit specific binding of a reference antibody to a common antigen by at least 20%, for example, at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more.
  • constant region or “constant domain” as understood in the art refers to an antibody portion, for example, a carboxyl terminal portion of a light and/or heavy chain which is not directly involved in binding of an antibody to an antigen but can exhibit various effector functions, such as interaction with an Fc receptor.
  • the term includes the portions of NAI-1539756353v1 25 an immunoglobulin molecule having a generally more conserved amino acid sequence relative to an immunoglobulin variable domain.
  • Antibody “effector functions” refer to those biological activities attributable to the Fc region (e.g., a native sequence Fc region or amino acid sequence variant Fc region) of an antibody, and vary with the antibody isotype.
  • Fc region herein is used to define a C-terminal region of an immunoglobulin heavy chain, including, for example, native sequence Fc regions, recombinant Fc regions, and variant Fc regions.
  • the human IgG heavy chain Fc region is often defined to stretch from an amino acid residue at position Cys226 (according to the EU numbering system), or from Pro230 (according to the EU numbering system), to the carboxyl-terminus thereof.
  • the C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody.
  • the term “heavy chain” when used in reference to an antibody refers to a polypeptide chain of about 50-70 kDa, wherein the amino-terminal portion includes a variable region of about 120 to 130 or more amino acids, and a carboxy-terminal portion includes one or more constant regions.
  • the “heavy chain” can refer to any distinct types, e.g., for example, alpha ( ⁇ ), delta ( ⁇ ), epsilon ( ⁇ ), gamma ( ⁇ ) and mu ( ⁇ ), based on the amino acid sequence of the constant domain, which give rise to IgA, IgD, IgE, IgG and IgM classes of antibodies, respectively, including subclasses of IgG, e.g., IgG1, IgG2, IgG3 and IgG4.
  • the term “light chain” when used in reference to an antibody can refer to a polypeptide chain of about 25 kDa, wherein the amino-terminal portion includes a variable region of about 100 to about 110 or more amino acids, and a carboxy-terminal portion includes a constant region.
  • the approximate length of a light chain is 211 to 217 amino acids.
  • an antibody is a 4-chain antibody unit comprising two heavy (H) chain / light (L) chain pairs.
  • an antibody comprises a first H / L chain pair and a second H / L chain pair, wherein the first H / L chain pair binds to an LAIR1 antigen and the second H/ L chain pair binds to another LAIR1 antigen or a non-LAIR1 antigen.
  • an antibody is a 2-chain antibody unit comprising a VHH-VHH pair.
  • the amino acid sequences of the VHH are identical.
  • the amino acid sequence of the VHH are different from each other.
  • an antibody comprises a first VHH and a second VHH, wherein the first VHH binds to an LAIR1 antigen and the second VHH binds to another LAIR1 antigen or a non-LAIR1 antigen.
  • the H and/or L chains comprise constant regions, for example, human constant regions.
  • the L chain constant region of such antibodies is a kappa or lambda light chain constant region, for example, a human kappa or lambda light chain constant region.
  • the H chain constant region of such antibodies comprises a gamma heavy chain constant region, for example, a human gamma heavy chain constant region.
  • such antibodies comprise IgG constant regions, for example, human IgG constant regions (e.g., IgG1, IgG2, IgG3, and/or IgG4 constant regions).
  • IgG constant regions for example, human IgG constant regions (e.g., IgG1, IgG2, IgG3, and/or IgG4 constant regions).
  • variant region or variant domain refers to a portion of the light or heavy chains of an antibody that is generally located at the amino-terminal of the light or heavy chain, has a length of about 120 to 130 amino acids in the heavy chain and about 100 to 110 amino acids in the light chain, and is used in the binding and specificity of each particular antibody for its particular antigen.
  • variable region of the heavy chain may be referred to as “VH.”
  • variable region of the light chain may be referred to as “VL.”
  • the term “variable” refers to the fact that certain segments of the variable regions differ extensively in sequence among antibodies. The V region mediates antigen binding and defines specificity of a particular antibody for its particular antigen. However, the variability is not evenly distributed across the 110-amino acid span of the variable regions.
  • variable regions consist of less variable (e.g., relatively invariant) stretches called framework regions (FRs) of about 15-30 amino acids separated by shorter regions of greater variability (e.g., extreme variability) called “hypervariable regions” or alternatively called “complementarity determining regions (CDRs).”
  • the variable regions of heavy and light chains each comprise four frameworks (FR1, FR2, FR3 and FR4), largely adopting a ⁇ sheet configuration, connected by three hypervariable regions, which form loops connecting, and in some cases forming part of, the ⁇ sheet structure.
  • the hypervariable regions in each chain are held together in close proximity by the frameworks and, with the hypervariable regions from the other chain, contribute to the formation of the antigen-binding site of antibodies (see, e.g., NAI-1539756353v1 27 Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, (1991)).
  • the constant regions are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular-cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
  • the variable regions differ extensively in sequence between different antibodies.
  • variable region is a human variable region.
  • HVR hypervariable region
  • HV complementarity determining region
  • antibodies comprise six hypervariable regions: three in the VH (H1 or VH CDR1, H2 or VH CDR2, and H3 or VH CDR3), and three in the VL (L1 or VL CDR1, L2 or VL CDR2, and L3 or VL CDR3).
  • a number of hypervariable region delineations are in use and are encompassed herein.
  • the Kabat CDRs are based on sequence variability and are the most commonly used (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)).
  • Chothia refers instead to the location of the structural loops (see, e.g., Chothia and Lesk, J. Mol. Biol.196:901-917 (1987)).
  • the end of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34).
  • the AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular’s AbM antibody modeling software (see, e.g., Martin, in Antibody Engineering, Vol.2, Chapter 3, Springer Verlag).
  • the “contact” hypervariable regions are based on an analysis of the available complex crystal structures. The residues from each of these hypervariable regions or CDRs are noted below.
  • IMGT ® ImMunoGeneTics
  • IMGT is an integrated information system specializing in immunoglobulins (IG), T-cell receptors (TR) and major histocompatibility complex (MHC) NAI-1539756353v1 28 of human and other vertebrates.
  • CDRs are referred to in terms of both the amino acid sequence and the location within the light or heavy chain.
  • location of the CDRs within the structure of the immunoglobulin variable domain is conserved between species and present in structures called loops, by using numbering systems that align variable domain sequences according to structural features, CDR and framework residues and are readily identified. This information can be used in grafting and replacement of CDR residues from immunoglobulins of one species into an acceptor framework from, typically, a human antibody.
  • Hypervariable regions may comprise “extended hypervariable regions” as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2) and 89-97 or 89-96 (L3) in the VL and 26-35 or 26- 35A (H1), 50-65 or 49-65 (H2) and 93-102, 94-102, or 95-102 (H3) in the VH.
  • L1 24-36 or 24-34
  • H2 46-56 or 50-56
  • L3 89-97 or 89-96
  • H1 50-65 or 49-65 (H2) and 93-102, 94-102, or 95-102 (H3) in the VH.
  • HVR hypervariable region
  • HV complementarity determining region
  • CDR complementarity determining region
  • the term "immune response” as used herein includes responses from both the innate immune system and the adaptive immune system. It includes both cell-mediated and/or humoral immune responses. It includes both T-cell and B-cell responses, as well as responses from other cells of the immune system such as NK cells, monocytes, macrophages, dendritic cells, etc.
  • pharmaceutically acceptable means being approved by a regulatory agency of the federal or a state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia or other generally recognized Pharmacopeia for use in animals, and more particularly in humans.
  • Excipient means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material.
  • Excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, carriers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof.
  • encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, carriers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing
  • excipient can also refer to a diluent, adjuvant (e.g., Freunds’ adjuvant (complete or incomplete)) or vehicle.
  • excipients are pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipients include buffers, such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid; low molecular weight (e.g., fewer than about 10 amino acid residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugar alcohols, such as mannitol or sorbitol; salt-forming counterions, such as sodium; and
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable excipients are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed.
  • a pharmaceutically acceptable excipient is an aqueous pH buffered solution.
  • excipients are sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like.
  • Water is an exemplary excipient when a composition (e.g., a pharmaceutical composition) is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions.
  • An excipient can also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • Compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations, and the like.
  • compositions can include standard excipients such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
  • Compositions, including pharmaceutical compounds may contain a prophylactically or therapeutically effective amount of an LAIR1 binding agent (e.g., an antibody), for example, in isolated or purified form, together with a suitable amount of excipient so as to provide the form for proper administration to the subject (e.g., patient).
  • an LAIR1 binding agent e.g., an antibody
  • the formulation should suit the mode of administration.
  • an “effective amount” is generally an amount sufficient to reduce the severity and/or frequency of symptoms, eliminate the symptoms and/or underlying cause, prevent or delay the occurrence of symptoms and/or their underlying cause, and/or improve or remediate the damage that results from or is associated with a disease, disorder, or condition.
  • the effective amount is a therapeutically effective amount or a prophylactically effective amount.
  • the term “therapeutically effective amount” as used herein refers to the amount of an agent (e.g., an antibody disclosed herein or any other agent disclosed herein) that is sufficient to reduce and/or ameliorate the severity and/or duration of a given disease, disorder or condition, and/or a symptom related thereto.
  • a therapeutically effective amount of an NAI-1539756353v1 31 agent, including a therapeutic agent can be an amount necessary for (i) reduction, delay or amelioration of the advancement or progression of a given disease, disorder, or condition, (ii) reduction, delay or amelioration of the recurrence, development or onset of a given disease, disorder or conditions, and/or (iii) to improve or enhance the prophylactic or therapeutic effect of another therapy (e.g., a therapy other than the administration of an agent disclosed herein).
  • another therapy e.g., a therapy other than the administration of an agent disclosed herein.
  • a “therapeutically effective amount” of a substance/molecule/agent of the present disclosure may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance/molecule/agent, to elicit a desired response in the individual.
  • a therapeutically effective amount encompasses an amount in which any toxic or detrimental effects of the substance/molecule/agent are outweighed by the therapeutically beneficial effects.
  • the term “therapeutically effective amount” refers to an amount of an agent effective to “treat” a disease, disorder, or condition, in a subject or mammal.
  • treating refers to reducing and/or ameliorating the severity and/or duration of a given disease, disorder or condition, and/or a symptom related thereto, such as (i) reduction, delay or amelioration of the advancement or progression of a given disease, disorder, or condition, (ii) reduction, delay or amelioration of the recurrence, development or onset of a given disease, disorder or conditions, and/or (iii) to improve or enhance the prophylactic or therapeutic effect of another therapy (e.g., a therapy other than the administration of an agent disclosed herein).
  • Another therapy e.g., a therapy other than the administration of an agent disclosed herein.
  • the full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a therapeutically or prophylactically effective amount may be administered in one or more administrations.
  • the terms “about” and “approximately” mean within 20%, within 15%, within 10%, within 9%, within 8%, within 7%, within 6%, within 5%, within 4%, within 3%, within 2%, within 1%, or less variation of a given value or range.
  • comparative terms such as reduce, decrease, increase, or any grammatical variation thereof, can refer to certain variation from the reference.
  • such variation can refer to about 10%, or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 1 fold, or about 2 fold, or about 3 fold, or about 4 fold, or about 5 fold, or about 10 fold, or about 20 fold, or about 30 fold, or about 40 fold, or about 100 fold or higher than the reference.
  • such variation can refer to about 1%, or about 2%, or about 3%, or about 4%, or about 5%, or about 6%, or about 7%, or about 8%, or about 9%, or NAI-1539756353v1 32 about 10%, or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% of the reference.
  • the singular forms “a”, “an” and “the” include plural forms unless the context clearly dictates otherwise.
  • the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).
  • the term “optional” or “optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances wherein the circumstance occurs, and the instances wherein the circumstance does not occur.
  • LAIR1 binds MARCO. In certain embodiments, LAIR1 binds SEQ ID NO:154. In certain embodiments, LAIR1 binds the extracellular domain of MARCO. In certain embodiments, LAIR1 binds within amino acid 65-520 of SEQ ID NO:154. In certain embodiments, LAIR1 binds within SEQ ID NO:155.
  • LAIR1 binds within the collagen-like domain of MARCO. In certain embodiments, LAIR1 binds within amino acids 147-419 of SEQ ID NO:154. In certain embodiments, LAIR1 binds within SEQ ID NO:156. In certain embodiments, LAIR1 binds within the SRCR domain of MARCO. In certain embodiments, LAIR1 binds within amino acids 424-519 of SEQ ID NO:154. In certain embodiments, LAIR1 binds within SEQ ID NO:157. NAI-1539756353v1 33 [00104] In certain embodiments, the LAIR1 binding agent disclosed herein inhibits, disrupts, or blocks binding of LAIR1 to collagen.
  • the LAIR1 binding agent disclosed herein blocks the interaction of LAIR1 to collagen. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits binding of LAIR1 to collagen. In certain embodiments, the LAIR1 binding agent disclosed herein blocks or inhibits a functional interaction between LAIR1 to collagen. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits, disrupts, or blocks binding of LAIR1 to MARCO. In certain embodiments, the LAIR1 binding agent disclosed herein blocks the interaction of LAIR1 to MARCO. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits binding of LAIR1 to MARCO. In certain embodiments, the LAIR1 binding agent disclosed herein blocks or inhibits a functional interaction between LAIR1 to MARCO.
  • the LAIR1 binding agent disclosed herein inhibits, disrupts, or blocks binding of LAIR1 to COLEC12. In certain embodiments, the LAIR1 binding agent disclosed herein blocks the interaction of LAIR1 to COLEC12. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits binding of LAIR1 to COLEC12. In certain embodiments, the LAIR1 binding agent disclosed herein blocks or inhibits a functional interaction between LAIR1 to COLEC12. [00105] In certain embodiments, the LAIR1 binding agent disclosed herein inhibits collagen-induced LAIR1 activity. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits collagen-induced LAIR1 suppressive activity.
  • the LAIR1 binding agent disclosed herein inhibits collagen-induced LAIR1 suppression of myeloid cells. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits collagen-induced LAIR1 suppression of myeloid cell activity. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits collagen-induced LAIR1 suppression of APCs. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits collagen-induced LAIR1 suppression of APC activity. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits collagen-induced LAIR1 suppression of dendritic cells. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits collagen-induced LAIR1 suppression of dendritic cell activity.
  • the myeloid cells, dendritic cells, or APCs are tumor-associated cells. In certain embodiments, the myeloid cells, dendritic cells, or APCs are residing in the tumor microenvironment. In certain embodiments, the myeloid cells, dendritic cells, or APCs are residing within a tumor.
  • the LAIR1 binding agent disclosed herein inhibits MARCO-induced LAIR1 activity. In certain embodiments, the LAIR1 binding agent NAI-1539756353v1 34 disclosed herein inhibits MARCO-induced LAIR1 suppressive activity. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits MARCO-induced LAIR1 suppression of myeloid cells.
  • the LAIR1 binding agent disclosed herein inhibits MARCO-induced LAIR1 suppression of myeloid cell activity. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits MARCO-induced LAIR1 suppression of APCs. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits MARCO-induced LAIR1 suppression of APC activity. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits MARCO-induced LAIR1 suppression of dendritic cells. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits MARCO-induced LAIR1 suppression of dendritic cell activity. In certain embodiments, the myeloid cells, dendritic cells, or APCs are tumor-associated cells.
  • the myeloid cells, dendritic cells, or APCs are residing in the tumor microenvironment. In certain embodiments, the myeloid cells, dendritic cells, or APCs are residing within a tumor.
  • LAIR1 Binding Agents Amino acid (aa) sequences for human LAIR1 (UniProtKB No. Q6GTX8), cynomolgus monkey (“cyno”) LAIR1 (UniProtKB No. A0A2K5TN26), and mouse LAIR1 (UniProtKB No. Q8BG84) are provided herein as SEQ ID NO:1, SEQ ID NO:5, and SEQ ID NO:149, respectively.
  • LAIR1 is a single pass type I transmembrane protein with a predicted molecular weight of approximately 32 kDa.
  • human LAIR1 is a protein of 287 amino acids (aa) - the signal sequence is aa 1-21, the extracellular domain is aa 22-165, the transmembrane region is aa 166-186, and the cytoplasmic domain is aa 187-287.
  • the Ig-like C2-type domain is aa 29-117 and the “stem region” is aa 118-165.
  • immunoreceptor tyrosine-based inhibitory motifs are positioned at aa 249-254 and 279-284.
  • LAIR1 is expressed on almost all immune cells, including NK cells, T-cells, B-cells, monocytes, dendritic cells, eosinophils, basophils, and mast cells.
  • LAIR1 is characterized by an extracellular domain comprising one Ig-like C2 type domain, a transmembrane domain, and a cytoplasmic domain containing 2 ITIM domains (see, e.g., Meyaard et al., 1997, Immunity, 7:283-290; Meyaard et al., 2008, J. Leuk.
  • LAIR1 is known to bind to multiple transmembrane and extracellular matrix collagens. MARCO and COLEC12 were identified as ligands for LAIR1. NAI-1539756353v1 35 [00109] Cyno LAIR1 has an amino acid sequence identity to human LAIR1 of 88%. As characterized within UniProtKB, cyno LAIR1 is a protein of 287 amino acids and it is believed that the structural characteristics of cyno LAIR1 are similar to human LAIR1.
  • the signal sequence is predicted to be aa 1-21
  • the extracellular domain is predicted to be aa 22-165
  • the transmembrane region is predicted to be aa 166-186
  • the cytoplasmic domain is predicted to be aa 187-287.
  • the Ig- like C2-type domain is predicted to be aa 29-117 and the “stem region” is predicted to be aa 118-165.
  • ITIMs are positioned at aa 249-254 and 279-284.
  • Mouse LAIR1 has an amino acid sequence identity to human LAIR1 of 42%.
  • mouse LAIR1 is a protein of 263 amino acids and has structural characteristics similar to human LAIR1.
  • the signal sequence is aa 1-21
  • the extracellular domain is aa 22-144
  • the transmembrane region is aa 145-165
  • the cytoplasmic domain is aa 166-263.
  • the Ig- like C2-type domain is aa 27-114 and the “stem region” is aa 115-144.
  • ITIMs are positioned at aa 226-231 and 255-260.
  • the LAIR1 binding agent disclosed herein binds LAIR1 or a LAIR1 fragment.
  • the LAIR1 fragment comprises the extracellular domain of LAIR1.
  • the LAIR1 fragment comprises the Ig-like C2 type domain (D1).
  • the LAIR1 fragment comprises the Ig-like C2 type domain and the stem region (D1-stem).
  • the extracellular domain of human LAIR1 comprises amino acids 22-165 of SEQ ID NO:1.
  • D1 of human LAIR1 comprises amino acids 29-117 of SEQ ID NO:1.
  • D1-stem of human LAIR1 comprises amino acids 29-165 of SEQ ID NO:1.
  • a human LAIR1 fragment comprises the amino acid sequence of SEQ ID NO:3.
  • a human LAIR1 fragment comprises the amino acid sequence of SEQ ID NO:4.
  • the extracellular domain of cyno LAIR1 comprises amino acids 22-165 of SEQ ID NO:5.
  • D1 of cyno LAIR1 comprises amino acids 29-117 of SEQ ID NO:5.
  • D1- stem of cyno LAIR1 comprises amino acids 29-165 of SEQ ID NO:5.
  • a fragment of cyno LAIR1 comprises the amino acid sequence of SEQ ID NO:7.
  • a fragment of cyno LAIR1 comprises the amino acid sequence of SEQ ID NO:8.
  • the extracellular domain of mouse LAIR1 comprises amino acids 22-144 of SEQ ID NO:149.
  • D1 of mouse LAIR1 comprises amino acids 27-114 of SEQ ID NO:149.
  • NAI-1539756353v1 36 D1-stem of mouse LAIR1 comprises amino acids 27-144 of SEQ ID NO:149.
  • a fragment of mouse LAIR1 comprises the amino acid sequence of SEQ ID NO:151.
  • a fragment of mouse LAIR1 comprises the amino acid sequence of SEQ ID NO:152.
  • LAIR1 e.g., human LAIR1, cyno LAIR1, or mouse LAIR1
  • the N-terminal amino acids and the C-terminal amino acids of any LAIR1 domain or region may vary by 1, 2, 3, 4, 5, or more amino acid residues.
  • the present disclosure provides LAIR1 binding agents.
  • the LAIR1 binding agent disclosed herein binds a fragment of LAIR1.
  • the LAIR1 binding agent binds within a specific region of LAIR1.
  • the LAIR1 binding agent binds within the extracellular domain of LAIR1.
  • the LAIR1 binding agent binds within the D1 domain of LAIR1. In certain embodiments, the LAIR1 binding agent binds within the D1-stem domain of LAIR1. In certain embodiments, the LAIR1 binding agent binds an epitope on LAIR1. In certain embodiments, the LAIR1 binding agent binds a conformational epitope on LAIR1. [00114] In certain embodiments, the LAIR1 binding agent binds human LAIR1. In certain embodiments, the LAIR1 binding agent binds cyno LAIR1. In certain embodiments, the LAIR1 binding agent binds mouse LAIR1. In certain embodiments, the LAIR1 binding agent binds human LAIR1 and cyno LAIR1.
  • the LAIR1 binding agent binds human LAIR1 and cyno LAIR1, but does not bind mouse LAIR1. In certain embodiments, the LAIR1 binding agent binds SEQ ID NO:1. In certain embodiments, the LAIR1 binding agent binds SEQ ID NO:2. In certain embodiments, the LAIR1 binding agent binds within amino acids 22-165 of SEQ ID NO:1. In certain embodiments, the LAIR1 binding agent binds within amino acids 29-117 of SEQ ID NO:1. In certain embodiments, the LAIR1 binding agent binds within amino acids 29-165 of SEQ ID NO:1. In certain embodiments, the LAIR1 binding agent binds SEQ ID NO:3.
  • the LAIR1 binding agent binds SEQ ID NO:4. In certain embodiments, the LAIR1 binding agent binds SEQ ID NO:5. In certain embodiments, the LAIR1 binding agent binds SEQ ID NO:6. In certain embodiments, the LAIR1 binding agent binds within amino acids 22-165 of SEQ ID NO:5. In certain embodiments, the LAIR1 binding agent binds within amino acids 29-117 of SEQ ID NO:5. In certain embodiments, the LAIR1 binding agent binds within amino acids 29-165 of SEQ ID NO:5. In certain embodiments, the LAIR1 binding agent binds SEQ ID NO:7. In certain embodiments, the LAIR1 binding agent binds SEQ ID NO:8.
  • the LAIR1 binding agent binds SEQ ID NO:149. In certain embodiments, the LAIR1 binding agent binds SEQ ID NO:150. In certain embodiments, the LAIR1 binding agent binds within amino acids 22-144 of SEQ ID NO:149. In certain embodiments, the LAIR1 binding agent binds within amino acids 27-114 of SEQ ID NO:149. In certain embodiments, the LAIR1 binding agent binds within amino acids 27-144 of SEQ ID NO:149. In certain embodiments, the LAIR1 binding agent binds SEQ ID NO:151. In certain embodiments, the LAIR1 binding agent binds SEQ ID NO:152.
  • the LAIR1 binding agent binds a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:2. In certain embodiments, the LAIR1 binding agent binds a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:3. In certain embodiments, the LAIR1 binding agent binds a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:4. In certain embodiments, the LAIR1 binding agent binds a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:6. In certain embodiments, the LAIR1 binding agent binds a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:7.
  • the LAIR1 binding agent binds a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:8. In certain embodiments, the LAIR1 binding agent binds a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:150. In certain embodiments, the LAIR1 binding agent binds a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:151. In certain embodiments, the LAIR1 binding agent binds a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:152. [00116] In certain embodiments, the LAIR1 binding agent binds an epitope comprising amino acids within SEQ ID NO:2.
  • the LAIR1 binding agent binds an epitope comprising amino acids within SEQ ID NO:3. In certain embodiments, the LAIR1 binding agent binds an epitope comprising amino acids within SEQ ID NO:4. In certain embodiments, the LAIR1 binding agent binds an epitope comprising at least one amino acid within amino acids 70-80 of SEQ ID NO:1. In certain embodiments, the LAIR1 binding agent binds an epitope comprising at least one amino acid within amino acids 61-80 of SEQ ID NO:1. In certain embodiments, the LAIR1 binding agent binds an epitope comprising amino acids within SEQ ID NO:6.
  • the LAIR1 binding agent binds an epitope comprising amino acids within SEQ ID NO:7. In certain embodiments, the LAIR1 binding agent binds an epitope comprising amino acids within SEQ ID NO:8. In certain embodiments, the LAIR1 binding agent binds an epitope comprising NAI-1539756353v1 38 amino acids within SEQ ID NO:150. In certain embodiments, the LAIR1 binding agent binds an epitope comprising amino acids within SEQ ID NO:151. In certain embodiments, the LAIR1 binding agent binds an epitope comprising amino acids within SEQ ID NO:152.
  • a variety of methods of measuring binding affinity are known in the art, any of which can be used for purposes of the present disclosure, including by RIA, for example, performed with the Fab version of an antibody of interest and its antigen (Chen et al., 1999, J. Mol Biol 293:865-81); by biolayer interferometry (BLI) or surface plasmon resonance (SPR) assays by OCTET®, using, for example, an OCTET®Red96 system, or by BIACORE®, using, for example, a BIACORE®TM-2000 or a BIACORE®TM-3000.
  • RIA for example, performed with the Fab version of an antibody of interest and its antigen (Chen et al., 1999, J. Mol Biol 293:865-81)
  • BLI biolayer interferometry
  • SPR surface plasmon resonance
  • an “on-rate” or “rate of association” or “association rate” or “k on ” may also be determined with the same biolayer interferometry (BLI) or surface plasmon resonance (SPR) techniques described above using, for example, the OCTET®Red96, the BIACORE®TM-2000, the BIACORE®TM-3000 system, the BIACORE®TM-8K, or the BIACORE®TM-8K+ system.
  • BLI biolayer interferometry
  • SPR surface plasmon resonance
  • the LAIR1 binding agent binds to LAIR1 (e.g., human LAIR1) with a dissociation constant (KD) of 1 ⁇ M or less, 100 nM or less, 40 nM or less, 20 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 50 pM or less, 10 pM or less, or 1 pM or less.
  • KD dissociation constant
  • the LAIR1 binding agent binds LAIR1 with a KD of about 20 nM or less, 10 nM or less, 5 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.5 nM or less, 0.1 nM or less, 50 pM or less, 25 pM or less, 10 pM or less, 1 pM or less. In certain embodiments, the LAIR1 binding agent binds LAIR1 with a KD of from 0.01 nM to 2.5 nM, from 0.1 nM to 5 nM, or from 1 nM to 5 nM.
  • the K D of the LAIR1 binding agent is determined using an LAIR1 protein immobilized on a Biacore chip and the binding agent flowed over the chip. In certain embodiments, the KD of the LAIR1 binding agent is determined using the binding agent captured by an anti-human IgG antibody on a Biacore chip and soluble LAIR1 flowed over the chip.
  • the LAIR1 binding agent binds LAIR1 with a half maximal effective concentration (EC50) of 1 ⁇ M or less, 100 nM or less, 40 nM or less, 20 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less.
  • the LAIR1 binding agent binds human LAIR1 with an EC 50 of 1 ⁇ M or less, 100 nM or less, 40 nM or less, 20 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less.
  • the LAIR1 binding agent binds cyno LAIR1 and/or human LAIR1 with an EC 50 of 40 nM or less, 20 nM or less, 10 nM or less, 1 nM or less or 0.1 nM or less. In certain embodiments, the LAIR1 binding agent binds LAIR1 with an EC50 of 0.1 nM to NAI-1539756353v1 39 about 3 nM, 0.1 nM to 2 nM, 0.1 nM to 1 nM, 0.5 nM to 3 nM, 0.5 nM to 2 nM, or 0.5 nM to 1 nM.
  • the LAIR1 binding agent disclosed herein has at least one of the following properties: (i) binding human LAIR1; (ii) binding cyno LAIR1; (iii) not binding mouse LAIR1; (iv) not binding human LAIR-2; (v) being a LAIR1 antagonist; (vi) inhibiting LAIR1 activity; (vii) inhibiting LAIR1 signaling in cells that express LAIR1; (viii) inhibiting binding of LAIR1 to collagen; (ix) inhibiting binding of LAIR1 to MARCO; (x) inhibiting binding of LAIR1 to COLEC12; (xi) inhibiting LAIR1-induced suppression of myeloid cells; (xii) inhibiting LAIR1-induced suppression of myeloid cell activity; (xiii) restoring FcR activation in myeloid cells; (xiv) restoring cytokine and/or chemokine production in myeloid cells; (xi)
  • the myeloid cells are monocytes, macrophages, dendritic cells, antigen- presenting cells (APCs), or any combination thereof.
  • the LAIR1 binding agent is an anti-LAIR1 antibody.
  • the anti-LAIR1 antibody is a recombinant antibody, a monoclonal antibody, a chimeric antibody, a humanized antibody, or a human antibody.
  • the anti-LAIR1 antibody is an IgG antibody (e.g., an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody).
  • the antibody comprises an IgG heavy chain (e.g., an IgG1 heavy chain, an IgG2 heavy chain, or an IgG4 heavy chain). In certain embodiments, the antibody comprises a human IgG1 heavy chain, a human IgG2 heavy chain, or a human IgG4 heavy chain. In certain embodiments, the anti- LAIR1 antibody comprises a kappa light chain. In certain embodiments, the anti-LAIR1 antibody comprises a kappa light chain constant region. In certain embodiments, the anti- LAIR1 antibody comprises a human kappa light chain constant region. In certain embodiments, the anti-LAIR1 antibody comprises a lambda light chain.
  • the anti-LAIR1 antibody comprises a lambda light chain constant region. In certain embodiments, the anti-LAIR1 antibody comprises a human lambda light chain constant region. In certain embodiments, the human kappa light chain constant region comprises the amino acid sequence set forth in SEQ ID NO:147. In certain embodiments, the human lambda light chain constant region comprises the amino acid sequence set forth in SEQ ID NO:148. NAI-1539756353v1 40 [00122] In certain embodiments, the antibody is a monospecific antibody. In certain embodiments, the antibody is a bispecific antibody. In certain embodiments, the antibody is a multispecific antibody. In certain embodiments, the antibody is a monovalent antibody. In certain embodiments, the antibody is a bivalent antibody.
  • the antibody is a tetravalent antibody.
  • the antibody is isolated. In certain embodiments, the antibody is substantially pure.
  • the LAIR1 binding agent is a polyclonal antibody.
  • Polyclonal antibodies can be prepared by any methods known to those of skill in the art. In certain embodiments, the polyclonal antibodies are produced by immunizing an animal (e.g., a rabbit, rat, mouse, goat, donkey) with an antigen of interest (e.g., a purified peptide fragment, a recombinant protein, or a fusion protein) using multiple subcutaneous or intraperitoneal injections.
  • an animal e.g., a rabbit, rat, mouse, goat, donkey
  • an antigen of interest e.g., a purified peptide fragment, a recombinant protein, or a fusion protein
  • the antigen is conjugated to a carrier such as keyhole limpet hemocyanin (KLH), serum albumin, bovine thyroglobulin, or soybean trypsin inhibitor.
  • KLH keyhole limpet hemocyanin
  • serum albumin serum albumin
  • bovine thyroglobulin bovine thyroglobulin
  • soybean trypsin inhibitor e.g., soybean trypsin inhibitor
  • the antigen (with or without a carrier protein) is diluted in sterile saline and usually combined with an adjuvant (e.g., complete or incomplete Freund’s adjuvant) to form a stable emulsion. After a period of time, polyclonal antibodies are recovered from the immunized animal (e.g., from blood or ascites).
  • an adjuvant e.g., complete or incomplete Freund’s adjuvant
  • the polyclonal antibodies are purified from serum or ascites according to standard methods in the art including, but not limited to, affinity chromatography, ion-exchange chromatography, gel electrophoresis, and/or dialysis.
  • the LAIR1 binding agent is a monoclonal antibody.
  • Monoclonal antibodies can be prepared by any method known to those of skill in the art.
  • monoclonal antibodies are prepared using hybridoma methods known to one of skill in the art. For example, using a hybridoma method, a mouse, rat, rabbit, hamster, or other appropriate host animal, is immunized as described above. In certain embodiments, lymphocytes are immunized in vitro.
  • the immunizing antigen is a human protein or a fragment thereof. In certain embodiments, the immunizing antigen is a mouse protein or a fragment thereof. In certain embodiments, the immunizing antigen is a cyno protein or a fragment thereof. In certain embodiments, the immunizing antigen is a combination of two or more (e.g., 2, 3, 4) related proteins or fragments thereof. [00126] Following immunization, lymphocytes are isolated and fused with a suitable myeloma cell line using, for example, polyethylene glycol or electrofusion.
  • hybridoma cells are selected using specialized media as known in the art and unfused lymphocytes and NAI-1539756353v1 41 myeloma cells do not survive the selection process.
  • Hybridomas that produce monoclonal antibodies directed specifically against a chosen antigen can be identified by a variety of methods including, but not limited to, immunoprecipitation, immunoblotting, and in vitro binding assays (e.g., flow cytometry, FACS, ELISA, SPR (e.g., Biacore), and radioimmunoassay).
  • the clones may be subcloned by limiting dilution techniques.
  • high-throughput methods are used to distribute single cell hybridoma cells into plates. In certain embodiments, high-throughput methods are used to directly distribute single cells from original fusion into plates.
  • the hybridomas can be propagated either in in vitro culture using standard methods or in vivo as ascites tumors in an animal.
  • the monoclonal antibodies can be purified from the culture medium or ascites fluid according to standard methods in the art including, but not limited to, affinity chromatography, ion-exchange chromatography, gel electrophoresis, and dialysis. [00127] In certain embodiments, monoclonal antibodies are made using recombinant DNA techniques as known to one skilled in the art.
  • the polynucleotides encoding an antibody are isolated from mature B-cells or hybridoma cells, such as by RT-PCR using oligonucleotide primers that specifically amplify the genes encoding the heavy and light chains of the antibody, and their sequence is determined using standard techniques.
  • the isolated polynucleotides encoding the heavy and light chains are then cloned into suitable expression vectors which produce the monoclonal antibodies when transfected into host cells such as E. coli, simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin proteins.
  • recombinant monoclonal antibodies are isolated from phage display libraries expressing variable domains or CDRs of a desired species. Screening of phage libraries can be accomplished by various techniques known in the art.
  • a monoclonal antibody is modified by using recombinant DNA technology to generate alternative antibodies.
  • the constant domains of the light chain and heavy chain of a mouse monoclonal antibody are substituted for constant regions of a human antibody to generate a chimeric antibody.
  • the constant regions are truncated or removed to generate a desired antibody fragment of a monoclonal antibody.
  • the LAIR1 binding agent is a humanized antibody.
  • a humanized antibody comprises one or more amino acid residues that have been introduced into it from a source that is non-human.
  • humanization is performed by substituting one or more non-human CDR sequences for the corresponding CDR sequences of a human antibody.
  • the humanized antibodies are constructed by substituting all six CDRs of a non-human antibody (e.g., a mouse antibody) for the corresponding CDRs of a human antibody.
  • a non-human antibody e.g., a mouse antibody
  • the choice of which human heavy chain variable region and/or light chain variable region to use for generating humanized antibodies can be made based on a variety of factors and by a variety of methods known in the art.
  • the “best-fit” method is used where the sequence of the variable region of a non-human (e.g., rodent) antibody is screened against the entire library of known human variable region sequences. The human sequence that is most similar to that of the non-human sequence is selected as the human variable region framework for the humanized antibody.
  • variable region framework sequence is selected as the variable region framework.
  • variable region framework sequence is derived from the consensus sequences of the most abundant human subclasses.
  • human germline genes are used as the source of the variable region framework sequences.
  • LAIR1 binding agent is a human antibody.
  • Human antibodies can be prepared using various techniques known in the art. In certain embodiments, human antibodies are generated from immortalized human B lymphocytes immunized in vitro.
  • human antibodies are generated from lymphocytes isolated from an immunized individual. In any case, cells that produce an antibody directed against a target antigen can be generated and isolated.
  • a human antibody is selected from a phage library, where that phage library expresses human antibodies.
  • phage display technology may be used to NAI-1539756353v1 43 produce human antibodies and antibody fragments in vitro, from immunoglobulin variable region gene repertoires from unimmunized human donors. Techniques for the generation and use of antibody phage libraries are well known in the art. Once antibodies are identified, affinity maturation strategies known in the art, including but not limited to, chain shuffling and site-directed mutagenesis, may be employed to generate higher affinity human antibodies.
  • human antibodies are produced in transgenic mice that contain human immunoglobulin loci. Upon immunization these mice are capable of producing the full repertoire of human antibodies in the absence of endogenous immunoglobulin production.
  • the LAIR1 binding agent is an antibody fragment comprising an antigen-binding site that bind to LAIR1.
  • the antibody fragment is Fab, Fab’, F(ab’)2, Fv, scFv, (scFv)2, single chain antibody molecule, dual variable domain antibody, single variable domain, linear antibody, V region, a multispecific antibody formed from antibody fragments, F(ab)2, Fd, Fc, diabody, di-diabody, disulfide- linked Fvs (dsFv), single-domain antibody (e.g., nanobody) or other fragments (e.g., fragments consisting of the variable regions of the heavy and light chains that are non- covalently coupled).
  • the LAIR1 binding agent is a scFv.
  • the scFv is a disulfide-linked scFv (dsscFv).
  • DsscFv antibodies comprise an engineered disulfide bond between the light chain variable region and heavy chain variable region of the scFv. In certain embodiments, the disulfide bond increases stability and/or thermostability of the scFv molecule.
  • the LAIR1 binding agent is a Fv. In certain embodiments, the LAIR1 binding agent is a Fab. In certain embodiments, the LAIR1 binding agent is a F(ab’) 2 . In certain embodiments, the LAIR1 binding agent is a Fab’.
  • Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody.
  • the antibody fragment disclosed herein is produced using recombinant technologies known in the art (e.g., E.coli or phage expression).
  • the LAIR1 binding agent is a bispecific antibody. Bispecific antibodies are capable of recognizing and binding at least two different antigens or epitopes. The different epitopes can either be within the same molecule (e.g., two epitopes on LAIR1) or on different molecules (e.g., one epitope on LAIR1 and one epitope on a different target).
  • the bispecific antibody has enhanced potency as compared to an individual antibody or to a combination of more than one antibody.
  • the bispecific antibody has reduced toxicity as compared to an individual antibody or to a combination of more than one antibody. It is known to those of skill in the art that any therapeutic agent may have unique pharmacokinetics (PK) (e.g., circulating half-life).
  • PK pharmacokinetics
  • the bispecific antibody has the ability to synchronize the PK of two active binding agents wherein the two individual binding agents have different PK profiles.
  • the bispecific antibody has the ability to concentrate the actions of two agents in a common area (e.g., tissue) in a subject.
  • the bispecific antibody has the ability to concentrate the actions of two agents to a common target (e.g., a specific cell type). In certain embodiments, the bispecific antibody has the ability to target the actions of two agents to more than one biological pathway or function. In certain embodiments, the bispecific antibody has the ability to target two different cells and bring them closer together. [00137] In certain embodiments, the bispecific antibody has decreased toxicity and/or side effects. In certain embodiments, the bispecific antibody has decreased toxicity and/or side effects as compared to a mixture of the two individual antibodies or the antibodies as single agents. In certain embodiments, the bispecific antibody has an increased therapeutic index.
  • the bispecific antibody has an increased therapeutic index as compared to a mixture of the two individual antibodies or the antibodies as single agents.
  • the bispecific antibody comprises heavy chain constant regions with modifications in the amino acids that are part of the interface between the two heavy chains. These modifications are made to enhance heterodimer formation and generally reduce or eliminate homodimer formation.
  • the bispecific antibody is generated using a knobs-into-holes (KIH) strategy.
  • the bispecific antibody comprises variant hinge regions incapable of forming disulfide linkages between identical heavy chains (e.g., reduce homodimer formation).
  • the bispecific antibody comprises heavy chains with changes in amino acids that result in altered electrostatic interactions. In certain embodiments, the bispecific antibodies comprise heavy chains with changes in amino acids that result in altered hydrophobic/hydrophilic interactions.
  • Bispecific antibodies can be intact antibodies or antibody fragments comprising antigen-binding sites.
  • the LAIR1 binding agent disclosed herein is an antibody that binds LAIR1. In certain embodiments, the anti-LAIR1 antibody binds human LAIR1. NAI-1539756353v1 45 In certain embodiments, the anti-LAIR1 antibody binds cyno LAIR1. In certain embodiments, the anti-LAIR1 antibody binds mouse LAIR1.
  • the anti-LAIR1 antibody binds human LAIR1 and cyno LAIR1. In certain embodiments, the anti-LAIR1 antibody binds human LAIR1 and cyno LAIR1, and does not bind mouse LAIR1. In certain embodiments, the anti-LAIR1 antibody binds an LAIR1 epitope. In certain embodiments, the anti-LAIR1 antibody binds an LAIR1 epitope within the extracellular domain of human LAIR1. In certain embodiments, the anti-LAIR1 antibody binds an LAIR1 epitope within the extracellular domain of cyno LAIR1.
  • the anti-LAIR1 antibody binds an epitope comprising at least one amino acid (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9) within amino acids 22-165 of SEQ ID NO:1. In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising at least one amino acid within amino acids 22-117 of SEQ ID NO:1. In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising at least one amino acid within amino acids 29-117 of SEQ ID NO:1. In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising amino acids within SEQ ID NO:3.
  • the anti-LAIR1 antibody binds an epitope comprising amino acids within SEQ ID NO:4. [00142] In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising at least one amino acid (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9) within amino acids 22-165 of SEQ ID NO:5. In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising at least one amino acid within amino acids 22-117 of SEQ ID NO:5. In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising at least one amino acid within amino acids 29-117 of SEQ ID NO:5.
  • amino acid e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9
  • the anti-LAIR1 antibody binds an epitope comprising amino acids within SEQ ID NO:7. In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising amino acids within SEQ ID NO:8. [00143] In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising at least one amino acid (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9) within amino acids 22-144 of SEQ ID NO:149. In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising at least one amino acid within amino acids 22-114 of SEQ ID NO:149.
  • the anti-LAIR1 antibody binds an epitope comprising at least one amino acid within amino acids 27-114 of SEQ ID NO:149. In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising amino acids within SEQ ID NO:151. In certain embodiments, the anti- LAIR1 antibody binds an epitope comprising amino acids within SEQ ID NO:152. [00144] In certain embodiments, the epitope is a conformational epitope. In certain embodiments, the epitope is a linear epitope. NAI-1539756353v1 46 [00145] In certain embodiments, the anti-LAIR1 antibody competes with a second agent for binding within the extracellular domain of human LAIR1.
  • the anti- LAIR1 antibody competes with a second agent for binding within the extracellular domain of cyno LAIR1. In certain embodiments, the anti-LAIR1 antibody competes with a second agent for binding within amino acids 22-165 of SEQ ID NO:1. In certain embodiments, the anti-LAIR1 antibody competes with a second agent for binding within amino acids 22-117 of SEQ ID NO:1. In certain embodiments, the anti-LAIR1 antibody competes with a second agent for binding within amino acid sequence SEQ ID NO:3. In certain embodiments, the anti-LAIR1 antibody competes with a second agent for binding within amino acid sequence SEQ ID NO:4.
  • the LAIR1 binding agent is a variant of the anti-LAIR1 antibody disclosed herein.
  • the anti-LAIR1 antibody variant comprises from 1 to 30, from 1 to 25, from 1 to 20, from 1 to 15, from 1 to 10, from 1 to 5, or from 1 to 3 amino acid substitutions.
  • the amino acid substitution(s) is in a CDR of the antibody. In certain embodiments, the amino acid substitution(s) is not in a CDR of the antibody. In certain embodiments, the amino acid substitution(s) is in a framework region of the antibody. In certain embodiments, the amino acid substitution(s) is a conservative amino acid substitution.
  • the anti-LAIR1 antibody disclosed herein comprises the six CDRs of antibody designated as 47A1, 47H1, Hz47H1.v4, 57D12, 61H4, 62G10, 108D10, or 43H2 based on the Kabat definition as set forth in Tables 1-7.
  • the anti-LAIR1 antibody disclosed herein comprises the six CDRs of antibody designated as 47A1, 47H1, Hz47H1.v4, 57D12, 61H4, 62G10, 108D10, or 43H2 based on the Chothia definition as set forth in Tables 1-7.
  • the anti-LAIR1 antibody disclosed herein comprises the six CDRs of antibody designated as 47A1, 47H1, Hz47H1.v4, 57D12, 61H4, 62G10, 108D10, or 43H2 based on the AbM definition as set forth in Tables 1- 7. In certain embodiments, the anti-LAIR1 antibody disclosed herein comprises the six CDRs of antibody designated as 47A1, 47H1, Hz47H1.v4, 57D12, 61H4, 62G10, 108D10, or 43H2 based on the IMGT definition as set forth in Tables 1-7.
  • the anti-LAIR1 antibody disclosed herein comprises the six CDRs of antibody designated as 47A1, 47H1, Hz47H1.v4, 57D12, 61H4, 62G10, 108D10, or 43H2 based on the Contact definition as set forth in Tables 1-7.
  • the anti-LAIR1 antibody disclosed herein comprises the six CDRs of antibody designated as 47A1, 47H1, Hz47H1.v4, NAI-1539756353v1 47 57D12, 61H4, 62G10, 108D10, or 43H2 based on the Exemplary definition as set forth in Tables 1-7.
  • the LAIR1 binding agent is an anti-LAIR1 antibody that comprises one, two, three, four, five, and/or six CDRs of any one of the antibodies disclosed herein.
  • the anti-LAIR1 antibody comprises (i) a VH comprising one, two, and/or three VH CDRs from Table 1, and/or (ii) a VL comprising one, two, and/or three VL CDRs from Table 1.
  • the anti-LAIR1 antibody comprises (i) a VH comprising one, two, and/or three VH CDRs from Table 2A, and/or (ii) a VL comprising one, two, and/or three VL CDRs from Table 2A.
  • the anti-LAIR1 antibody comprises (i) a VH comprising one, two, and/or three VH CDRs from Table 2B, and/or (ii) a VL comprising one, two, and/or three VL CDRs from Table 2B. In certain embodiments, the anti-LAIR1 antibody comprises (i) a VH comprising one, two, and/or three VH CDRs from Table 3, and/or (ii) a VL comprising one, two, and/or three VL CDRs from Table 3.
  • the anti-LAIR1 antibody comprises (i) a VH comprising one, two, and/or three VH CDRs from Table 4, and/or (ii) a VL comprising one, two, and/or three VL CDRs from Table 4. In certain embodiments, the anti-LAIR1 antibody comprises (i) a VH comprising one, two, and/or three VH CDRs from Table 5, and/or (ii) a VL comprising one, two, and/or three VL CDRs from Table 5.
  • the anti-LAIR1 antibody comprises (i) a heavy chain variable region comprising one, two, and/or three VH CDRs from Table 6, and/or (ii) a VL comprising one, two, and/or three VL CDRs from Table 6. In certain embodiments, the anti-LAIR1 antibody comprises (i) a VH comprising one, two, and/or three VH CDRs from Table 7, and/or (ii) a VL comprising one, two, and/or three VL CDRs from Table 7.
  • the LAIR1 binding agent is an anti-LAIR1 antibody that comprises (i) a VH comprising three VH CDRs from Table 1, and (ii) a VL comprising three VL CDRs from Table 1.
  • the anti-LAIR1 antibody comprises (i) a VH comprising three VH CDRs from Table 2A, and (ii) a VL comprising three VL CDRs from Table 2A.
  • the anti-LAIR1 antibody comprises (i) a VH comprising three VH CDRs from Table 2B, and (ii) a VL comprising three VL CDRs from Table 2B.
  • the anti-LAIR1 antibody comprises (i) a VH comprising three VH CDRs from Table 3, and (ii) a VL comprising three VL CDRs from Table 3. In certain embodiments, the anti-LAIR1 antibody comprises (i) a VH comprising three VH CDRs from Table 4, and (ii) a VL comprising three VL CDRs from Table 4. In certain embodiments, the anti-LAIR1 antibody comprises (i) a VH comprising three VH CDRs from NAI-1539756353v1 48 Table 5, and (ii) a VL comprising three VL CDRs from Table 5.
  • the anti-LAIR1 antibody comprises (i) a VH comprising three VH CDRs from Table 6, and (ii) a VL comprising three VL CDRs from Table 6. In certain embodiments, the anti-LAIR1 antibody comprises (i) a VH comprising three VH CDRs from Table 7, and (ii) a VL comprising three VL CDRs from Table 7.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or (b) a VL comprising a VL CDR1, a VL C
  • the LAIR1 binding agent (e.g., an antibody) comprises: (a) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from an antibody disclosed herein (e.g., an antibody disclosed in Tables 1-7).
  • the LAIR1 binding agent (e.g., an antibody) is a variant of the LAIR1 binding agent (e.g., an antibody) disclosed herein.
  • the LAIR1 binding agent (e.g., an antibody) variant comprises amino acid substitutions in the VH and/or the VL as compared to the LAIR1 binding agent disclosed herein.
  • the LAIR1 binding agent (e.g., an antibody) variant comprises amino acid substitutions in the VH CDR1, VH CDR2, and/or VH CDR3 and/or the VL CDR1, VL CDR2, and/or VL CDR3 as compared to the LAIR1 binding agent (e.g., an antibody) disclosed herein (e.g., an antibody disclosed in Tables 1-7).
  • the LAIR1 binding agent variant comprises one or more (e.g., 1, 2, 3, 4, etc.) amino acid substitutions in a CDR of an antibody disclosed herein (e.g., an antibody disclosed in Tables 1-7).
  • the amino acid substitutions are conservative substitutions.
  • a CDR comprises one amino acid substitution.
  • a CDR comprises two amino acid substitutions.
  • a CDR comprises three amino acid substitutions.
  • a CDR comprises four amino acid substitutions.
  • the CDR is a VH CDR1.
  • the CDR is a VH CDR2.
  • the CDR is a VH CDR3.
  • the CDR is a VL CDR1. In certain embodiments, the CDR is a VL CDR2. In certain embodiments, the CDR is a VL CDR3. In certain embodiments, the substitutions are made as part of a humanization process. In certain embodiments, the substitutions are made as part of a germline humanization process. In certain embodiments, the substitutions are made as part of an affinity maturation process. In certain embodiments, the substitutions are made as part of an optimization process. [00152] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises one or more VH CDRs or VL CDRs that have been modified to reduce deamidation within the CDR sequence.
  • the LAIR1 binding agent e.g., an antibody
  • Deamidation is a chemical reaction in which an amide functional group in the side chain of the amino acids asparagine (Asn or N) or glutamine (Gln or Q) is removed or converted to another functional group.
  • asparagine is converted to aspartic acid NAI-1539756353v1 58 or isoaspartic acid and glutamine is converted to glutamic acid or polyglutamic acid.
  • deamidation may change the structure, function, and/or stability of a polypeptide, potentially resulting in decreased biological activity.
  • the VH CDR1, VH CDR2, and/or VH CDR3 of an antibody disclosed herein is modified to reduce deamidation.
  • the VL CDR1, VL CDR2, and/or VL CDR3 of an antibody disclosed herein is modified to reduce deamidation.
  • the LAIR1 binding agent e.g., an antibody
  • the LAIR1 binding agent comprises one or more VH CDRs or VL CDRs that have been modified to reduce isomerization. Isomerization is a chemical process by which a compound is transformed into any of its isomeric forms, i.e., forms with the same chemical composition but with different structure or configuration and, potentially with different physical and chemical properties. Studies have shown that aspartate (Asp or D) isomerization within a CDR can impact antibody binding and/or stability.
  • the VH CDR1, VH CDR2, and/or VH CDR3 of an antibody disclosed herein is modified to reduce isomerization.
  • the VL CDR1, VL CDR2, and/or VL CDR3 is modified to reduce isomerization.
  • the LAIR1 binding agent e.g., an antibody
  • the LAIR1 binding agent comprises one or more VH CDRs or VL CDRs that have been modified to reduce oxidation. Oxidation is a chemical process by which an oxygen is added to an atom, for example, methionine is converted to methionine sulfoxide by addition of an oxygen to the sulfur atom.
  • Oxidation of one or more amino acids can potentially affect the physical and chemical properties of a protein. Studies have shown that oxidation of methionine (Met or M) within a CDR has the potential to impact antibody binding and/or stability.
  • the VH CDR1, VH CDR2, and/or VH CDR3 of an antibody disclosed herein is modified to reduce oxidation.
  • the VL CDR1, VL CDR2, and/or VL CDR3 of an antibody disclosed herein is modified to reduce oxidation.
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH and/or a VL that comprises a modification within the amino acid sequence wherein the modification eliminates a glycosylation site.
  • the LAIR1 binding agent (e.g., an antibody) comprises one or more VH CDRs or VL CDRs that have been modified to eliminate a glycosylation site.
  • the consensus glycosylation site for N-linked glycans is N-X-S/T, wherein X can be any amino acid except proline.
  • a glycosylation site within a variable region and/or within a CDR will impact antibody structure, binding, and/or stability.
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 47A1 (Table 1), a humanized version thereof, or variants thereof.
  • the LAIR1 binding agent (e.g., antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from antibody 47A1 (Table 1).
  • the LAIR1 binding agent comprises a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 47A1 (Table 1).
  • the LAIR1 binding agent e.g., an antibody
  • the LAIR1 binding agent comprises: (a) a VH comprising a VH CDR1, a VH CDR2, a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 47A1 (Table 1).
  • the LAIR1 binding agent provided herein comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:115; and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:116.
  • the LAIR1 binding agent provided herein comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:115; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:116.
  • CDR sequences can be determined according to well-known numbering systems or a combination thereof. In certain embodiments, the CDRs are according to Kabat numbering. In certain embodiments, the CDRs are according to AbM numbering. In certain embodiments, the CDRs are according to Chothia numbering.
  • the CDRs are according to Contact numbering.
  • the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia.
  • Various exemplary CDR numbering systems are described and illustrated above in Section 5.1.
  • the LAIR1 binding agent provided herein comprises (a) a VH comprising a VH CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:9, 15, 18, and 19; a VH CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:10, 16, 17, and 20; and a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:11 and 21; and/or (b) a VL region comprising a VL CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:12 and 22; a VL CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NAI-1539756353v1 60 NOs:13 and 23; and a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:14 and 24.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:11; and/or (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:14.
  • the LAIR1 binding agent (e.g., an antibody) comprises: (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:11; and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:14.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:15, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:16, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:11; and/or (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:14.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:15, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:16, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:11; and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:14.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:17, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:11; and/or (b) a VL NAI-1539756353v1 61 comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:14.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:17, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:11, and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:14.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:18, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, and VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:11, and/or (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:14.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:18, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, and VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:11; and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:14.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:19, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:20, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:21; and/or (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:22, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:24.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:19, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:20, and a VH CDR3 comprising the amino acid NAI-1539756353v1 62 sequence set forth in SEQ ID NO:21; and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:22, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:24.
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:115; and/or a VL having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:116.
  • the binding of the LAIR1 binding agent (e.g., an antibody) thereof to LAIR1 is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).
  • the LAIR1 binding agent e.g., an antibody
  • the LAIR1 binding agent comprises a VH comprising an amino acid sequence of SEQ ID NO:115 and/or a VL comprising an amino acid sequence of SEQ ID NO:116.
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:115 and a VL comprising an amino acid sequence of SEQ ID NO:116.
  • the LAIR1-binding agent is antibody 47A1 (Table 1).
  • the LAIR1-binding agent is a humanized version of antibody 47A1 (Table 1).
  • the LAIR1-binding agent is a variant of antibody 47A1 (Table 1) or a variant of a humanized version of 47A1.
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 47H1 (Table 2A), humanized versions thereof (e.g., Hz47H1.v4, Table 2B), or variants thereof.
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from antibody 47H1 (Table 2A).
  • the LAIR1 binding agent comprises a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 47H1 (Table 2A).
  • the LAIR1 binding agent e.g., an antibody
  • the LAIR1 binding agent comprises: (a) a VH comprising a VH CDR1, a VH CDR2, a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 47H1 (Table 2A).
  • the LAIR1 binding agent provided herein comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:117; and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:118.
  • the LAIR1 binding agent provided herein comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:117; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:118.
  • CDR sequences can be determined according to well-known numbering systems or a combination thereof. In certain embodiments, the CDRs are according to Kabat numbering. In certain embodiments, the CDRs are according to AbM numbering. In certain embodiments, the CDRs are according to Chothia numbering.
  • the CDRs are according to Contact numbering. In certain embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia.
  • the LAIR1 binding agent provided herein comprises (a) a VH comprising a VH CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 25, 31, 34, and 35; a VH CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 32, 33, and 36; and a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 27 and 37; and/or (b) a VL region comprising a VL CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 28 and 38; a VL CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 29 and 39; and a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 30 and 40.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:26, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:26, a VH NAI-1539756353v1 64 CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:31, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:32, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:31, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:32, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:33, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:33, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:34, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:26, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and/or (b) a VL CDR1 comprising the NAI-1539756353v1 65 amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:34, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:26, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:36 or set forth in SEQ ID NO:45, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:37; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:38, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:39, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:40.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:36, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:37; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:38, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:39, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:40.
  • the LAIR1 binding agent (e.g., an antibody) comprises: (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:26, or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27, or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:117; and/or a VL having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:118.
  • the binding of the LAIR1 binding agent (e.g., an antibody) thereof to LAIR1 is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).
  • the LAIR1 binding agent e.g., an antibody
  • the LAIR1 binding agent comprises a VH comprising an amino acid sequence of SEQ ID NO:117, and/or a VL comprising an amino acid sequence of SEQ ID NO:118.
  • the LAIR1 binding agent comprises a VH comprising an amino acid sequence of SEQ ID NO:117, and a VL comprising an amino acid sequence of SEQ ID NO:118.
  • the LAIR1-binding agent comprises: (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:26, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and (b) a VL comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:118.
  • the LAIR1-binding agent (e.g., an antibody) comprises: (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:26, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27, wherein the VH comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:117, and (b) a VL comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:118.
  • the LAIR1-binding agent (e.g., an antibody) comprises: (a) a VH comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:117, and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid NAI-1539756353v1 67 sequence set forth in SEQ ID NO:30.
  • the LAIR1-binding agent (e.g., an antibody) comprises: (a) a VH comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:117, and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30, wherein the VL comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:118.
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody Hz47H1.v4 (Table 2B), or variants thereof.
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from antibody Hz47H1.v4 (Table 2B).
  • the LAIR1 binding agent comprises a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody Hz47H1.v4 (Table 2B).
  • the LAIR1 binding agent e.g., an antibody
  • the LAIR1 binding agent comprises: (a) a VH comprising a VH CDR1, a VH CDR2, a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody Hz47H1.v4 (Table 2B).
  • the LAIR1 binding agent provided herein comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:119; and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:120.
  • the LAIR1 binding agent provided herein comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:119; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:120.
  • CDR sequences can be determined according to well-known numbering systems or a combination thereof.
  • the CDRs are according to Kabat numbering.
  • the CDRs are according to AbM numbering.
  • the CDRs are according to Chothia numbering.
  • the CDRs are according to Contact numbering. In certain embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia.
  • the LAIR1 binding agent provided herein comprises (a) a VH comprising a VH CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 25, 31, 34, and 35; a VH CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 41, 43, 44 and 45; and a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 27 and 37; and/or (b) a VL region comprising a VL CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 28 and 38; a VL CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 42 and 39; and a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 30 and 40.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:41, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:41, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:31, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:43, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:31, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:43, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the NAI-1539756353v1 69 amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:44, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:44, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:34, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:41, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:34, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:41, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:45 or set forth in SEQ ID NO:45, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:37, and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:38, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:39, and a VL CDR3 comprising NAI-1539756353v1 70 the amino acid sequence set forth in SEQ ID NO:40.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:45, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:37; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:38, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:39, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:40.
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:119; and/or a VL having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:120.
  • the binding of the LAIR1 binding agent (e.g., an antibody) thereof to LAIR1 is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).
  • the LAIR1 binding agent e.g., an antibody
  • the LAIR1 binding agent comprises a VH comprising an amino acid sequence of SEQ ID NO:119, and/or a VL comprising an amino acid sequence of SEQ ID NO:120.
  • the LAIR1 binding agent comprises a VH comprising an amino acid sequence of SEQ ID NO:119, and a VL comprising an amino acid sequence of SEQ ID NO:120.
  • the LAIR1 binding agent comprises: (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:41, or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27, or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions, a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, or a variant thereof comprising 1, 2,
  • the LAIR1 binding agent (e.g., an antibody) comprises one or more VH CDRs or VL CDRs that have been modified to reduce deamidation within the CDR sequence.
  • the VH CDR2 of antibody 47H1 or Hz47H1.v4 is modified to reduce deamidation.
  • the LAIR1 binding agent (e.g., an antibody) comprises one or more VH CDRs or VL CDRs that have been modified to reduce isomerization.
  • the VL CDR2 of antibody 47H1 or Hz47H1.v4 is modified to reduce isomerization.
  • the LAIR1-binding agent (e.g., an antibody) comprises: (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:41, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27, and (b) a VL comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:120.
  • the LAIR1-binding agent (e.g., an antibody) comprises: (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:41, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27, wherein the VH comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:119, and (b) a VL comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:120.
  • the LAIR1-binding agent (e.g., an antibody) comprises: (a) a VH comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:119, and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30.
  • the LAIR1-binding agent (e.g., an antibody) comprises: (a) a VH comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:119, and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30, wherein the VL comprises at least 80%, at least 85%, at least 90%, at least NAI-1539756353v1 72 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:120.
  • the LAIR1-binding agent (e.g., an antibody) comprises: (a) a heavy chain comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:41, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27, and (b) a light chain comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30, wherein the heavy chain comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:134, and wherein the light chain
  • the LAIR1- binding agent (e.g., an antibody) comprises: (a) a heavy chain comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:41, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27, and (b) a light chain comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30, wherein the heavy chain comprises at least 95% sequence identity to the amino acid sequence of SEQ ID NO:134, and wherein the light chain comprises at least 95% sequence identity to the amino acid sequence of SEQ ID NO:136.
  • a heavy chain comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ
  • the LAIR1-binding agent (e.g., an antibody) comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:134 and (b) a light chain comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30, wherein the light chain comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to the amino acid sequence of SEQ ID NO:136.
  • the LAIR1-binding agent (e.g., an antibody) comprises: (a) a heavy chain comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:41, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27, NAI-1539756353v1 73 wherein the heavy chain comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to the amino acid sequence of SEQ ID NO:134, and (b) a light chain comprising the amino acid sequence of SEQ ID NO:136.
  • the LAIR1-binding agent is an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:134 and a light chain comprising the amino acid sequence of SEQ ID NO:136.
  • the LAIR1 binding agent e.g., an antibody
  • the LAIR1 binding agent is antibody 47H1.
  • the LAIR1 binding agent e.g., an antibody
  • the LAIR1 binding agent is a humanized version of antibody 47H1 (e.g., Hz47H1.v4).
  • the LAIR1 binding agent is a variant of antibody 47H1 or a variant of a humanized version of 47H1 (e.g., Hz47H1.v4).
  • the LAIR1 binding agent is antibody Hz47H1.v4.
  • the LAIR1 binding agent e.g., an antibody
  • the LAIR1 binding agent comprises a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 57D12 (Table 3), a humanized version thereof, or variants thereof.
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from antibody 57D12 (Table 3).
  • the LAIR1 binding agent comprises a VL comprising a VL CDR1, VL CDR2, and a VL CDR3 from antibody 57D12 (Table 3).
  • the LAIR1 binding agent comprises: (a) a VH comprising a VH CDR1, a VH CDR2, a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 57D12 (Table 3).
  • the LAIR1 binding agent provided herein comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:121; and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:122.
  • the LAIR1 binding agent provided herein comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:121; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:122.
  • CDR sequences can be determined according to well-known numbering systems or a combination thereof. In certain embodiments, the CDRs are according to Kabat numbering. In certain embodiments, the CDRs are according to AbM numbering. In certain embodiments, the CDRs are according to Chothia numbering.
  • the CDRs are according to Contact numbering.
  • the CDR sequences are NAI-1539756353v1 74 determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia.
  • the LAIR1 binding agent (e.g., an antibody) provided herein comprises (a) a VH comprising a VH CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 46, 52, 55 and 56; a VH CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 47, 53, 54 and 57; and a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 48 and 58; and/or (b) a VL region comprising a VL CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 49 and 59; a VL CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 50 and 60; and a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 51 and 61.
  • a VH comprising a VH CDR1 comprising an amino
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:46, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:47, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:48; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:49, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:50, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:51.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:46, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:47, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:48; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:49, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:50, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:51.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:52, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:53, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:48; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:49, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:50, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:51.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:52, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:53, a VH NAI-1539756353v1 75 CDR3 comprising the amino acid sequence set forth in SEQ ID NO:48; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:49, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:50, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:51.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:46, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:54, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:48; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:49, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:50, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:51.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:46, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:54, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:48; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:49, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:50, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:51.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:55, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:47, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:48, and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:49, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:50, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:51.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:55, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:47, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:48; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:49, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:50, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:51.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:56, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:57, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:58; and/or (b) a VL CDR1 comprising the NAI-1539756353v1 76 amino acid sequence set forth in SEQ ID NO:59, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:60, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:61.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:56, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:57, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:58; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:59, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:60, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:61.
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:121, and/or a VL having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:122.
  • the binding of the LAIR1 binding agent (e.g., an antibody) thereof to LAIR1 is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).
  • the LAIR1 binding agent e.g., an antibody
  • the LAIR1 binding agent comprises a VH comprising an amino acid sequence of SEQ ID NO:121, and/or a VL comprising an amino acid sequence of SEQ ID NO:122.
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:121, and a VL comprising an amino acid sequence of SEQ ID NO:122.
  • the LAIR1 binding agent (e.g., an antibody) is antibody 57D12 (Table 3).
  • the LAIR1 binding agent (e.g., an antibody) is a humanized version of antibody 57D12 (Table 3).
  • the LAIR1 binding agent (e.g., an antibody) is a variant of antibody 57D12 (Table 3) or a variant of a humanized version of antibody 57D12 (Table 3).
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 and/or a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 61H4 (Table 4), a humanized version thereof, or variants thereof.
  • the LAIR1 binding agent comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from antibody 61H4 (Table 4).
  • the LAIR1 NAI-1539756353v1 77 binding agent comprises a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 61H4 (Table 4).
  • the LAIR1 binding agent comprises: (a) a VH comprising a VH CDR1, a VH CDR2, a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 61H4 (Table 4).
  • the LAIR1 binding agent provided herein comprises a VH CDR1, a VH CDR2; and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:123 and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:124.
  • the LAIR1 binding agent provided herein comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:123; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:124.
  • CDR sequences can be determined according to well-known numbering systems or a combination thereof. In certain embodiments, the CDRs are according to Kabat numbering. In certain embodiments, the CDRs are according to AbM numbering. In certain embodiments, the CDRs are according to Chothia numbering.
  • the CDRs are according to Contact numbering. In certain embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia.
  • the LAIR1 binding agent provided herein comprises (a) a VH comprising a VH CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 62, 68, 71, and 72; a VH CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 63, 69, 70, and 73; and a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 64 and 74; and/or (b) a VL region comprising a VL CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 65 and 75; a VL CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 66 and 76; and a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 67 and 77.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:62, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:63, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:64; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:65, a VL CDR2 comprising the amino acid NAI-1539756353v1 78 sequence set forth in SEQ ID NO:66, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:67.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:62, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:63, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:64; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:65, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:66, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:67.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:68, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:69, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:64; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:65, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:66, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:67.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:68, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:69, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:64; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:65, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:66, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:67.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:62, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:70, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:64; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:65, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:66, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:67.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:62, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:70, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:64; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:65, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:66, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:67.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:71, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:63, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:64; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:65, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:66, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:67.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:71, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:63, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:64; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:65, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:66, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:67.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:72, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:73, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:74; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:75, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:76, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:77.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:72, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:73, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:74; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:75, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:76, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:77.
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:123, and/or a VL having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:124.
  • the binding of the LAIR1 binding agent (e.g., an antibody) thereof to LAIR1 is NAI-1539756353v1 80 maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).
  • the LAIR1 binding agent e.g., an antibody
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:123 and a VL comprising an amino acid sequence of SEQ ID NO:124.
  • the LAIR1-binding agent is antibody 61H4 (Table 4).
  • the LAIR1-binding agent is a humanized version of antibody 61H4 (Table 4).
  • the LAIR1-binding agent is a variant of antibody 61H4 (Table 4) or a variant of a humanized antibody 61H4 (Table 4).
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 and/or a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 62G10 or Hz62G10.v1 (Table 5), a humanized version thereof, or variants thereof.
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from antibody 62G10 or Hz62G10.v1 (Table 5).
  • the LAIR1 binding agent comprises a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 62G10 or Hz62G10.v1 (Table 5).
  • the LAIR1 binding agent comprises: (a) a VH comprising a VH CDR1, a VH CDR2, a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 62G10 or Hz62G10.v1 (Table 5).
  • the LAIR1 binding agent provided herein comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:125; and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:126.
  • the LAIR1 binding agent provided herein comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:125; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:126.
  • the LAIR1 binding agent provided herein comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:127; and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NAI-1539756353v1 81 NO:128.
  • the LAIR1 binding agent provided herein comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:127; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:128.
  • CDR sequences can be determined according to well-known numbering systems or a combination thereof. In certain embodiments, the CDRs are according to Kabat numbering. In certain embodiments, the CDRs are according to AbM numbering. In certain embodiments, the CDRs are according to Chothia numbering.
  • the CDRs are according to Contact numbering. In certain embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia.
  • the LAIR1 binding agent provided herein comprises (a) a VH comprising a VH CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 25, 31, 34, and 35; a VH CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 78, 82, 83, and 84; and a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 79 and 85; and/or (b) a VL region comprising a VL CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 80 and 86; a VL CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 29 and 39; and a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 81 and 87.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:78, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:78, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:31, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:82, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:31, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:82, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:83, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:83, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:34, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:78, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NAI-1539756353v1 83 NO:34, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:78, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:84, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:85; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:86, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:39, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:87.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:84, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:85; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:86, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:39, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:87.
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:125, and/or a VL having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:126.
  • the binding of the LAIR1 binding agent (e.g., an antibody) thereof to LAIR1 is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).
  • the LAIR1 binding agent e.g., an antibody
  • the LAIR1 binding agent comprises a VH comprising the amino acid sequence of SEQ ID NO:125 and a VL region comprising the amino acid sequence of SEQ ID NO:126.
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:125 and/or a VL region comprising the amino acid sequence of SEQ ID NO:126. NAI-1539756353v1 84 [00228]
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:127, and/or a VL having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the binding of the LAIR1 binding agent (e.g., an antibody) thereof to LAIR1 is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).
  • the LAIR1 binding agent e.g., an antibody
  • the LAIR1 binding agent comprises a VH comprising the amino acid sequence of SEQ ID NO:127, and/or a VL comprising the amino acid sequence of SEQ ID NO:128.
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:127, and a VL comprising the amino acid sequence of SEQ ID NO:128.
  • the LAIR1-binding agent comprises: (a) a heavy chain comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:78, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79, and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81, wherein the heavy chain comprises at least 80%, at least 85%, at
  • the LAIR1-binding agent comprises: (a) a heavy chain comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:78, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79, and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81, wherein the heavy chain comprises at least 95% sequence identity to the amino acid sequence of SEQ ID NAI-1539756353v1 85 NO:138, and wherein the light chain comprises at least 95% sequence identity to the amino acid sequence of SEQ ID NO:140.
  • the LAIR1-binding agent comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:138 and (b) a light chain comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81, wherein the light chain comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to the amino acid sequence of SEQ ID NO:140.
  • the LAIR1-binding agent comprises: (a) a heavy chain comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:78, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79, wherein the heavy chain comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to the amino acid sequence of SEQ ID NO:138, and (b) a light chain comprising the amino acid sequence of SEQ ID NO:140.
  • the LAIR1-binding agent is an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:138 and a light chain comprising the amino acid sequence of SEQ ID NO:140.
  • the LAIR1-binding agent e.g., an antibody
  • the LAIR1-binding agent is antibody 62G10 (Table 5).
  • the LAIR1-binding agent is a humanized version of antibody 62G10 (e.g., Hz62G10.v1) (Table 5).
  • the LAIR1- binding agent e.g., an antibody
  • the LAIR1 binding (e.g., an antibody) agent comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:88, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:89; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:90, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:91, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:92.
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:129 and a VL comprising an amino acid sequence of SEQ ID NO:130.
  • the LAIR1 binding agent (e.g., an antibody) is antibody 108D10 (Table 6).
  • the LAIR1 binding agent (e.g., an antibody) is a humanized version of antibody 108D10 (Table 6).
  • the LAIR1 binding agent (e.g., an antibody) is a variant of antibody 108D10 (Table 6) or a variant of humanized antibody 108D10 (Table 6).
  • the LAIR1 binding agent comprises a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 43H2 (Table 7).
  • the LAIR1 binding agent comprises: (a) a VH comprising a VH CDR1, a VH CDR2, a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 43H2 (Table 7).
  • the LAIR1 binding agent provided herein comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:131; and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:132.
  • the LAIR1 binding agent provided herein comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:131; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:132.
  • CDR sequences can be determined according to well-known numbering systems or a combination thereof. In certain embodiments, the CDRs are according to Kabat numbering. In certain embodiments, the CDRs are according to AbM numbering. In certain embodiments, the CDRs are according to Chothia numbering.
  • the CDRs are according to Contact numbering. In certain embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia.
  • the LAIR1 binding agent provided herein comprises (a) a VH comprising a VH CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 99, 105, 108, and 109; a VH CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 100, 106, 107, and 110; and a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 101 and 111; and/or (b) a VL region comprising a VL CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 102 and 112; a VL CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 103 and 113; and a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:99, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:100, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:101; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:102, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:103, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:104.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:99, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:100, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:101; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:102, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:103, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:104.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:105, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:106, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:101; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:102, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:103, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:104.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:105, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:106, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:101; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:102, a VL CDR2 comprising the NAI-1539756353v1 91 amino acid sequence set forth in SEQ ID NO:103, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:104.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:99, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:107, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:101; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:102, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:103, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:104.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:99, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:107, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:101; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:102, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:103, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:104.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:108, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:100, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:101; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:102, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:103, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:104.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:109, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:110, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:111; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:112, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:113, and a VL CDR3 comprising the amino acid sequence NAI-1539756353v1 92 set forth in SEQ ID NO:114.
  • the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:109, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:110, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:111; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:112, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:113, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:114.
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:131; and/or a VL having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:132.
  • the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:131 and a VL comprising an amino acid sequence of SEQ ID NO:132.
  • the LAIR1 binding agent (e.g., an antibody) is antibody 43H2 (Table 7).
  • the LAIR1 binding agent (e.g., an antibody) is a humanized version of antibody 43H2 (Table 7).
  • the LAIR1 binding agent e.g., an antibody
  • LAIR1 binding agents that compete with one or more of the LAIR1 binding agents disclosed herein for binding to LAIR1.
  • the LAIR1 binding agent competes with one or more of the LAIR1 binding agents disclosed herein for binding to human LAIR1.
  • the LAIR1 binding agent that competes with one or more of the LAIR1 binding agents disclosed herein is an antibody.
  • the LAIR1 binding agent provided herein specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti- NAI-1539756353v1 93 LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:115 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:116.
  • LAIR1 e.g., human LAIR1
  • LAIR1 antibody specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti- NAI-1539756353v1 93 LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:115 and a VL CDR1, a V
  • the LAIR1 binding agent provided herein specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti-LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:115, and a VL comprising the amino acid sequence of SEQ ID NO:116.
  • the LAIR1 binding agent provided herein specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:117 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:118.
  • LAIR1 e.g., human LAIR1
  • an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:117 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:118.
  • the LAIR1 binding agent provided herein specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti-LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:117, and a VL comprising the amino acid sequence of SEQ ID NO:118.
  • the LAIR1 binding agent provided herein specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:119 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:120.
  • LAIR1 e.g., human LAIR1
  • an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:119 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:120.
  • the LAIR1 binding agent provided herein specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti-LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:119, and a VL comprising the amino acid sequence of SEQ ID NO:120.
  • the LAIR1 binding agent provided herein specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:121 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:122.
  • LAIR1 e.g., human LAIR1
  • an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:121 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:122.
  • the LAIR1 binding agent provided herein specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti-LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:121, and a VL comprising the amino acid sequence of SEQ ID NO:122.
  • the LAIR1 binding agent provided herein specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:123 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:124.
  • LAIR1 e.g., human LAIR1
  • an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:123 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:124.
  • the LAIR1 binding agent provided herein specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti-LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:123, and a VL comprising the amino acid sequence of SEQ ID NO:124.
  • the LAIR1 binding agent provided herein specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:125 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:126.
  • LAIR1 e.g., human LAIR1
  • an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:125 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:126.
  • the LAIR1 binding agent provided herein specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti-LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:125, and a VL comprising the amino acid sequence of SEQ ID NO:126.
  • the LAIR1 binding agent provided herein specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:127 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:128.
  • LAIR1 e.g., human LAIR1
  • an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:127 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:128.
  • the LAIR1 binding agent provided herein specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti-LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:127, and a VL comprising the amino acid sequence of SEQ ID NO:128.
  • the LAIR1 binding agent provided herein specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:129 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:130.
  • LAIR1 e.g., human LAIR1
  • an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:129 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:130.
  • the LAIR1 binding agent provided herein specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti-LAIR1 antibody NAI-1539756353v1 95 comprising a VH comprising the amino acid sequence of SEQ ID NO:129, and a VL comprising the amino acid sequence of SEQ ID NO:130.
  • the LAIR1 binding agent provided herein specifically binds to LAIR1 (e.g., mouse LAIR1) competitively with an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:131 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:132.
  • LAIR1 e.g., mouse LAIR1
  • an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:131 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:132.
  • the LAIR1 binding agent provided herein specifically binds to LAIR1 (e.g., mouse LAIR1) competitively with an anti-LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:131, and a VL comprising the amino acid sequence of SEQ ID NO:132.
  • LAIR1 e.g., mouse LAIR1
  • functional epitopes can be mapped, e.g., by combinatorial alanine scanning, to identify amino acids in the LAIR1 protein that are necessary for interaction with LAIR1 binding agents (such as antibodies) provided herein.
  • LAIR1 binding agents such as antibodies
  • LAIR1 binding agents such as antibodies
  • the present disclosure provides an antibody that specifically binds to the same epitope as any of the LAIR1 binding agents (such as antibodies or fragments thereof) provided herein.
  • the LAIR1 binding agent provided herein binds to the same epitope as an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:115 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:116.
  • the LAIR1 binding agent provided herein binds to the same epitope as an anti- LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:115, and a VL comprising the amino acid sequence of SEQ ID NO:116.
  • the LAIR1 binding agent provided herein binds to the same epitope as an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:117 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:118.
  • the LAIR1 binding agent provided herein binds to the same epitope as an anti- NAI-1539756353v1 96 LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:117, and a VL comprising the amino acid sequence of SEQ ID NO:118.
  • the LAIR1 binding agent provided herein binds to the same epitope as an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:119 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:120.
  • the LAIR1 binding agent provided herein binds to the same epitope as an anti- LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:119, and a VL comprising the amino acid sequence of SEQ ID NO:120.
  • the LAIR1 binding agent provided herein binds to the same epitope as an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:121 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:122.
  • the LAIR1 binding agent provided herein binds to the same epitope as an anti- LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:121, and a VL comprising the amino acid sequence of SEQ ID NO:122.
  • the LAIR1 binding agent provided herein binds to the same epitope as an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:123 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:124.
  • the LAIR1 binding agent provided herein binds to the same epitope as an anti- LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:123, and a VL comprising the amino acid sequence of SEQ ID NO:124.
  • the LAIR1 binding agent provided herein binds to the same epitope as an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:125 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:126.
  • the LAIR1 binding agent provided herein binds to the same epitope as an anti- LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:125, and a VL comprising the amino acid sequence of SEQ ID NO:126.
  • the LAIR1 binding agent provided herein binds to the same epitope as an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:127 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:128.
  • the LAIR1 binding agent provided herein binds to the same epitope as an anti- LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:127, and a VL comprising the amino acid sequence of SEQ ID NO:128.
  • the LAIR1 binding agent provided herein binds to the same epitope as an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:129 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:130.
  • the LAIR1 binding agent provided herein binds to the same epitope as an anti- LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:129, and a VL comprising the amino acid sequence of SEQ ID NO:130.
  • the LAIR1 binding agent provided herein binds to the same epitope as an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:131 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:132.
  • the LAIR1 binding agent provided herein binds to the same epitope as an anti- LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:131, and a VL comprising the amino acid sequence of SEQ ID NO:132.
  • the LAIR1 binding agent disclosed herein comprises an antibody in which at least one or more of the constant regions of the antibody has been modified or deleted.
  • an antibody comprises one or more modifications to one or more of the heavy chain constant regions (CH1, CH2, CH3, or CH4) and/or to the light chain constant region (CL).
  • an antibody comprises one or more modifications to the hinge region.
  • the heavy chain constant region of the modified antibody comprises at least one human constant region. In certain embodiments, the heavy chain constant region of the modified antibody comprises more than one human constant region. In certain embodiments, modifications to the constant region comprise additions, deletions, or substitutions of one or more amino acids in one or NAI-1539756353v1 98 more regions. In certain embodiments, one or more regions are partially or entirely deleted from the constant regions of a modified antibody. In certain embodiments, the entire CH2 domain has been removed from an antibody ( ⁇ CH2 constructs). In certain embodiments, one or more regions are partially or entirely deleted from the hinge region of a modified antibody.
  • a deleted constant region is replaced by a short amino acid spacer that provides some of the molecular flexibility typically imparted by the absent constant region.
  • a deleted hinge region is replaced by a short amino acid spacer that provides some of the molecular flexibility typically imparted by the absent hinge region.
  • a modified antibody comprises a CH3 domain directly fused to the hinge region of the antibody.
  • a modified antibody comprises a peptide spacer inserted between the hinge region and modified CH2 and/or CH3 domains.
  • binding of the C1q component of complement to the Fc region of IgG or IgM antibodies when the antibodies are bound to antigen activates the complement system.
  • Activation of complement is important in the opsonization and lysis of cell pathogens.
  • the activation of complement also stimulates the inflammatory immune response and can be involved in autoimmune hypersensitivity.
  • the Fc region of an antibody can bind a cell expressing a Fc receptor (FcR).
  • FcR Fc receptor
  • the LAIR1 binding agent e.g., an antibody
  • the LAIR1 binding agent comprises a variant constant region or Fc region.
  • amino acid sequences of the constant region or Fc region of human IgG1, IgG2, IgG3, and IgG4 are known to those of ordinary skill in the art (e.g., a representative human IgG1 constant region is SEQ ID NO:141).
  • constant regions or Fc regions with amino acid variations have been identified in native antibodies.
  • a variant constant region or Fc region is engineered with substitutions at specific amino acid positions as compared to a native constant region or Fc region.
  • variant constant region or Fc regions are well-known in the art and include, but are NAI-1539756353v1 99 not limited to, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:158, and SEQ ID NO:159.
  • a modified antibody provides for altered effector functions that, in turn, affect the biological profile of the antibody. For example, in certain embodiments, the deletion or inactivation (through point mutations or other means) of a constant region reduces binding of a modified antibody to a Fc receptor. In certain embodiments, constant region modifications increase the serum half-life of an antibody.
  • constant region modifications reduce the serum half-life of an antibody. In certain embodiments, constant region modifications decrease or remove ADCC and/or complement-dependent cytotoxicity (CDC) of an antibody. In certain embodiments, a human IgG1 Fc region with specific amino acid substitutions corresponding to IgG2 or IgG4 residues reduce effector functions (e.g., ADCC and CDC) in a modified antibody. In certain embodiments, a modified antibody does not have one or more effector functions. In certain embodiments, a modified antibody has no ADCC activity and/or no CDC activity. In certain embodiments, a modified antibody does not bind an Fc receptor and/or complement factors.
  • a modified antibody does not have any detectable effector functions (e.g., an “effectorless” antibody).
  • constant region modifications increase or enhance ADCC and/or CDC of an antibody.
  • the constant region is modified to eliminate disulfide linkages or oligosaccharide moieties.
  • the constant region is modified to add/substitute one or more amino acids to provide one or more cytotoxin, oligosaccharide, or carbohydrate attachment sites.
  • antibody variants are prepared by introducing appropriate nucleotide changes into the encoding DNA, and/or by synthesis of the desired antibody or polypeptide. Using these engineering techniques to modify an antibody it may be possible to disrupt the activity or effector function provided by a specific sequence or region while substantially maintaining the structure, binding activity, and other desired characteristics of the modified antibody.
  • the present disclosure further embraces additional variants and equivalents that are substantially homologous to the recombinant, monoclonal, chimeric, humanized, and human antibodies, or antibody fragments thereof, disclosed herein. In certain embodiments, it is desirable to improve the binding affinity of the antibody.
  • it is desirable to modulate biological properties of the antibody including but not limited to, specificity, thermostability, expression level, effector function(s), glycosylation, NAI-1539756353v1 100 immunogenicity, and/or solubility.
  • amino acid changes may alter post-translational processes of an antibody, such as changing the number or position of glycosylation sites or altering membrane anchoring characteristics.
  • Variations may be a substitution, deletion, or insertion of one or more nucleotides encoding the antibody or polypeptide that results in a change in the amino acid sequence as compared with the native antibody or polypeptide sequence.
  • amino acid substitutions are the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, such as the replacement of a leucine with a serine (i.e., conservative amino acid replacements).
  • the substitution, deletion, or insertion includes less than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid substitutions, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less than 4 amino acid substitutions, less than 3 amino acid substitutions, or less than 2 amino acid substitutions relative to the parent molecule.
  • variants may include addition of amino acid residues at the amino- and/or carboxyl-terminal end of the antibody or polypeptide.
  • the length of additional amino acids residues may range from one residue to a hundred or more residues.
  • a variant comprises an N-terminal methionyl residue.
  • the variant comprises an additional polypeptide/protein to create a fusion protein.
  • a variant is engineered to be detectable and may comprise a detectable label and/or protein (e.g., a fluorescent tag, a fluorescent protein, or an enzyme).
  • a cysteine residue not involved in maintaining the proper conformation of an antibody is substituted or deleted to modulate the antibody’s characteristics, for example, to improve oxidative stability and/or prevent aberrant disulfide crosslinking.
  • one or more cysteine residues are added to create disulfide bond(s) to improve stability.
  • an antibody of the present disclosure is “deimmunized”.
  • the deimmunization of antibodies generally consists of introducing specific amino acid mutations (e.g., substitutions, deletions, additions) that result in removal of T-cell epitopes (known or predicted) without significantly reducing the binding affinity or other desired activities of the antibody.
  • NAI-1539756353v1 101 The variant antibodies or polypeptides disclosed herein may be generated using methods known in the art, including but not limited to, site-directed mutagenesis, alanine scanning mutagenesis, and PCR mutagenesis.
  • the LAIR1 binding agent disclosed herein is chemically modified.
  • the LAIR1 binding agent is the anti-LAIR1 antibody that is chemically modified by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, and/or linkage to a cellular ligand or other protein. Any of numerous chemical modifications may be carried out by known techniques.
  • the LAIR1 binding agent is attached (either directly or indirectly) to a half-life extending moiety including, but not limited to, polyethylene glycol (PEG), a PEG mimetic, XTEN®, serum albumin, polysialic acid, N-(2- hydroxypropyl)methacrylamide, or dextran.
  • the LAIR1 binding agent is an antibody, wherein the antibody is attached (either directly or indirectly) to a half- life extending moiety including, but not limited to, polyethylene glycol (PEG), a PEG mimetic, XTEN®, serum albumin, polysialic acid, N-(2-hydroxypropyl)methacrylamide, or dextran.
  • PEG polyethylene glycol
  • XTEN® XTEN®
  • serum albumin serum albumin
  • polysialic acid polysialic acid
  • N-(2-hydroxypropyl)methacrylamide or dextran.
  • the LAIR1 binding agent is an antibody fragment (e.g., scFv, Fv, Fab, F(ab′)2, or F(ab′)), wherein the antibody fragment is attached (either directly or indirectly) to a half-life extending moiety including, but not limited to, polyethylene glycol (PEG), a PEG mimetic, XTEN®, serum albumin, polysialic acid, N-(2- hydroxypropyl)methacrylamide, or dextran.
  • PEG polyethylene glycol
  • PEG mimetic e.g., a PEG mimetic
  • XTEN® e.g., XTEN®
  • serum albumin e.g., polysialic acid
  • N-(2- hydroxypropyl)methacrylamide e.g., N-(2- hydroxypropyl)methacrylamide
  • a non- immunoglobulin-based binding agent is an agent that competes with the LAIR1 binding agent disclosed herein in a competitive binding assay.
  • alternative LAIR1 binding agents comprise a scaffold protein.
  • scaffold proteins can be assigned to one of three groups based on the architecture of their backbone (1) scaffolds consisting of ⁇ - helices; (2) small scaffolds with few secondary structures or an irregular architecture of ⁇ - helices and ⁇ -sheets; and (3) scaffolds consisting of predominantly ⁇ -sheets.
  • Scaffold proteins include, but are not limited to, (i) anticalins, which are based upon the lipocalin scaffold; (ii) adnectins, which are based on the 10th domain of human fibronectin type 3; (iii) affibodies, which are based on the B-domain in the Ig-binding region of Staphylococcus aureus protein A; (iv) darpins, which are based on ankyrin repeat domain proteins; (v) fynomers, which are based on the SH3 domain of the human Fyn protein kinase; (vi) affitins, NAI-1539756353v1 102 which are based on Sac7d from Sulfolobus acidocaldarius; (vii) affilins, which are based on human ⁇ -B-crystallin or human ubiquitin; (viii) avimers, which are based on the A-domains of membrane receptor proteins; (ix) knot
  • the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 shown in Table 1.
  • the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:11, a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:14.
  • the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3 and/or a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 47A1.
  • the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 shown in Tables 2A or 2B.
  • the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:26 or set forth in SEQ ID NO:41, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27, a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29 or set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30.
  • the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 47H1 or Hz47H1.v4.
  • the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 shown in Table 3.
  • the LAIR1 binding agent NAI-1539756353v1 103 comprises an engineered scaffold protein comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:46, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:47, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:48, a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:49, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:50, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:51.
  • the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 57D12. [00289] In certain embodiments, the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 shown in Table 4.
  • the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:62, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:63, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:64, a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:65, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:66, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:67.
  • the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 61H4.
  • the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 shown in Table 5.
  • the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:78, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79, a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81.
  • the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 62G10 or Hz62G10.v1.
  • NAI-1539756353v1 104 [00291]
  • the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 shown in Table 6.
  • the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:88, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:89, a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:90, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:91, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:92.
  • the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 108D10.
  • the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 shown in Table 7.
  • the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:99, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:100, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:101, a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:102, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:103, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:104.
  • the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 43H2.
  • the present disclosure further provides a composition comprising a LAIR1 binding agent (e.g., an antibody) disclosed herein.
  • the composition comprises an anti-LAIR1 antibody disclosed herein.
  • the composition comprises a monoclonal anti-LAIR1 antibody disclosed herein.
  • the composition comprises an antibody selected from the group consisting of: antibody 47A1, antibody 47H1, antibody 57D12, antibody 61H4, antibody 62G10, antibody 108D10, and humanized versions thereof.
  • the composition comprises an antibody selected from the group consisting of: antibody 47A1, antibody 47H1, antibody Hz47H1.v4, antibody 57D12, antibody 61H4, antibody 62G10, antibody Hz62G10.v1, antibody 108D10, and any combinations thereof.
  • NAI-1539756353v1 105 The present disclosure further provides a pharmaceutical composition comprising a LAIR1 binding agent (e.g., an antibody) disclosed herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises an anti-LAIR1 antibody disclosed herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a monoclonal anti-LAIR1 antibody disclosed herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises an antibody selected from the group consisting of: antibody 47A1, antibody 47H1, antibody 57D12, antibody 61H4, antibody 62G10, antibody 108D10, and humanized versions thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises an antibody selected from the group consisting of: antibody 47A1, antibody 47H1, antibody Hz47H1.v4, antibody 57D12, antibody 61H4, antibody 62G10, antibody Hz62G10.v1, antibody 108D10, and any combinations thereof; and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises antibody Hz47H1.v4 and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises antibody Hz62G10.v1 and a pharmaceutically acceptable carrier.
  • the LAIR1 binding agent e.g., an antibody
  • the LAIR1 binding agent is isolated.
  • the LAIR1 binding agent e.g., an antibody
  • the LAIR1 binding agents disclosed herein can be produced by any suitable method known in the art. Such methods range from direct protein synthesis methods to constructing a DNA sequence encoding polypeptide sequences and expressing those sequences in a suitable host.
  • a DNA sequence is constructed using recombinant technology by isolating or synthesizing a DNA sequence encoding a wild-type protein of interest.
  • the sequence can be mutagenized by site-specific mutagenesis to provide functional variants thereof.
  • a DNA sequence encoding a polypeptide of interest is constructed by chemical synthesis using an oligonucleotide synthesizer.
  • Oligonucleotides can be designed based on the amino acid sequence of the desired polypeptide and selecting those codons that are favored in the host cell in which the recombinant polypeptide of interest will be produced. Standard methods can be applied to synthesize a polynucleotide sequence encoding an isolated polypeptide of interest. For example, a complete amino acid sequence can be used to construct a back-translated gene. Further, a DNA oligomer containing a nucleotide sequence coding for the particular isolated polypeptide can be synthesized. For example, several oligonucleotides coding for portions of NAI-1539756353v1 106 the desired polypeptide can be synthesized and then ligated.
  • the individual oligonucleotides typically contain 5′ or 3′ overhangs for complementary assembly.
  • the polynucleotide sequences encoding a particular polypeptide of interest can be inserted into an expression vector and operatively linked to an expression control sequence appropriate for expression of the protein in a desired host. Proper assembly can be confirmed by nucleotide sequencing, restriction enzyme mapping, and/or expression of a biologically active polypeptide in a suitable host.
  • recombinant expression vectors are used to amplify and express DNA encoding the LAIR1 binding agents disclosed herein.
  • recombinant expression vectors can be replicable DNA constructs which have synthetic or cDNA-derived DNA fragments encoding a polypeptide chain of a LAIR1 binding agent, such as an anti-LAIR1 antibody, or antigen-binding fragment thereof, operatively linked to suitable transcriptional and/or translational regulatory elements derived from mammalian, microbial, viral or insect genes.
  • a transcriptional unit generally comprises an assembly of: (i) a genetic element or elements having a regulatory role in gene expression, for example, transcriptional promoters or enhancers, (ii) a structural or coding sequence that is transcribed into mRNA and translated into protein, and (iii) appropriate transcription and translation initiation and termination sequences.
  • DNA regions are “operatively linked” when they are functionally related to each other.
  • DNA for a signal peptide secretory leader
  • a promoter is operatively linked to a coding sequence if it controls the transcription of the sequence
  • a ribosome binding site is operatively linked to a coding sequence if it is positioned so as to permit translation.
  • structural elements intended for use in yeast expression systems include a leader sequence enabling extracellular secretion of translated protein by a host cell.
  • a polypeptide in situations where recombinant protein is expressed without a leader or transport sequence, may include an N-terminal methionine residue. This residue can optionally be subsequently cleaved from the expressed recombinant protein to provide a final product.
  • the choice of an expression control sequence and an expression vector generally depends upon the choice of host. A wide variety of expression host/vector combinations can NAI-1539756353v1 107 be employed.
  • Useful expression vectors for eukaryotic hosts include, for example, vectors comprising expression control sequences from SV40, bovine papilloma virus, adenovirus, and cytomegalovirus.
  • Useful expression vectors for bacterial hosts include known bacterial plasmids, such as plasmids from E. coli, including pCR1, pBR322, pMB9 and their derivatives, and wider host range plasmids, such as M13 and other filamentous single- stranded DNA phages.
  • Suitable host cells for expression of the LAIR1 binding agent or a LAIR1 protein or fragment thereof to use as an antigen or immunogen include prokaryotes, yeast cells, insect cells, or higher eukaryotic cells under the control of appropriate promoters.
  • Prokaryotes include gram-negative or gram-positive organisms, for example E. coli or Bacillus.
  • Higher eukaryotic cells include established cell lines of mammalian origin as disclosed herein. Cell- free translation systems may also be employed.
  • Appropriate cloning vectors and expression vectors for use with bacterial, fungal, yeast, and mammalian cellular hosts, as well as methods of protein production, including antibody production are well known in the art.
  • Suitable mammalian host cell lines include, but are not limited to, COS-7 (monkey kidney-derived), L-929 (murine fibroblast-derived), C127 (murine mammary tumor-derived), 3T3 (murine fibroblast-derived), CHO (Chinese hamster ovary-derived), HeLa (human cervical cancer-derived), BHK (hamster kidney fibroblast- derived), HEK-293 (human embryonic kidney-derived) cell lines and variants thereof.
  • Mammalian expression vectors can comprise non-transcribed elements such as an origin of replication, a suitable promoter and enhancer linked to the gene to be expressed, and other 5’or 3’ flanking non-transcribed sequences, and 5’ or 3’non-translated sequences, such as necessary ribosome binding sites, a polyadenylation site, splice donor and acceptor sites, and transcriptional termination sequences.
  • non-transcribed elements such as an origin of replication, a suitable promoter and enhancer linked to the gene to be expressed, and other 5’or 3’ flanking non-transcribed sequences, and 5’ or 3’non-translated sequences, such as necessary ribosome binding sites, a polyadenylation site, splice donor and acceptor sites, and transcriptional termination sequences.
  • Expression of recombinant proteins in insect cell culture systems e.g., baculovirus
  • Baculovirus systems for production of heterologous proteins in insect cells are well-known to those of skill in the art.
  • Proteins produced by a host cell can be purified according to any suitable method.
  • Standard methods include chromatography (e.g., ion exchange, affinity, and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique NAI-1539756353v1 108 for protein purification.
  • Affinity tags such as hexahistidine (His6; SEQ ID NO:153), maltose binding domain, influenza coat sequence, and glutathione-S-transferase can be attached to the protein to allow easy purification by passage over an appropriate affinity column.
  • Affinity chromatography methods used for purifying immunoglobulins can include, but are not limited to, Protein A, Protein G, and Protein L chromatography.
  • Isolated proteins can be physically characterized using techniques that include, but are not limited to, proteolysis, size exclusion chromatography (SEC), mass spectrometry (MS), nuclear magnetic resonance (NMR), isoelectric focusing (IEF), high performance liquid chromatography (HPLC), and x- ray crystallography.
  • SEC size exclusion chromatography
  • MS mass spectrometry
  • NMR nuclear magnetic resonance
  • IEF isoelectric focusing
  • HPLC high performance liquid chromatography
  • x- ray crystallography x- ray crystallography
  • the purity of isolated proteins can be determined using techniques known to those of skill in the art, including but not limited to, SDS-PAGE, SEC, capillary gel electrophoresis, IEF, and capillary isoelectric focusing (cIEF).
  • supernatants from expression systems that secrete recombinant protein into culture media are first concentrated using a commercially available protein concentration filter, for example, an Amicon® or Millipore Pellicon® ultrafiltration unit. Following the concentration step, the concentrate can be applied to a suitable purification matrix.
  • a suitable purification matrix for example, an anion exchange resin is employed, for example, a matrix or substrate having pendant diethylaminoethyl (DEAE) groups.
  • the matrices can be acrylamide, agarose, dextran, cellulose, or other types commonly employed in protein purification.
  • a cation exchange step is employed.
  • Suitable cation exchangers include various insoluble matrices comprising sulfopropyl or carboxymethyl groups.
  • a hydroxyapatite media is employed, including but not limited to, ceramic hydroxyapatite (CHT).
  • CHT ceramic hydroxyapatite
  • one or more reverse-phase HPLC steps employing hydrophobic RP-HPLC media, e.g., silica gel having pendant methyl or other aliphatic groups, are employed to further purify a recombinant protein.
  • hydrophobic interaction chromatography HIC is used to separate recombinant proteins based on their hydrophobicity.
  • LAIR1 binding agents of the present disclosure may be analyzed for their physical/chemical properties and/or biological activities by various assays known in the art. In certain embodiments, the LAIR1 binding agent is tested for its ability to bind LAIR1. Binding assays include, but are not limited to, SPR (e.g., Biacore), ELISA, and FACS.
  • the LAIR1 binding agent is tested for its ability to inhibit, reduce, or block binding to collagen, MARCO, and/or COLEC12.
  • binding agents may be evaluated for solubility, stability, thermostability, viscosity, expression levels, expression quality, and/or purification efficiency.
  • monoclonal antibodies generated against LAIR1 are grouped based upon the epitope each individual antibody recognizes, a process known as “epitope binning”. Generally, antibodies are tested in a pairwise combinatorial manner and antibodies that compete with each other are grouped together into bins.
  • a first antibody is immobilized on a surface and a premixed solution of a second antibody and antigen is flowed over the immobilized first antibody.
  • the antigen is immobilized on a surface and the two antibodies are flowed over the immobilized antigen and compete to bind.
  • antibodies that block one another can be identified.
  • a competitive blocking profile is created for each antibody relative to the other antibodies. The blocking results determine which bin each antibody is placed in.
  • High- throughput methods of epitope binning are known in the art and allow for screening and characterization of large numbers of antibodies within a short period of time. Antibodies that bind similar epitopes often share similar functions and/or capabilities.
  • an epitope bin comprises at least one antibody from the group consisting of: 47A1, 47H1, 57D12, 61H4, 62G10, and 108D10. In certain embodiments, an epitope bin comprises at least antibodies 47A1, 57D12, and 61H4. In certain embodiments, an epitope bin comprises antibodies 47A1, 57D12, and 61H4. In certain embodiments, an epitope bin comprises at least antibodies 47H1, 62G10, and 108D10. In certain embodiments, an epitope bin comprises antibodies 47H1, 62G10, and 108D10.
  • Epitope mapping is the process of identifying the binding site, or epitope on a target protein/antigen where an antibody (or other binding agent) binds.
  • a variety of methods are known in the art for mapping epitopes on target proteins. These methods include (i) mutagenesis, including but not limited to, shotgun mutagenesis, site-directed mutagenesis, and alanine scanning; (ii) domain or fragment scanning; (iii) peptide scanning (e.g., Pepscan technology); (iv) display methods, including but not limited to, phage display, microbial display, and ribosome/mRNA display; (v) methods involving proteolysis and mass spectroscopy; (vi) methods involving amide hydrogen/deuterium exchange; and (vii) structural determination, including but not limited to, x-ray crystallography and NMR.
  • purified anti-LAIR1 antibodies are characterized by assays including, but not limited to, N-terminal sequencing, amino acid analysis, HPLC, mass spectrometry, differential scanning fluorimetry (DSF), nanoDSF, capillary isoelectric focusing (cIEF), ion exchange chromatography, and papain digestion.
  • assays are provided for identifying LAIR1 binding agents that affect LAIR1 activity.
  • assays are provided for identifying the anti-LAIR1 antibody that affects LAIR1 activity.
  • These assays may include, but are not limited to, cell activation assays (e.g., cell proliferation assays), cytotoxic T-cell (CTL) assays, NK cell assays, mixed lymphocyte reaction (MLR) assays, cytokine/chemokine production assays, FcR binding assays, and cell migration assays.
  • cell activation assays e.g., cell proliferation assays
  • CTL cytotoxic T-cell
  • NK cell assays e.g., NK cell assays
  • MLR mixed lymphocyte reaction
  • cytokine/chemokine production assays cytokine/chemokine production assays
  • FcR binding assays e.g., FcR binding assays
  • cell migration assays e.g., cell migration assays.
  • Affect or affecting LAIR1 activity may include, for example, inhibiting, reducing, blocking, antagonizing, suppressing, and/or inter
  • LAIR1 generally acts as a negative regulator/inhibitory molecule, in certain embodiments, inhibiting, reducing, blocking, antagonizing, suppressing, and/or interfering with LAIR1 activity results in a release of LAIR1-induced suppression of a biological function (e.g., an activation signal).
  • LAIR1 is expressed on T-cells, B-cells, NK cells, and myeloid cells.
  • Myeloid cells include, but may not be limited to, monocytes, macrophages, dendritic cells, and APCs.
  • LAIR1 activity or LAIR1 signaling activity includes, but is not limited to, suppression of myeloid cells, suppression of myeloid cell activity, suppression of tumor-associated myeloid cells, suppression of NK cells, suppression of NK cell activity, suppression of T-cells, and suppression of T-cell activity.
  • inhibiting, reducing, blocking, antagonizing, suppressing, and/or interfering with LAIR1 activity results in a release of LAIR1-induced suppression of an activation signal.
  • the anti-LAIR1 antibody inhibits LAIR1 signaling.
  • the anti-LAIR1 antibody inhibits LAIR1 signaling thereby reversing an LAIR1-induced suppressive effect.
  • the anti-LAIR1 antibody inhibits an LAIR1-induced extinction signal.
  • the anti-LAIR1 antibody disrupts the LAIR1 signaling pathway.
  • the anti-LAIR1 antibody disrupts the LAIR1 signaling pathway and activates myeloid cells.
  • the anti-LAIR1 antibody disrupts the LAIR1 signaling pathway and activates APCs.
  • the anti- LAIR1 antibody disrupts the LAIR1 signaling pathway and activates dendritic cells.
  • the anti-LAIR1 antibody disrupts the LAIR1 signaling pathway and activates NK cells.
  • the anti-LAIR1 antibody disrupts the LAIR1 signaling pathway and activates T-cells.
  • the anti-LAIR1 antibody NAI-1539756353v1 111 disrupts the LAIR1 signaling pathway and activates CTLs.
  • the anti- LAIR1 antibody disrupts the LAIR1 signaling pathway and activates tumor-associated T- cells.
  • the terms “inhibiting”, “reducing”, “blocking”, “antagonizing”, “suppressing”, and “interfering” are relative to levels and/or activity in the absence of treatment with the LAIR1 binding agent.
  • the terms “inhibiting”, “reducing”, “blocking”, “antagonizing”, “suppressing”, and “interfering” are relative to levels and/or activity prior to treatment with the LAIR1 binding agent.
  • the LAIR1 binding agent inhibits human LAIR1 activity.
  • the anti-LAIR1 antibody inhibits human LAIR1 activity.
  • the anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody 47A1.
  • the anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody 47H1.
  • the anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody Hz47H1.v4.
  • the anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody 57D12. In certain embodiments, the anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody 61H4. In certain embodiments, the anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody 62G10. In certain embodiments, the anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody Hz62H10.v1. In certain embodiments, the anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody 108D10. [00314] In certain embodiments, the LAIR1 binding agent inhibits mouse LAIR1 activity. In certain embodiments, the anti-LAIR1 antibody inhibits mouse LAIR1 activity.
  • the anti-LAIR1 antibody that inhibits mouse LAIR1 activity is antibody 43H2.
  • the present disclosure also provides conjugates comprising the LAIR1 binding agent disclosed herein.
  • a conjugate comprises the anti-LAIR1 antibody disclosed herein.
  • the antibody is attached to a second molecule.
  • the antibody is conjugated to a cytotoxic agent or moiety.
  • the antibody is conjugated to a cytotoxic agent to form an antibody- drug conjugate (ADC).
  • ADC antibody- drug conjugate
  • the cytotoxic agent is a chemotherapeutic agent including, but not limited to, methotrexate, adriamycin/doxorubicin, melphalan, mitomycin C, chlorambucil, duocarmycin, daunorubicin, pyrrolobenzodiazepines (PBDs), or other intercalating agents.
  • the cytotoxic agent is a microtubule inhibitor including, but not limited to, auristatins, maytansinoids (e.g., DM1 and DM4), and tubulysins.
  • the cytotoxic agent is an enzymatically active toxin of NAI-1539756353v1 112 bacterial, fungal, plant, or animal origin, or fragments thereof, including, but not limited to, diphtheria A chain, non-binding active fragments of diphtheria toxin, exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), Momordica charantia inhibitor, curcin, crotin, Sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes.
  • diphtheria A chain non-binding active fragments of diphtheria toxin
  • exotoxin A chain ricin A chain
  • abrin A chain abrin
  • an antibody is conjugated to one or more small molecule toxins, such as calicheamicins, maytansinoids, trichothenes, and CC1065.
  • small molecule toxins such as calicheamicins, maytansinoids, trichothenes, and CC1065.
  • a derivative of any one of these toxins may be used as long as the derivative retains the cytotoxic activity of the parent molecule.
  • Conjugates comprising the LAIR1 binding agent e.g., the anti-LAIR1 antibody disclosed herein
  • Conjugates comprising the LAIR1 binding agent (e.g., the anti-LAIR1 antibody disclosed herein) may be made using any suitable method known in the art.
  • conjugates are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyidithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCl), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis(p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p- diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene).
  • SPDP N-succinimidyl-3-(2-pyridyidithi
  • the LAIR1 binding agent disclosed herein is conjugated to a detectable substance or molecule that allows the agent to be used for diagnosis and/or detection.
  • the anti-LAIR1 antibody disclosed herein is conjugated to a detectable substance or molecule that allows the antibody to be used for diagnosis and/or detection.
  • a labeled anti-LAIR1 antibody is used to monitor immune cells in a tumor or in the microenvironment of a tumor.
  • a labeled anti-LAIR1 antibody is used to monitor immune cells in a tumor or in the microenvironment of a tumor after treatment.
  • a detectable substance can include but is not limited to, enzymes, such as horseradish peroxidase, alkaline phosphatase, beta-galactosidase, and acetylcholinesterase; prosthetic groups, such as biotin and flavine(s); fluorescent materials, such as, umbelliferone, fluorescein, fluorescein isothiocyanate (FITC), rhodamine, tetramethylrhodamine isothiocyanate (TRITC), dichlorotriazinylamine fluorescein, dansyl chloride, cyanine (Cy3), and phycoerythrin; bioluminescent materials, such as luciferase; radioactive materials, such as 212 Bi, 14 C, 57 Co, 51 Cr, 67 Cu, 18 F, 68 Ga, 67 Ga, 153 Gd, 159 Gd, 68 Ge, 3 H, 166 Ho, 131 I, 125 I, 123 I, 121 I,
  • the anti-LAIR1 antibody disclosed herein can also be conjugated to a second antibody to form an antibody heteroconjugate.
  • the LAIR1 binding agent as disclosed herein may be attached to a solid support.
  • the anti-LAIR1 antibody as disclosed herein is attached to a solid support.
  • Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride, or polypropylene.
  • an immobilized anti-LAIR1 antibody is used in an immunoassay.
  • an immobilized anti-LAIR1 antibody is used in purification of the target antigen.
  • the anti-LAIR1 antibody disclosed herein is used in an immunoassay.
  • Immunoassays are known to those of skill in the art and include, but are not limited to, ELISA, SPR (e.g., Biacore), FACS, and immunohistochemistry (IHC).
  • the anti-LAIR1 antibody disclosed herein is used on a tissue sample or a tumor sample.
  • the present disclosure further encompasses polynucleotides comprising polynucleotides that encode a polypeptide (e.g., the LAIR1 binding agent (see Section 5.3) disclosed herein).
  • the disclosure encompasses one or more polynucleotides that encode a binding agent (e.g., the LAIR1 binding agent (see Section 5.3)) disclosed herein.
  • a binding agent e.g., the LAIR1 binding agent (see Section 5.3)
  • polynucleotides that encode a polypeptide encompasses a polynucleotide that includes only coding sequences for the polypeptide as well as a polynucleotide that includes additional coding and/or non-coding sequences.
  • the polynucleotides of the disclosure can be in the form of RNA or in the form of DNA.
  • DNA includes cDNA, genomic DNA, and synthetic DNA; and can be double-stranded or single- stranded, and if single stranded can be the coding strand or non-coding (anti-sense) strand.
  • a polynucleotide comprises a polynucleotide encoding a heavy chain variable region and/or a light chain variable region of the LAIR1 binding agent disclosed herein. In certain embodiments, a polynucleotide comprises a polynucleotide encoding a heavy chain variable region of the LAIR1 binding agent disclosed herein.
  • a polynucleotide comprises a polynucleotide encoding a light chain variable region of the LAIR1 binding agent disclosed herein. In certain embodiments, a polynucleotide comprises a polynucleotide encoding a heavy chain variable region of the NAI-1539756353v1 114 LAIR1 binding agent disclosed herein and a polynucleotide encoding a light chain variable region of the LAIR1 binding agent. [00323] In certain embodiments, a polynucleotide comprises a polynucleotide encoding a heavy chain and/or a light chain of the LAIR1 binding agent disclosed herein.
  • a polynucleotide comprises a polynucleotide encoding a heavy chain of the LAIR1 binding agent disclosed herein. In certain embodiments, a polynucleotide comprises a polynucleotide encoding a light chain of the LAIR1 binding agent disclosed herein. In certain embodiments, a polynucleotide comprises a polynucleotide encoding a heavy chain of the LAIR1 binding agent disclosed herein and a polynucleotide encoding a light chain of the LAIR1 binding agent.
  • the polynucleotide comprises a polynucleotide encoding a polypeptide comprising an amino acid sequence selected from the group consisting of: SEQ ID NOs:115-140. [00325] In certain embodiments, the polynucleotide comprises a polynucleotide encoding a polypeptide comprising more than one amino acid sequence selected from the group consisting of: SEQ ID NOs:115-132.
  • the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:115 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:116. In certain embodiments, the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:117 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:118.
  • the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:119 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:120. In certain embodiments, the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:121 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:122.
  • the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:123 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:124. In certain embodiments, the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:125 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:126.
  • the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:127 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:128.
  • the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:129 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:130.
  • the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:131 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:132. [00326] In certain embodiments, the polynucleotide comprises a polynucleotide encoding a polypeptide comprising more than one amino acid sequence selected from the group consisting of: SEQ ID NOs:133-140.
  • the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:133 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:135. In certain embodiments, the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:134 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:136.
  • the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:137 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:139. In certain embodiments, the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:138 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:140.
  • the present disclosure also provides variants of the polynucleotides disclosed herein, wherein the variant encodes, for example, fragments, analogs, and/or derivatives of a polypeptide.
  • the present disclosure provides a polynucleotide comprising a polynucleotide having a nucleotide sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, and in certain embodiments, at least 96%, at least 97%, at least 98%, or at least 99% identical to a polynucleotide encoding a polypeptide disclosed herein.
  • a polynucleotide comprises a polynucleotide having a nucleotide sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, and in certain embodiments, at least 96%, at least 97%, at least 98%, or at least 99% identical to a polynucleotide encoding an amino acid sequence selected from the group consisting of: SEQ ID NOs:115-140.
  • a polynucleotide that comprises a polynucleotide that hybridizes to a polynucleotide encoding an amino acid sequence selected from the group consisting of: SEQ ID NOs:115-140.
  • the hybridization is under conditions of high stringency as is known to those skilled in the art.
  • NAI-1539756353v1 116 [00329]
  • the phrase “a polynucleotide having a nucleotide sequence at least 95% identical to a polynucleotide sequence” is intended to mean that the nucleotide sequence of the polynucleotide is identical to a reference sequence except that the polynucleotide sequence can include up to five point mutations per each 100 nucleotides of the reference nucleotide sequence.
  • a polynucleotide having a nucleotide sequence at least 95% identical to a reference nucleotide sequence up to 5% of the nucleotides in the reference sequence can be deleted or substituted with another nucleotide, or a number of nucleotides up to 5% of the total nucleotides in the reference sequence can be inserted into the reference sequence. It is understood by those of skill in the art that an appropriate calculation would be made for other “% identical” statements, for example, 90% identical or 85% identical.
  • the polynucleotide variants can contain alterations in the coding regions, non- coding regions, or both.
  • a polynucleotide variant contains alterations that produce silent substitutions, additions, or deletions, but does not alter the properties or activities of the encoded polypeptide.
  • a polynucleotide variant comprises silent substitutions that results in no change to the amino acid sequence of the polypeptide (due to the degeneracy of the genetic code).
  • a polynucleotide variant comprises one or more mutated codons comprising one or more (e.g., 1, 2, or 3) substitutions to the codon that change the amino acid encoded by that codon.
  • Methods for introducing one or more substitutions into a codon are known in the art, including but not limited to, PCR mutagenesis and site-directed mutagenesis.
  • Polynucleotide variants can be produced for a variety of reasons, for example, to optimize codon expression for a particular host (e.g., change codons in the human mRNA to those preferred by a bacterial host such as E. coli).
  • a polynucleotide variant comprises at least one silent mutation in a non-coding or a coding region of the sequence.
  • a polynucleotide variant is produced to modulate or alter expression (or expression levels) of the encoded polypeptide.
  • a polynucleotide variant is produced to increase expression of the encoded polypeptide.
  • a polynucleotide variant is produced to decrease expression of the encoded polypeptide.
  • a polynucleotide variant has increased expression of the encoded polypeptide as compared to a parental polynucleotide sequence.
  • a polynucleotide variant has decreased expression of the encoded polypeptide as compared to a parental polynucleotide sequence.
  • a polynucleotide comprises the coding sequence for a polypeptide fused in the same reading frame to a polynucleotide that aids in expression and secretion of a polypeptide from a host cell.
  • the polynucleotide that aids in expression and secretion is a leader sequence that functions as a secretory sequence for controlling transport of a polypeptide.
  • a polynucleotide comprises the coding sequence for a polypeptide fused in the same reading frame to a marker or tag sequence.
  • a marker sequence is a hexa-histidine tag (HIS-tag; SEQ ID NO:153) that allows for efficient purification of the polypeptide fused to the marker.
  • a marker sequence is a hemagglutinin (HA) tag derived from the influenza hemagglutinin protein when a mammalian host is used.
  • the marker sequence is a FLAGTM tag. In certain embodiments, a marker may be used in conjunction with other markers or tags.
  • a polynucleotide is isolated. In certain embodiments, a polynucleotide is substantially pure.
  • Vectors comprising any of the polynucleotides disclosed herein are also provided. In certain embodiments, a vector comprises a polynucleotide encoding the LAIR1 binding agent disclosed herein. In certain embodiments, a vector comprises a polynucleotide encoding a polypeptide that is part of the LAIR1 binding agent disclosed herein.
  • a vector comprises a polynucleotide encoding the anti-LAIR1 antibody disclosed herein. In certain embodiments, a vector comprises a polynucleotide encoding a heavy chain variable region disclosed herein. In certain embodiments, a vector comprises a polynucleotide encoding a light chain variable region disclosed herein. In certain embodiments, a vector comprises a first polynucleotide encoding a heavy chain variable region and a second polynucleotide encoding a light chain variable region disclosed herein. In certain embodiments, a vector comprises a polynucleotide encoding a heavy chain of an anti-LAIR antibody disclosed herein.
  • a vector comprises a polynucleotide encoding a light chain of an anti-LAIR antibody disclosed herein. In certain embodiments, a vector comprises a polynucleotide encoding a heavy chain and a polynucleotide encoding a light chain of an anti-LAIR antibody disclosed herein. NAI-1539756353v1 118 [00336] Cells comprising any of the polynucleotides disclosed herein are provided. In certain embodiments, a cell comprises one or more polynucleotides encoding the LAIR1 binding agent disclosed herein.
  • a cell comprises one or more polynucleotides encoding a polypeptide that is part of the LAIR1 binding agent disclosed herein. In certain embodiments, a cell comprises one or more polynucleotides encoding the anti-LAIR1 antibody disclosed herein. In certain embodiments, a cell comprises a polynucleotide encoding a heavy chain variable region disclosed herein. In certain embodiments, a cell comprises a polynucleotide encoding a light chain variable region disclosed herein. In certain embodiments, a cell comprises a first polynucleotide encoding a heavy chain variable region and a second polynucleotide encoding a light chain variable region disclosed herein.
  • a cell comprises a single polynucleotide encoding a heavy chain variable region and a light chain variable region disclosed herein. In certain embodiments, a cell comprises a polynucleotide encoding a heavy chain of an anti- LAIR antibody disclosed herein. In certain embodiments, a cell comprises a polynucleotide encoding a light chain of an anti-LAIR antibody disclosed herein. In certain embodiments, a cell comprises a first polynucleotide encoding a heavy chain and a second polynucleotide encoding a light chain of an anti-LAIR antibody disclosed herein.
  • a cell comprises a single polynucleotide encoding a heavy chain and a light chain of an anti- LAIR antibody disclosed herein.
  • cells comprising the vectors disclosed herein are provided.
  • a cell comprises one or more vectors expressing the LAIR1 binding agent disclosed herein.
  • a cell comprises one or more vectors expressing a polypeptide that is part of the LAIR1 binding agent disclosed herein.
  • a cell comprises one or more vectors expressing the anti-LAIR1 antibody disclosed herein.
  • a cell comprises a vector encoding the LAIR1 binding agent disclosed herein.
  • a cell comprises a first vector expressing a heavy chain variable region disclosed herein and a second vector expressing a light chain variable region disclosed herein. In certain embodiments, a cell comprises a single vector expressing a heavy chain variable region and a light chain variable region disclosed herein. In certain embodiments, a cell comprises a first vector expressing a heavy chain of the anti-LAIR1 antibody disclosed herein and a second vector expressing a light chain of the anti-LAIR1 antibody disclosed herein. In certain embodiments, a cell comprises a single vector expressing a heavy chain and a light chain of the anti-LAIR1 antibody disclosed herein.
  • a cell produces the LAIR1 binding agent disclosed herein. In certain embodiments, a cell produces the anti-LAIR1 antibody disclosed herein. In certain embodiments, a cell produces an antibody selected from the group consisting of: 47A1, 47H1, Hz47H1.v4, 57D12, 61H4, 62G10, Hz62G10.v1, 108D10, and 43H2. In certain embodiments, the cell is a prokaryotic cell. In certain embodiments, the cell is a eukaryotic cell. In certain embodiments, the cell is a mammalian cell. In certain embodiments, the cell is isolated. In certain embodiments, the cell is a hybridoma.
  • a hybridoma produces an antibody selected from the group consisting of: 47A1, 47H1, Hz47H1.v4, 57D12, 61H4, 62G10, Hz62G10.v1, 108D10, and 43H2.
  • compositions such as a pharmaceutical composition, comprising at least one of the following: a binding agent provided herein (e.g., one antibody or antigen-binding fragment thereof of the present disclosure), a nucleic acid provided herein, a vector provided herein, or a cell provided herein.
  • a pharmaceutical composition comprises a therapeutically effective amount of a LAIR1 binding agent (see Section 5.3) provided herein (e.g., an antibody or antigen-binding fragment thereof provided herein) and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprises a therapeutically effective amount of a nucleic acid provided herein (such as a nucleic acid encoding an antibody or antigen- binding fragment thereof provided herein) and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprises a therapeutically effective amount of a vector provided herein (such as a vector comprising a nucleic acid as disclosed herein and expressing a LAIR1 binding agent as disclosed herein) and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprises a therapeutically effective amount of a cell provided herein (such as a cell comprising a nucleic acid encoding an antibody or antigen-binding fragment thereof provided herein and/or expressing an antibody or antigen-binding fragment thereof provided herein) and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition disclosed herein is used in combination a second pharmaceutical composition comprising a PD-1 antagonist (e.g., PD-1 NAI-1539756353v1 120 antagonists disclosed in Section 5.6).
  • the LAIR1-binding agent and the PD-1 antagonist are not provided in the same composition (e.g., different pharmaceutical compositions), such as when the LAIR1-binding agent and the PD-1 antagonist are to be separately administered (e.g., separately administered at different time or through different administering routes).
  • the pharmaceutical composition disclosed herein further comprises a PD-1 antagonist (e.g., PD-1 antagonists disclosed in Section 5.6) such that the LAIR1 binding agent and the PD-1 antagonist are included in the same pharmaceutical composition.
  • compositions provided herein are prepared for storage by mixing the binding agents, nucleic acids, vectors, or cells provided herein having the desired degree of purity with optional pharmaceutically acceptable excipients (see, e.g., Remington, Remington’s Pharmaceutical Sciences (18th ed.1980)) in the form of aqueous solutions or lyophilized or other dried forms.
  • pharmaceutically acceptable excipients see, e.g., Remington, Remington’s Pharmaceutical Sciences (18th ed.1980)
  • the binding agents, nucleic acids, vectors, or cells of the present disclosure may be formulated in any suitable form for delivery to a target cell/tissue as described in Remington, Remington’s Pharmaceutical Sciences (18th ed.1980).
  • Osteosarcoma is one type of bone cancer that usually occurs in the osteoblast cells that form bone. It develops most often in children, adolescents, and young adults. Sites for osteosarcoma include long bones around the knee, upper leg, or thighbone, the lower leg, upper arm bone, or any bone in the body, including those in the pelvis, shoulder, and skull. Osteosarcoma may grow into nearby tissues, such as tendons or muscles, and may spread, or metastasize, through the bloodstream to other organs or bones in the body.
  • the present disclosure provides methods for treating osteosarcoma using a combination of a LAIR1-binding agent (e.g., LAIR1 binding agents disclosed in Section 5.3 herein, and LAIR1 binding agents described in International Patent Publication No. WO 2021/262597, which is incorporated herein by reference) and a PD-1 antagonist (e.g., PD-1 antagonists disclosed in Section 5.6 herein).
  • a LAIR1-binding agent e.g., LAIR1 binding agents disclosed in Section 5.3 herein, and LAIR1 binding agents described in International Patent Publication No.
  • the present disclosure provides a method for disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a cell mixture, wherein the cell mixture comprises osteosarcoma cells.
  • the method comprises contacting the cell mixture with a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • the cell mixture comprises intratumoral cells.
  • the cell mixture comprises immune cells (e.g., intratumoral immune cells).
  • the intratumoral cells e.g., intratumoral immune cells
  • the cell mixture comprises at least one of myeloid cells, NK cells, T-cells, cytotoxic T-cells, monocytes, macrophages, dendritic cells, APCs, MDSCs, and T-regs.
  • the method results in disrupting, inhibiting, or blocking collagen- induced LAIR1 activity.
  • the method results in disrupting, inhibiting, or blocking LAIR1-induced suppression of myeloid cells.
  • the method results in disrupting, inhibiting, or blocking of LAIR1-induced suppression of myeloid cell activity. In certain embodiments, the method results in disrupting, inhibiting, or blocking of LAIR1-induced suppression of NK cells or NK cell activity. In certain embodiments, the method results in disrupting, inhibiting, or blocking of LAIR1-induced suppression of T-cells or T-cell activity. In certain embodiments, the method (i) restores FcR signaling activity in myeloid cells; (ii) restores cytokine and/or chemokine production by myeloid cells; and/or (iii) restores immune cell (e.g., T-cell) proliferation and/or activity.
  • the myeloid cell is a monocyte, a macrophage, a dendritic cell, or an APC.
  • the present disclosure provides a method for disrupting, inhibiting, or blocking the binding of LAIR1 to MARCO in a cell mixture, wherein the cell mixture comprises osteosarcoma cells.
  • the method comprises contacting the cell mixture with a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • the cell mixture comprises intratumoral cells.
  • the cell mixture comprises immune cells (e.g., intratumoral immune cells).
  • the intratumoral cells are or were present in osteosarcoma or a tumor microenvironment thereof.
  • the cell mixture comprises at least one of myeloid cells, NK cells, T cells, cytotoxic T-cells, monocytes, macrophages, dendritic cells, APCs, MDSCs, and T-regs.
  • the method results in disrupting, inhibiting, or blocking MARCO- induced LAIR1 activity.
  • the method results in disrupting, inhibiting, NAI-1539756353v1 122 or blocking LAIR1-induced suppression of myeloid cells.
  • the method results in disrupting, inhibiting, or blocking of LAIR1-induced suppression of myeloid cell activity. In certain embodiments, the method results in disrupting, inhibiting, or blocking of LAIR1-induced suppression of NK cells or NK cell activity. In certain embodiments, the method results in disrupting, inhibiting, or blocking of LAIR1-induced suppression of T-cells or T-cell activity. In certain embodiments, the method (i) restores FcR signaling activity in myeloid cells; (ii) restores cytokine and/or chemokine production by myeloid cells; and/or (iii) restores immune cell (e.g., T-cell) proliferation and/or activity.
  • the myeloid cell is a monocyte, a macrophage, a dendritic cell, or an APC.
  • the present disclosure provides a method for disrupting, inhibiting, or blocking the binding of LAIR1 to COLEC12 in a cell mixture, wherein the cell mixture comprises osteosarcoma cells.
  • the method comprises contacting the cell mixture with a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • the cell mixture comprises intratumoral cells.
  • the cell mixture comprises immune cells (e.g., intratumoral immune cells).
  • the intratumoral cells are or were present in osteosarcoma or a tumor microenvironment thereof.
  • the cell mixture comprises at least one of myeloid cells, NK cells, T-cells, cytotoxic T-cells, monocytes, macrophages, dendritic cells, APCs, MDSCs, and T-regs.
  • the method for treating osteosarcoma or for activating, promoting, increasing, and/or enhancing an immune response to osteosarcoma cells disclosed herein disrupts, inhibits, or blocks collagen-induced LAIR1 activity in a cell, wherein the method comprises contacting the cell with a LAIR1-binding agent disclosed herein and a PD- 1 antagonist disclosed herein.
  • the method for treating osteosarcoma or for activating, promoting, increasing, and/or enhancing an immune response to osteosarcoma cells disclosed herein disrupts and/or inhibits LAIR1 signaling in a cell, wherein the method comprises contacting the cell with a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • the cell is an intratumoral cell, and is or was present in osteosarcoma or a tumor microenvironment thereof.
  • the cell is an immune cell.
  • the immune cell is a myeloid cell, a NK cell, a T-cell, a cytotoxic T-cell, a monocyte, a macrophage, a dendritic cell, an APC, a MDSC, or a T-reg. NAI-1539756353v1 123 [00350]
  • the method for treating osteosarcoma or for activating, promoting, increasing, and/or enhancing an immune response to osteosarcoma cells disclosed herein disrupts, inhibits, or blocks LAIR1-induced suppression of a myeloid cell, wherein the method comprises contacting the myeloid cell with a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • the method for treating osteosarcoma or for activating, promoting, increasing, and/or enhancing an immune response to osteosarcoma cells disclosed herein disrupts, inhibits, or blocks LAIR1- induced suppression of a T-cell or T-cell activity, wherein the method comprises contacting the T-cell with a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • the T-cell is a cytotoxic T-cell (CTL).
  • the method for treating osteosarcoma or for activating, promoting, increasing, and/or enhancing an immune response to osteosarcoma cells disclosed herein disrupts, inhibits, or blocks the activity of a MDSC, wherein the method comprises contacting the MDSC with a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • the method for treating osteosarcoma or for activating, promoting, increasing, and/or enhancing an immune response to osteosarcoma cells disclosed herein disrupts, inhibits, or blocks the activity of a Treg, wherein the method comprises contacting the T-reg with a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • the NK cell, the T-cell, the MDSC, or the Treg is an intratumoral cell, and is or was present in osteosarcoma or a tumor microenvironment thereof.
  • the present disclosure provides methods of disrupting, inhibiting, or blocking the binding of LAIR1 to collagen, MARCO, and/or COLEC12 in a subject having osteosarcoma, comprising administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • the present disclosure provides methods for disrupting, inhibiting, or blocking collagen-induced LAIR1 activity in a subject having osteosarcoma comprising administering to the subject a therapeutically effective amount of a LAIR1- binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • the present disclosure provides methods for disrupting, inhibiting, or blocking LAIR1-induced suppression of a myeloid cell or myeloid cell activity in a subject having osteosarcoma comprising administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • the method restores FcR activity in myeloid cells; (ii) restores cytokine and/or chemokine production by myeloid cells; and/or (iii) restores immune cell (e.g., T-cell) proliferation and/or activity.
  • the myeloid cell is a monocyte, a macrophage, a dendritic cell, or an APC.
  • the present disclosure provides methods for disrupting, inhibiting, or blocking LAIR1-induced suppression of a NK cell or NK cell activity in a subject having osteosarcoma comprising administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • the present disclosure provides methods for disrupting, inhibiting, or blocking LAIR1-induced suppression of a T-cell or T-cell activity in a subject having osteosarcoma comprising administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • the T-cell is a cytotoxic T-cell (CTL). In certain embodiments, the T-cell is a tumor-associated T-cell.
  • CTL cytotoxic T-cell
  • the present disclosure provides methods for disrupting, inhibiting, or blocking the activity of a MDSC in a subject having osteosarcoma comprising administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • the present disclosure provides methods for disrupting, inhibiting, or blocking the activity of a Treg in a subject having osteosarcoma comprising administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • the present disclosure provides methods for activating, promoting, increasing, and/or enhancing an immune response in a subject having osteosarcoma using a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • the activating, promoting, increasing, and/or enhancing of an NAI-1539756353v1 125 immune response comprises stimulating myeloid cells, monocytes, macrophages, dendritic cells, and/or APCs.
  • the activating, promoting, increasing, and/or enhancing of an immune response comprises increasing cell-mediated immunity.
  • the activating, promoting, increasing, and/or enhancing of an immune response comprises increasing effector T-cell activity, and/or increasing CTL activity. In certain embodiments, the activating, promoting, increasing, and/or enhancing of an immune response comprises inhibiting or decreasing the suppressive activity of Tregs, and/or the suppressive activity of MDSCs. In certain embodiments, the immune response is a result of antigenic stimulation from an osteosarcoma cell or osteosarcoma.
  • the present disclosure provides methods for inhibiting growth of osteosarcoma or osteosarcoma cells comprising contacting a cell mixture with a LAIR1-binding agent and a PD-1 antagonist in vitro., wherein the cell mixture comprises osteosarcoma cells.
  • a cell mixture comprises osteosarcoma cells.
  • an osteosarcoma cell line mixed with immune cells e.g., T-cells or myeloid cells
  • the osteosarcoma cells are from a patient sample such as, for example, a tissue biopsy, pleural effusion, or blood sample, mixed with immune cells (e.g., T-cells or myeloid cells), and cultured in medium to which is added a test agent that binds LAIR1.
  • a patient sample such as, for example, a tissue biopsy, pleural effusion, or blood sample
  • immune cells e.g., T-cells or myeloid cells
  • the present disclosure provides the use of a LAIR1- binding agent disclosed herein in combination with a PD-1 antagonist disclosed herein in the manufacture or preparation of a medicament for inhibiting growth of osteosarcoma or osteosarcoma cells.
  • the combination of the LAIR1-binding agent and the PD-1 antagonist increases, promotes, and/or enhances the activity of effector immune cells.
  • the combination of the LAIR1-binding agent and the PD-1 antagonist inhibits osteosarcoma cell growth.
  • the present disclosure provides a method of inhibiting osteosarcoma growth comprises contacting the osteosarcoma and/or osteosarcoma microenvironment with a combination of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein in vivo.
  • contacting an osteosarcoma and/or osteosarcoma microenvironment with a combination of a LAIR1-binding agent and a PD-1 antagonist is undertaken in an animal model (e.g., a mouse model).
  • a test agent may be administered to mice that have osteosarcoma.
  • the test agent is a LAIR1 binding agent that binds mouse LAIR1.
  • the test agent is a surrogate antibody that binds mouse LAIR1.
  • the test agent is an anti-mouse LAIR1 antibody disclosed herein.
  • the test agent is anti-mouse LAIR1 antibody 43H2 (see Table 7 disclosed herein).
  • the combination of the LAIR1-binding agent and the PD-1 antagonist increases, promotes, and/or enhances the activity of immune cells in the mice.
  • the combination of the LAIR1-binding agent and the PD-1 antagonist inhibits tumor growth. In certain embodiments, the combination of the LAIR1-binding agent and the PD-1 antagonist causes the osteosarcoma to regress. In certain embodiments, the LAIR1-binding agent and the PD-1 antagonist are administered at the same time or shortly after introduction of osteosarcoma cells into the animal to prevent tumor growth (“preventative model”). In certain embodiments, the LAIR1-binding agent and the PD-1 antagonist are administered after osteosarcoma has grown to a specified size or have become “established” for treatment (“therapeutic model”).
  • the LAIR1- binding agent and the PD-1 antagonist are administered to a transgenic animal (e.g., a transgenic mouse) that expresses human LAIR1, wherein the transgenic animal has osteosarcoma derived from human cells.
  • the LAIR1-binding agent is an anti-mouse LAIR1 antibody disclosed herein.
  • the LAIR1- binding agent is anti-mouse LAIR1 antibody 43H2.
  • the LAIR1- binding agent is an anti-human LAIR1 antibody disclosed herein and a PD-1 antagonist disclosed herein.
  • a method of inhibiting osteosarcoma growth in a subject comprises administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • a method of increasing or enhancing an immune response to osteosarcoma or osteosarcoma cells in a subject comprises administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • a method of activating or enhancing a persistent or long-term immune response to osteosarcoma or osteosarcoma cells in a subject comprises administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • a method of inhibiting osteosarcoma relapse or osteosarcoma regrowth in a subject comprises administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • a method of inducing a persistent or long-term immunity that inhibits osteosarcoma relapse or osteosarcoma regrowth in a subject comprises administering to the subject a therapeutically effective amount of a LAIR1- binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein NAI-1539756353v1 127
  • the present disclosure provides use of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein in the manufacture or preparation of a medicament for inhibiting growth of osteosarcoma or osteosarcoma cells.
  • the subject has osteosarcoma or the subject had osteosarcoma that was at least partially removed.
  • the present disclosure provides methods of treating osteosarcoma comprising administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • the LAIR1-binding agent binds LAIR1 and inhibits or reduces growth of osteosarcoma.
  • the LAIR1-binding agent binds LAIR1-expressing cells, enhances an immune response to osteosarcoma, and inhibits or reduces growth of the osteosarcoma.
  • the LAIR1-binding agent binds LAIR1-expressing cells, activates myeloid cells, enhances an immune response to osteosarcoma, and inhibits or reduces growth of the osteosarcoma.
  • the subject has osteosarcoma.
  • the subject has had osteosarcoma, which is at least partially removed.
  • the present disclosure provides use of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein in the manufacture or preparation of a medicament for the treatment of osteosarcoma.
  • the present disclosure provides methods of activating myeloid cells in the tumor microenvironment in a subject having osteosarcoma, comprising administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • the myeloid cells comprise at least one dendritic cells, monocytes, macrophages, and APCs.
  • the present disclosure provides methods of activating T- cells in the tumor microenvironment in a subject having osteosarcoma, comprising administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein.
  • the T-cells are CTLs, and/or tumor-associated T-cells.
  • the method disclosed herein is an in vitro method comprising contacting an osteosarcoma cell with a LAIR-binding agent disclosed herein and a PD-1 antagonist.
  • the method disclosed herein is an in vivo method comprising administering a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist to a subject having osteosarcoma.
  • the appropriate dosages of the LAIR1-binding agent and the PD-1 antagonist used with the presently disclosed methods depend on severity and course of the osteosarcoma, the responsiveness of the osteosarcoma, whether the LAIR1-binding agent and the PD-1 antagonist are administered for therapeutic or preventative purposes, previous therapy, the patient’s clinical history, and so on.
  • the LAIR1-binding agent and the PD-1 antagonist can be administered one time or over a series of treatments lasting from several days to several months, or until a cure is effected or a diminution of the osteosarcoma is achieved.
  • Any suitable PD-1 antagonists can be used with the presently disclosed subject matter.
  • the PD-1 antagonist is an antagonistic anti-PD-1 antibody.
  • the antagonistic anti-PD-1 antibody is selected from the group consisting of pembrolizumab (MK-3475; KEYTRUDA), pidilizumab (CT-011), nivolumab (OPDIVO), durvalumab (MEDI0680), budigalimab (ABBV-181), cemiplimab (REGN2810), tislelizumab (BGB-A317), spartalizumab (PDR-001), STI-A1110, and combinations thereof.
  • Exemplary antagonistic anti-PD-1 antibodies are described in in US Patent Nos.10316089, 9580504, 9856320, 8609089, and 8952136; the contents of each which are incorporated by reference herein in their entireties.
  • the antagonistic anti-PD-1 antibodies are described in International Patent Publication No. WO 2014/179664, for example, an antibody identified as APE2058, APE1922, APE1923, APE1924, APE 1950, or APE1963, or an antibody containing the CDR regions of any of these antibodies, the content of WO 2014/179664 is incorporated herein by reference.
  • the PD-1 antagonist is a fusion protein that comprises PD-L2, for example, AMP-224.
  • the PD-1 antagonist is a peptide inhibitor, for example, AU P-12.
  • the method disclosed herein comprises administering the LAIR-1 binding agent disclosed herein in combination with an antagonistic anti-PD-1 antibody, wherein the antagonistic anti-PD-1 antibody is administered once or sequentially.
  • administration of the LAIR1-binding agent can occur prior to, concurrently with, or subsequent to the administration of the PD-1 antagonist.
  • combined administration of the LAIR1-binding agent and the PD-1 antagonist includes co-administration, either in a single pharmaceutical formulation or using separate formulations, or consecutive administration in either order but generally within a time period such that all active agents can exert their biological activities.
  • preparation of agents and/or dosing schedules for the PD-1 antagonist are according to manufacturers' instructions or as determined empirically by the skilled practitioner.
  • NAI-1539756353v1 129 [00371]
  • the method disclosed herein comprises administering the LAIR1 binding agent and the PD-1 antagonist, in combination with at least one additional therapeutic agent or therapy.
  • Combination therapy using agents with different mechanisms of action may result in additive or synergetic effects.
  • Combination therapy may allow for a lower dose of each agent than is used in monotherapy, thereby reducing toxic side effects and/or increasing the therapeutic index of the agent(s).
  • Combination therapy may decrease the likelihood that resistance to an agent will develop.
  • the combination therapy disclosed herein results in additive or synergistic results. In certain embodiments, the combination therapy disclosed herein results in an increase in the therapeutic index of the LAIR1-binding agent and/or the PD-1 antagonist. In certain embodiments, the combination therapy disclosed herein results in an increase in the therapeutic index of the at least one additional therapeutic agent or therapy. In certain embodiments, the combination therapy disclosed herein results in a decrease in the toxicity and/or side effects of the LAIR1-binding agent and/or the PD-1 antagonist. In certain embodiments, the combination therapy disclosed herein results in a decrease in the toxicity and/or side effects of the at least one additional therapeutic agent or therapy.
  • the at least one additional therapeutic agent or therapy comprises a therapeutic agent or therapy that affects the immune response (e.g., enhances or activates the response) and a therapeutic agent that affects (e.g., inhibits or kills) the tumor/cancer cells.
  • the at least one additional therapeutic agent or therapy comprises one additional therapeutic agent or therapy. In certain embodiments, the at least one additional therapeutic agent or therapy comprises two or more additional therapeutic agent or therapy.
  • the at least one additional therapeutic agent is a modulator of PD-L1 activity, a modulator of PD-L2 activity, a modulator of CTLA-4 activity, a modulator of CD28 activity, a modulator of CD80 activity, a modulator of CD86 activity, a modulator of 4-1BB activity, an modulator of OX40 activity, a modulator of KIR activity, a modulator of Tim-3 activity, a modulator of LAG3 activity, a modulator of CD27 activity, a modulator of CD40 activity, a modulator of GITR activity, a modulator of TIGIT activity, a modulator of CD20 activity, a modulator of CD96 activity, or a modulator of IDO1 activity.
  • the at least one additional therapeutic agent is selected from the group consisting of PD-L1 antagonists, PD-L2 antagonists, CTLA-4 antagonists, CD80 antagonists, CD86 antagonists, KIR antagonists, Tim-3 antagonists, LAG3 antagonists, NAI-1539756353v1 130 TIGIT antagonists, CD20 antagonists, CD96 antagonists, IDO1 antagonists, and any combinations thereof.
  • the at least one additional therapeutic agent is selected from the group consisting of anti-PD-L1 antibodies, anti-PD-L2 antibodies, anti-CTLA-4 antibodies, anti-TIGIT antibodies, anti-CD28 antibodies, anti-CD80 antibodies, anti-CD86 antibodies, anti-4-1BB antibodies, anti-OX40 antibodies, anti-KIR antibodies, anti-Tim-3 antibodies, anti-LAG3 antibodies, anti-CD27 antibodies, anti-CD40 antibodies, anti-GITR antibodies, anti-TIGIT antibodies, anti-CD20 antibodies, anti-CD96 antibodies, an anti-IDO1 antibodies, and any combinations thereof.
  • Any suitable PD-L1 antagonists can be used with the presently disclosed subject matter.
  • PD-L1 antagonists disclosed herein can block, inhibit, or neutralize the function or activity of PD-L1 (e.g., the binding of PD-L1 to PD-1).
  • the PD-L1 antagonist is an anti-PD-L1 antibody.
  • the PD-L1 antagonist is a small molecule antagonist.
  • Exemplary anti-PD-L1 antibodies that can be used with the present disclosure include but not limited to BMS-936559 (MDX-1105), MEDI4736, MPDL3280A (RG7446), MSB0010718C, atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi).
  • Exemplary small molecule PD-L1 antagonists that can be used with the present disclosure include but not limited to CA-170, INCB-086550, MX-10181, GS-4224, and IMMH-010, and the PD-L1 antagonists disclosed in Sasikumar and Ramachandra, Front Immunol.2022;13:752065; Liu et al., Cancer Cell International. 2021;21: Article number: 239, the content of each of which is incorporated herein by reference.
  • the CTLA-4 antagonist is an antibody that specifically binds CTLA-4.
  • the antibody that binds CTLA-4 is ipilimumab (YERVOY) or tremelimumab (CP-675,206).
  • the CTLA-4 antagonist a CTLA-4 fusion protein, for example, KAHR-102.
  • the LAG3 antagonist is an antibody that specifically binds LAG3.
  • the antibody that binds LAG3 is I ⁇ 701, IMP731, BMS- 986016, LAG525, and GSK2831781.
  • the LAG3 antagonist includes a soluble LAG3 receptor, for example, IMP321.
  • the KIR antagonist is an antibody that specifically binds KIR.
  • the antibody that binds KIR is lirilumab. NAI-1539756353v1 131
  • the at least one additional therapeutic agent is selected from the group consisting of: a CD28 agonist, a 4-1BB agonist, an OX40 agonist, a CD27 agonist, a CD80 agonist, a CD86 agonist, a CD40 agonist, and a GITR agonist.
  • the OX40 agonist includes OX40 ligand, or an OX40- binding portion thereof.
  • the OX40 agonist may be MEDI6383.
  • the OX40 agonist is an antibody that specifically binds OX40.
  • the antibody that binds OX40 is MEDI6469, MEDI0562, or MOXR0916 (RG7888).
  • the OX40 agonist is a vector (e.g., an expression vector or virus, such as an adenovirus) capable of expressing OX40 ligand.
  • the OX40-expressing vector is tasadenoturev (DNX-2401).
  • the 4-1BB (CD137) agonist is a binding molecule, such as an anticalin.
  • the anticalin is PRS-343.
  • the 4-1BB agonist is an antibody that specifically binds 4-1BB.
  • antibody that binds 4-1BB is PF-2566 (PF-05082566) or urelumab (BMS-663513).
  • the CD27 agonist is an antibody that specifically binds CD27.
  • the antibody that binds CD27 is varlilumab (CDX-1127).
  • the GITR agonist comprises a GITR ligand or a GITR- binding portion thereof.
  • the GITR agonist is an antibody that specifically binds GITR.
  • the antibody that binds GITR is TRX518, MK-4166, or INBRX-110.
  • the at least one additional therapeutic agent used herein include, but are not limited to, cytokines such as chemokines, interferons, interleukins, lymphokines, and members of the tumor necrosis factor (TNF) family.
  • the at least one additional therapeutic agent is an immunostimulatory oligonucleotides, such as CpG dinucleotides.
  • the at least one additional therapeutic agent is selected from the group consisting of granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage colony stimulating factor (M-CSF), granulocyte colony stimulating factor (G- CSF), interleukin 3 (IL- 3), interleukin 12 (IL-12), interleukin 1 (IL-1), interleukin 2 (IL-2), B7-1 (CD80), B7-2 (CD86), 4-1BB ligand, and anti-CD3 antibody.
  • GM-CSF granulocyte-macrophage colony stimulating factor
  • M-CSF macrophage colony stimulating factor
  • G- CSF granulocyte colony stimulating factor
  • IL- 3 interleukin 12
  • IL-1 interleukin 1
  • IL-2 interleukin 2
  • B7-1 CD80
  • B7-2 CD86
  • 4-1BB ligand anti-CD3 antibody
  • the at least one additional therapeutic agent is selected from the group consisting of anti-tubulin agents, auristatins, DNA minor groove binders, DNA replication inhibitors, alkylating agents (e.g., platinum complexes such as cisplatin, mono(platinum), bis(platinum) and tri-nuclear platinum complexes and carboplatin), NAI-1539756353v1 132 anthracyclines, antibiotics, anti-folates, anti-metabolites, chemotherapy sensitizers, duocarmycins, etoposides, fluorinated pyrimidines, ionophores, lexitropsins, nitrosoureas, platinols, purine antimetabolites, puromycins, radiation sensitizers, steroids, taxanes, topoisomerase inhibitors, vinca alkaloids, alkylating agents, antimetabolites, antimitotics, topoisomerase inhibitors, and angio
  • the at least one additional therapeutic agent comprises a chemotherapeutic agent or a cocktail of chemotherapeutic agents.
  • chemotherapeutic agents that can be used with the present disclosure include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamime; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride
  • alkylating agents such as thio
  • paclitaxel TAXOL
  • docetaxel TAXOTERE
  • chlorambucil gemcitabine
  • 6- thioguanine mercaptopurine
  • platinum analogs such as cisplatin and carboplatin
  • vinblastine platinum
  • etoposide VP-16
  • ifosfamide mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; ibandronate; CPT 11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine (XELODA); and pharmaceutically acceptable salts, acids or derivatives of any of the above.
  • DMFO difluoromethylornithine
  • XELODA retinoic acid
  • esperamicins capecitabine
  • the chemotherapeutic agent is an anti-hormonal agent that acts to regulate or inhibit hormone action on tumors, such as anti-estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (FARESTON); and anti- androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
  • anti-estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (FARESTON); and anti- and
  • the chemotherapeutic agent is a topoisomerase inhibitor.
  • Topoisomerase inhibitors include, but are not limited to, doxorubicin HC1, daunorubicin citrate, mitoxantrone HC1, actinomycin D, etoposide, topotecan HC1, teniposide (VM-26), and irinotecan, as well as pharmaceutically acceptable salts, acids, or derivatives of any of these.
  • the chemotherapeutic agent is an anti-metabolite.
  • Anti- metabolites include, but are not limited to, gemcitabine, fluorouracil, capecitabine, methotrexate sodium, ralitrexed, pemetrexed, tegafur, cytosine arabinoside, thioguanine, 5- azacytidine, 6-mercaptopurine, azathioprine, 6-thioguanine, pentostatin, fludarabine phosphate, and cladribine, as well as pharmaceutically acceptable salts, acids, or derivatives of any of these.
  • the chemotherapeutic agent is an antimitotic agent, including, but not limited to, agents that bind tubulin.
  • the agent is a taxane.
  • the agent is paclitaxel or docetaxel, or a pharmaceutically acceptable salt, acid, or derivative of paclitaxel or docetaxel.
  • the agent is paclitaxel (TAXOL), docetaxel (TAXOTERE), albumin-bound paclitaxel (nab- paclitaxel; ABRAXANE), DHA-paclitaxel, or PG-paclitaxel.
  • the antimitotic agent comprises a vinca alkaloid, such as vincristine, vinblastine, vinorelbine, or vindesine, or pharmaceutically acceptable salts, acids, or derivatives thereof.
  • the antimitotic agent is an inhibitor of kinesin Eg5 or an inhibitor of a mitotic kinase such as Aurora A or Plkl.
  • the at least one additional therapeutic agent comprises a small molecule acting as an inhibitor against tumor-associated antigens including, but not limited to, EGFR, HER2 (ErbB2), and/or VEGF.
  • the at least one additional therapeutic agent comprises a protein kinase inhibitor selected from the group consisting of: gefitinib (IRESSA), erlotinib (TARCEVA), sunitinib (SUTENT), lapatanib, vandetanib (ZACTIMA), AEE788, CI-1033, cediranib (RECENTIN), sorafenib (NEXAVAR), and pazopanib (GW786034B).
  • the at least one additional therapeutic agent comprises comprises an mTOR inhibitor.
  • the at least one additional therapeutic agent comprises a biological molecule, such as an antibody.
  • treatment can involve the combined administration of a LAIR1-binding agent of the present disclosure with antibodies against tumor-associated antigens including, but not limited to, antibodies that bind EGFR, HER2/ErbB2, and/or VEGF.
  • the at least one additional therapeutic agent comprises an antibody that is an angiogenesis inhibitor (e.g., an anti-VEGF or VEGF receptor antibody).
  • the additional therapeutic agent is bevacizumab (AVASTIN), ramucirumab, trastuzumab (HERCEPTIN), pertuzumab (OMNITARG), panitumumab (VECTIBIX), nimotuzumab, zalutumumab, or cetuximab (ERBITUX).
  • the at least one additional therapeutic agent comprises an ILT3 antibody.
  • the anti-ILT3 antibody and the anti-LAIR1 antibody are formulated into two separate pharmaceutical compositions for use. In certain embodiments, the anti-ILT3 antibody and the anti-LAIR1 antibody are formulated into the same pharmaceutical composition for use.
  • an anti-ILT3 antibody includes a VH including a VH CDR1, a VH CDR2, a VH CDR3, and a VL including a VL CDR1, a VL CDR2, and a VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 are from any one of the VH and VL sequences of the antibodies described in U.S. Provisional Application No.63/265,824 (e.g., 3A3, 5A7, 12A12, 16C5, 45G10, 48A6, 53F10, or NAI-1539756353v1 135 Hz5A7.v5).
  • the anti-ILT3 antibody is a humanized version of an antibody disclosed herein, (e.g., 3A3, 5A7, 12A12, 16C5, 45G10, 48A6, 53F10).
  • treatment with a LAIR1-binding agent disclosed herein can include combination treatment with other biologic molecules, such as one or more cytokines (e.g., lymphokines, interleukins, tumor necrosis factors, and/or growth factors) or can be accompanied by surgical removal of tumors, removal of cancer cells, or any other therapy deemed necessary by a treating physician.
  • cytokines e.g., lymphokines, interleukins, tumor necrosis factors, and/or growth factors
  • the at least one additional therapeutic agent comprises a growth factor selected from the group consisting of: adrenomedullin (AM), angiopoietin (Ang), BMPs, BDNF, EGF, erythropoietin (EPO), FGF, GDNF, G-CSF, GM-CSF, GDF9, HGF, HDGF, IGF, migration-stimulating factor, myostatin (GDF-8), NGF, neurotrophins, PDGF, thrombopoietin, TGF-a, TGF- ⁇ , TNF-a, VEGF, PIGF, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-12, IL-15, and IL-18.
  • a growth factor selected from the group consisting of: adrenomedullin (AM), angiopoietin (Ang), BMPs, BDNF, EGF, erythropoiet
  • treatment with the LAIR1 binding agent and the PD-1 antagonist disclosed herein can occur prior to, concurrently with, or subsequent to the administration of the at least one additional therapeutic agent.
  • combined administration includes co-administration, either in a single pharmaceutical formulation or using separate formulations, or consecutive administration in either order but generally within a time period such that all active agents can exert their biological activities.
  • preparation of agents and/or dosing schedules for additional therapeutic agents are according to manufacturers' instructions or as determined empirically by the skilled practitioner.
  • the LAIR1 binding agent and/or the PD-1 antagonist is administered to the subject that have previously undergone treatment with the at least one additional therapeutic agent.
  • the LAIR1 binding agent and/or the PD-1 antagonist is administered substantially simultaneously or concurrently with the at least one additional therapeutic agent. In certain embodiments, the LAIR1 binding agent and/or the PD-1 antagonist is administered within 1 year of the treatment with the at least one additional therapeutic agent. In certain embodiments, the LAIR1 binding agent and/or the PD-1 antagonist is administered within 10, 8, 6, 4, or 2 months of any treatment with the at least one additional therapeutic agent. In certain embodiments, the LAIR1 binding agent and/or the PD-1 antagonist is administered within 4, 3, 2, or 1 weeks of any treatment with the at least one additional therapeutic agent.
  • kits comprising an LAIR1 binding agent (e.g., an anti- LAIR1 antibody) provided herein or a composition (e.g., a pharmaceutical composition) comprising thereof and a PD-1 antagonist or a composition (e.g., a pharmaceutical composition) comprising thereof, packaged into suitable packaging material.
  • an LAIR1 binding agent e.g., an anti- LAIR1 antibody
  • a composition e.g., a pharmaceutical composition
  • a PD-1 antagonist or a composition e.g., a pharmaceutical composition
  • kits optionally includes a label or packaging insert including a description of the components or instructions for use in vitro, in vivo, or ex vivo, of the components therein.
  • packaging material refers to a physical structure housing the components of the kit.
  • the packaging material can maintain the components sterilely, and can be made of material commonly used for such purposes (e.g., paper, corrugated fiber, glass, plastic, foil, ampoules, vials, tubes, etc.).
  • Kits provided herein can include labels or inserts.
  • Labels or inserts include “printed matter,” e.g., paper or cardboard, separate or affixed to a component, a kit or packing material (e.g., a box), or attached to, for example, an ampoule, tube, or vial containing a kit component.
  • Labels or inserts can additionally include a computer readable medium, such as a disk (e.g., hard disk, card, memory disk), optical disk such as CD- or DVD-ROM/RAM, DVD, MP3, magnetic tape, or an electrical storage media such as RAM and ROM or hybrids of these such as magnetic/optical storage media, FLASH media, or memory type cards.
  • Labels or inserts can include information identifying manufacturer information, lot numbers, manufacturer location, and date.
  • Kits provided herein can additionally include other components. Each component of the kit can be enclosed within an individual container, and all of the various containers can be within a single package. Kits can also be designed for cold storage. A kit can further be designed to contain antibodies provided herein, or cells that contain nucleic acids encoding the antibodies provided herein. The cells in the kit can be maintained under appropriate storage conditions until ready to use. [00406] Also provided herein are panels of antibodies that immunospecifically bind to an LAIR1 antigen. In specific embodiments, provided herein are panels of antibodies having different association rate constants, different dissociation rate constants, different affinities for LAIR1 antigen, and/or different specificities for an LAIR1 antigen.
  • Panels of antibodies can be used, for example, in 96 well or 384 well plates, such as for assays such as ELISAs.
  • reference to a range of 90-100% includes 91-99%, 92-98%, 93-95%, 91-98%, 91-97%, 91-96%, 91-95%, 91-94%, 91-93%, and so forth.
  • Reference to a range of 90-100% also includes 91%, 92%, 93%, 94%, 95%, 95%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth.
  • reference to a range of 25- 250, 250-500, 500-1,000, 1,000-2,500, 2,500-5,000, 5,000-25,000, 25,000-50,000 includes any numerical value or range within or encompassing such values, e.g., 25, 26, 27, 28, 29...250, 251, 252, 253, 254...500, 501, 502, 503, 504..., etc.
  • a series of ranges are disclosed throughout this document. The use of a series of ranges includes combinations of the upper and lower ranges to provide another range. This construction applies regardless of the breadth of the range and in all contexts throughout this patent document.
  • references to a series of ranges NAI-1539756353v1 138 such as 5-10, 10-20, 20-30, 30-40, 40-50, 50-75, 75-100, 100-150, includes ranges such as 5- 20, 5-30, 5-40, 5-50, 5-75, 5-100, 5-150, and 10-30, 10-40, 10-50, 10-75, 10-100, 10-150, and 20-40, 20-50, 20-75, 20-100, 20-150, and so forth.
  • modifications which do not substantially affect the activity of the various embodiments disclosed herein are also provided within the definition of the subject matter disclosed herein. Accordingly, the following examples are intended to illustrate but not limit the present disclosure 6.
  • a method of disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a subject having osteosarcoma comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 ⁇ 10 -9 M; and/or (iii) binds to cynomolgus LAIR1 with a K D of less than 1 ⁇ 10 -8 M; and (b) a PD-1 antagonist.
  • KD dissociation constant
  • a method of disrupting, inhibiting, or blocking collagen-induced LAIR1 activity in a subject having osteosarcoma comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 ⁇ 10 -9 M; and/or (iii) binds to cynomolgus LAIR1 with a K D of less than 1 ⁇ 10 -8 M; and (b) a PD-1 antagonist.
  • KD dissociation constant
  • a method of disrupting, inhibiting, or blocking LAIR1-induced suppression of an immune cell or immune cell activity in a subject having osteosarcoma comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; NAI-1539756353v1 139 (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 ⁇ 10 -9 M; and/or (iii) binds to cynomolgus LAIR1 with a K D of less than 1 ⁇ 10 -8 M; and (b) a PD-1 antagonist, wherein the immune cell or immune cell activity is a myeloid cell or myeloid cell activity, a natural killer (NK) cell or NK cell activity, a T-cell or T-cell activity, a myeloid- derived suppressor cell (MDSC) or MDSC
  • the myeloid cell is a monocyte, a macrophage, a dendritic cell, or an APC; and/or (ii) the T-cell is a cytotoxic T-cell (CTL). 5.
  • a method of treating osteosarcoma in a subject comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (K D ) of less than 1 ⁇ 10 -9 M; and/or (iii) binds to cynomolgus LAIR1 with a K D of less than 1 ⁇ 10 -8 M; and (b) a PD-1 antagonist.
  • NAI-1539756353v1 140 7.
  • a method of activating immune cells in the tumor microenvironment in a subject having osteosarcoma comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (K D ) of less than 1 ⁇ 10 -9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 ⁇ 10 -8 M; and (b) a PD-1 antagonist, wherein the immune cells are myeloid cells, NK cells, and/or T-cells.
  • an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii
  • the myeloid cells are monocytes, macrophages, dendritic cells, or APCs; and/or (ii) the T-cells are cytotoxic T-cells (CTLs).
  • CTLs cytotoxic T-cells
  • an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof and (b) a PD-1 antagonist for (a) treatment of osteosarcoma; (b) disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a subject having osteosarcoma; (c) disrupting, inhibiting, or blocking collagen-induced LAIR1 activity in a subject having osteosarcoma; (d) disrupting, inhibiting, or blocking LAIR1-induced suppression of an immune cell or immune cell activity in a subject having osteosarcoma; (e) inhibiting tumor growth, increasing or enhancing an immune response to a tumor or tumor cells, activating or enhancing a persistent or long-term immune response to a tumor or tumor cells, inhibiting tumor relapse or
  • NAI-1539756353v1 141 Use of (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof and (b) a PD-1 antagonist in the manufacture of a medicament for (a) treatment of osteosarcoma; (b) disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a subject having osteosarcoma; (c) disrupting, inhibiting, or blocking collagen-induced LAIR1 activity in a subject having osteosarcoma; (d) disrupting, inhibiting, or blocking LAIR1-induced suppression of an immune cell or immune cell activity in a subject having osteosarcoma; (e) inhibiting tumor growth, increasing or enhancing an immune response to a tumor or tumor cells, activating or enhancing a persistent or long-term immune response to a tumor or tumor cells, inhibiting tumor relapse or tumor regrowth, and/or inducing a persistent or long-term immunity that inhibits tumor relapse or tumor regrowth, in a subject having osteosarcoma; and
  • a method of disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a cell mixture comprising osteosarcoma cells to enhance the immune response to the osteosarcoma cells comprising contacting the cell mixture with (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 ⁇ 10 -9 M; and/or (iii) binds to cynomolgus LAIR1 with a K D of less than 1 ⁇ 10 -8 M; and (b) a PD-1 antagonist.
  • an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissoci
  • the cell mixture comprises at least one of myeloid cells, NK cells, T-cells, cytotoxic T-cells, MDSCs, and T-regs. NAI-1539756353v1 142 13.
  • the method of embodiment 12, wherein the myeloid cells comprise at least one of monocytes, macrophages, dendritic cells, and APCs. 14.
  • a method of disrupting, inhibiting, or blocking LAIR1-induced suppression of an immune cell or immune cell activity to enhance the immune response to osteosarcoma cells comprising contacting a cell mixture comprising the osteosarcoma cells and the immune cell with (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (K D ) of less than 1 ⁇ 10 -9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 ⁇ 10 -8 M; and (b) a PD-1 antagonist, wherein the immune cell or immune cell activity is a myeloid cell or myeloid cell activity, a NK cell or NK cell activity, a T-cell or T-cell activity, a MDSC or MDSC activity, a Treg or
  • the myeloid cell is a monocyte, a macrophage, a dendritic cell, or an APC; and/or (ii) the T-cell is a cytotoxic T-cell (CTL).
  • the PD-1 antagonist is an antagonistic anti-PD-1 antibody.
  • the anti-PD-1 antibody is selected from the group consisting of pembrolizumab, pidilizumab, nivolumab, durvalumab, budigalima, cemiplimab, tislelizumab, spartalizumab, and STI-A1110. 18.
  • the antibody comprises: (i) a heavy chain variable region complementarity determining region 1 (VH CDR1), a heavy chain variable region complementarity determining region 2 (VH CDR2) and a heavy chain variable region complementarity determining region 3 (VH CDR3) as set forth in a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:119; and a light chain variable region complementarity determining region 1 (VL CDR1), a light NAI-1539756353v1 143 chain variable region complementarity determining region 2 (VL CDR2), and a light chain variable region complementarity determining region 3 (VL CDR3) as set forth in a light chain variable region (VL) comprising the amino acid sequence of
  • the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:25, SEQ ID NO:31, SEQ ID NO:34, or SEQ ID NO:35; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:44, or SEQ ID NO:45; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:27, or NAI-1539756353v1 144 SEQ ID NO:37, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:28 or SEQ ID NO:38; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:42 or SEQ ID NO:39; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:30 or SEQ ID NO:40.
  • the antibody comprises at least one of (i)-(v):
  • the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25
  • the VH CDR2 comprises the amino acid sequence of SEQ ID NO:41
  • the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27
  • the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28
  • the VL CDR2 comprises the amino acid sequence of SEQ ID NO:42
  • the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30
  • the VH CDR1 comprises the amino acid sequence of SEQ ID NO:31
  • the VH CDR2 comprises the amino acid sequence of SEQ ID NO:43
  • the VH CDR3 comprises the amino acid of SEQ ID NO:27
  • the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28
  • the VL CDR2 comprises the amino acid sequence of SEQ ID NO:42
  • the VL CDR3 comprises the amino acid sequence of
  • the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:134 and a light chain comprising the amino acid sequence of SEQ ID NO:136.
  • the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:25, SEQ ID NO:31, SEQ ID NO:34, or SEQ ID NO:35; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:26, SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:36; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:27 or SEQ ID NO:37 , and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:28 or SEQ ID NO:38; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:29 or SEQ ID NO:39; (3)
  • the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:26, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:31, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:32, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid
  • NAI-1539756353v1 147 28 The method or use of embodiment 26 or 27, wherein the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:117, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:118. 29. The method or use of any one of embodiments 26-28, wherein the VH comprises the amino acid sequence of SEQ ID NO:117, and/or the VL comprises the amino acid sequence of SEQ ID NO:118. 30.
  • the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:9, SEQ ID NO:15, SEQ ID NO:18, or SEQ ID NO:19; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:10, SEQ ID NO:16, SEQ ID NO:17, or SEQ ID NO:20; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:11 or SEQ ID NO:21, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:12 or SEQ ID NO:22; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:13 or SEQ ID NO:23; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:14 or SEQ ID NO:24.
  • the antibody comprises at least one of (i)-(v):
  • the VH CDR1 comprises the amino acid sequence of SEQ ID NO:9
  • the VH CDR2 comprises the amino acid sequence of SEQ ID NO:10
  • the VH CDR3 comprises the amino acid sequence of SEQ ID NO:11
  • the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:12
  • the VL CDR2 comprises the amino acid sequence of SEQ ID NO:13
  • the VL CDR3 comprises the amino acid sequence of SEQ ID NO:14
  • the VH CDR1 comprises the amino acid sequence of SEQ ID NO:15
  • the VH CDR2 comprises the amino acid sequence of SEQ ID NO:16
  • the VH CDR3 comprises the amino acid sequence of SEQ ID NO:11
  • the VL CDR2 comprises the amino acid sequence NAI-1539756353v1
  • the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:46, SEQ ID NO:52, SEQ ID NO:55, or SEQ ID NO:56; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:47, SEQ ID NO:53, SEQ ID NO:54 or SEQ ID NO:57; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:48 or SEQ ID NO:58 , NAI-1539756353v1 149 and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:49 or SEQ ID NO:59; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:50 or SEQ ID NO:60; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:51 or SEQ ID NO:61.
  • the antibody comprises at least one of (i)-(v):
  • the VH CDR1 comprises the amino acid sequence of SEQ ID NO:46
  • the VH CDR2 comprises the amino acid sequence of SEQ ID NO:47
  • the VH CDR3 comprises the amino acid sequence of SEQ ID NO:48
  • the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:49
  • the VL CDR2 comprises the amino acid sequence of SEQ ID NO:50
  • the VL CDR3 comprises the amino acid sequence of SEQ ID NO:51
  • the VH CDR1 comprises the amino acid sequence of SEQ ID NO:52
  • the VH CDR2 comprises the amino acid sequence of SEQ ID NO:53
  • the VH CDR3 comprises the amino acid sequence of SEQ ID NO:48
  • the VL CDR2 comprises the amino acid sequence of SEQ ID NO:50
  • the VL comprises the amino acid sequence
  • the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:62, SEQ ID NO:68, SEQ ID NO:71, or SEQ ID NO:72; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:63, SEQ ID NO:69, SEQ ID NO:70, or SEQ ID NO:73; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:64 or SEQ ID NO:74, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:65 or SEQ ID NO:75; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:66 or SEQ ID NO:76; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:67 or SEQ ID NO:77.
  • a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:62, SEQ
  • the antibody comprises at least one of (i)-(v):
  • the VH CDR1 comprises the amino acid sequence of SEQ ID NO:62
  • the VH CDR2 comprises the amino acid sequence of SEQ ID NO:63
  • the VH CDR3 comprises the amino acid sequence of SEQ ID NO:64
  • the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:65
  • the VL CDR2 comprises the amino acid sequence NAI-1539756353v1 151 of SEQ ID NO:66
  • the VL CDR3 comprises the amino acid sequence of SEQ ID NO:67
  • the VH CDR1 comprises the amino acid sequence of SEQ ID NO:68
  • the VH CDR2 comprises the amino acid sequence of SEQ ID NO:69
  • the VH CDR3 comprises the amino acid sequence of SEQ ID NO:64
  • the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:65
  • the VL CDR2 comprises the amino acid sequence of SEQ ID NO:65
  • the antibody comprises (a) a VH comprising: NAI-1539756353v1 152 (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:25, SEQ ID NO:31, SEQ ID NO:34, or SEQ ID NO:35; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:78, SEQ ID NO:82, SEQ ID NO:83, or SEQ ID NO:84; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:79 or SEQ ID NO:85, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:80 or SEQ ID NO:86; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:29 or SEQ ID NO:39; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:81 or SEQ ID NO:87.
  • the antibody comprises at least one of (i)-(v):
  • the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25
  • the VH CDR2 comprises the amino acid sequence of SEQ ID NO:78
  • the VH CDR3 comprises the amino acid sequence of SEQ ID NO:79
  • the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:80
  • the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29
  • the VL CDR3 comprises the amino acid sequence of SEQ ID NO:81
  • the VH CDR1 comprises the amino acid sequence of SEQ ID NO:31
  • the VH CDR2 comprises the amino acid sequence of SEQ ID NO:82
  • the VH CDR3 comprises the amino acid sequence of SEQ ID NO:79
  • the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29
  • the VL comprises the VL C
  • any one of embodiments 42, 43, and 46 wherein the VH comprises the amino acid sequence of SEQ ID NO:127, and/or the VL comprises the amino acid sequence of SEQ ID NO:128.
  • the antibody comprises a heavy chain having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:138 and a light chain having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:140.
  • the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:138 and a light chain comprising the amino acid sequence of SEQ ID NO:140. 50.
  • the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:25, NAI-1539756353v1 154 SEQ ID NO:31, SEQ ID NO:34, or SEQ ID NO:35; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:88, SEQ ID NO:32, SEQ ID NO:93, or SEQ ID NO:94; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:89 or SEQ ID NO:95, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:90 or SEQ ID NO:96; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:91 or SEQ ID NO:97; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:92 or SEQ ID NO:98.
  • a VH comprising: (1) the VH CDR1 comprising the amino acid
  • the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:88, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:89; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:90, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:91, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:92; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:31, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:32, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:89; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:90, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:91, and
  • the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:99, SEQ ID NO:105, SEQ ID NO:108, or SEQ ID NO:109; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:100, SEQ ID NO:106, SEQ ID NO:107 or SEQ ID NO:110; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:101 or SEQ ID NO:111, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:102 or SEQ ID NO:112; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:103 or SEQ ID NO:113; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:104 or SEQ ID NO:114.
  • a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:99, SEQ
  • the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:99, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:100, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:101; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:102, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:103, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:104; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:105, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:106, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:101; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:102, the VL CDR2 comprises the amino amino acid sequence of SEQ ID NO:101; and the VL comprises the VL CDR1
  • any one of embodiments 1-57 wherein the antibody is a recombinant antibody, a monoclonal antibody, a chimeric antibody, a humanized antibody, a bispecific antibody, or a multispecific antibody.
  • the antibody is an IgG1 antibody, an IgG2 antibody, or an IgG4 antibody; optionally wherein the antibody is a human IgG1 antibody, a human IgG2 antibody, or a human IgG4 antibody. 60.
  • any one of embodiments 1-59 wherein the antibody comprises a kappa light chain or a lambda light chain, optionally wherein the antibody comprises a human kappa light chain or a human lambda light chain.
  • the antibody is attached to a half-life extending moiety.
  • the antibody is an antibody fragment, optionally wherein the antibody fragment comprises at least one antigen binding site that binds to LAIR1.
  • the antibody fragment is a Fab, a Fab’, a F(ab’)2, a Fv, a scFv, a (scFv)2, a single chain antibody, a dual variable region antibody, a diabody, or a nanobody. 64.
  • any one of embodiments 1-63 wherein the antibody inhibits binding of LAIR-1 to one or more LAIR ligands and optionally has at least one of the following properties: (i) binding human LAIR1; (ii) binding cyno LAIR1; (iii) not binding mouse LAIR1; (iv) not binding human LAIR-2; (v) being a LAIR1 antagonist; (vi) inhibiting LAIR1 activity; (vii) inhibiting LAIR1 signaling in cells that express LAIR1; (viii) inhibiting binding of LAIR1 to collagen; (ix) inhibiting binding of LAIR1 to MARCO; NAI-1539756353v1 158 (x) inhibiting binding of LAIR1 to COLEC12; (xi) inhibiting LAIR1-induced suppression of myeloid cells; (xii) inhibiting LAIR1-induced suppression of myeloid cell activity; (xiii) restoring FcR activation in myeloid cells; (xiv) restoring cytokine
  • human osteosarcoma is enriched with cells expressing LAIR1 protein.
  • LAIR1 expression essentially overlapped with IBA1 and CD163 expression in non-cancerous cells, indicating that the cells expressing LAIR1 are of myeloid origin ( Figures 1A and 1B).
  • OSCAR mediates an anti-LAIR1 antibody induced inflammatory activation in myeloid cells (data not shown)
  • OSCAR expression was assessed in ten biopsied human osteosarcoma samples. In situ hybridization was performed and the samples were hybridized with OSCAR probes (Cat No.553178; Advanced Cell Diagnostics).
  • Probes for PPIB were used as the house-keeping mRNA control on the Leica Bond platform.
  • the slides were evaluated for the spatial distribution of OSCAR mRNA.
  • OSCAR was widely expressed in non-cancerous cells surrounding cancer cells, which was consistent with the LAIR1 expression patten in intratumoral myeloid cells in human osteosarcoma samples. This result supports that LAIR1 plays an important role in suppression of myeloid cells in osteosarcoma.
  • LAIR1 mediates suppression of immune cells through interaction with collagen. See International Publication No. WO 2021/262597. Thus, collagen abundance was assessed in osteosarcoma resection specimens using immunohistochemistry.
  • the collagen expression level was compared across different cancer types, including osteosarcoma (OS), liposarcoma, pleomorphic sarcoma (PISarc), angiosarcoma, mesothelioma (MESO), pancreatic ductal adenocarcinoma (PDAC), gastric cancer, ovarian cancer, colorectal cancer (CRC), hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), lung squamous cell carcinoma (LuSCC), head and neck squamous cell carcinoma (HNSCC), lung adenocarcinoma (LUAD), glioblastoma (GBM), small cell lung cancer (SCLC).
  • OS osteosarcoma
  • PISarc pleomorphic sarcoma
  • angiosarcoma mesothelioma
  • MEO mesothelioma
  • PDAC pancreatic ductal adenocarcinoma
  • gastric cancer ovarian cancer
  • osteosarcoma was found to be one of the most stroma- rich cancers among the 33 indications compared including pancreatic adenocarcinoma (PAAD), sarcoma (SARC), mesothelioma (MESO), breast invasive carcinoma (BRCA), lung squamous cell carcinoma (LUSC), uterine carcinoma (UCS), lung adenocarcinoma (LUAD), head and neck squamous cell carcinoma (HNSC), stomach adenocarcinoma (STAD), esophageal carcinoma (ESCA), rectum adenocarcinoma (READ), testicular germ cell tumors (TGCT), colon adenocarcinoma (COAD), urothelial bladder carcinoma (BLCA), cholangiocarcinoma (CHOL), skin cutaneous melanoma
  • PAAD pancreatic adenocarcinoma
  • SARC sarcoma
  • MEO mesothelioma
  • BRCA
  • IP intraperitoneal
  • Group 2- anti-LAIR1 antibody murine anti-LAIR1 antibody clone 43H2, see WO 2021/262597) a. 10 mg/kg IP administration on days 7, 14, and 21 3) Group 3- anti-PD-1 antibody (Clone RMP1-14) a. 10 mg/kg IP administration on days 7, 11, 15, and 19 NAI-1539756353v1 161 4) Group 4- anti-LAIR1 antibody + anti-mouse PD-1 antibody (RMP1-14 clone, Bio X cell) a. Anti-LAIR1: 10 mg/kg IP on days 7, 14, and 21 b.
  • Anti-PD-1 10 mg/kg IP on days 7, 11, 15, and 19 [00422] All treatment groups are sacrificed 25-28 days post the inoculation. Various tissues including the lung tissue are collected and evaluated for tumor volume (burden) and tumor- infiltrating lymphocytes. It is observed that the anti-LAIR1 antibody administration reduces tumor growth and tumor metastasis in the mice. In addition, the anti-LAIR1 antibody increases the number of infiltrating lymphocytes in the tumors.
  • Co-administration of the anti- LAIR1 antibody and anti-PD-1 antibody further enhances the effect of the anti-LAIR1 antibody on reduction of tumor growth and tumor metastasis, indicating a synergistic effect resulting from myeloid reprogramming imposed by the anti-LAIR1 antibody and immune cell activation imposed by the anti-PD-1 antibody.
  • SEQUENCES [00423] Following are sequences disclosed in the application. CDR sequences are listed in Tables 1-7 as SEQ ID NOs:9-114.

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Abstract

The present disclosure relates to methods of using a combination of agents that bind leukocyte-associated immunoglobulin-like receptor 1 (LAIR1 or LAIR-1) (e.g., anti-LAIR1 antibodies) and PD-1 antagonists for treating osteosarcoma.

Description

Attorney Docket No.13370-177-228 METHODS OF TREATING OSTEOSARCOMA USING LAIR1 BINDING AGENTS AND PD-1 ANTAGONISTS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to United States Provisional Application No. 63/495,526 filed April 11, 2023, the content of which is incorporated by reference in its entirety herein. SEQUENCE LISTING [0002] This application contains a computer readable Sequence Listing, which has been submitted in XML file format with this application, the entire content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “13370-177-228_SEQLISTING.xml”, was created on April 2, 2024 and is 182,313 bytes in size. 1. FIELD [0003] The present disclosure relates to methods of using a combination of agents that bind leukocyte-associated immunoglobulin-like receptor 1 (LAIR1 or LAIR-1) (e.g., anti-LAIR1 antibodies) and PD-1 antagonists for treating osteosarcoma. 2. BACKGROUND [0004] A majority of cells in the immune system express at least one, and often many, inhibitory receptors. These inhibitory receptors, including leukocyte-associated immunoglobulin-like receptor-1 (LAIR1; also known as CD305), may play important roles in the inhibitory mechanisms of the immune system. However, therapeutic success with binding agents targeting LAIR1 has not yet been achieved. Accordingly, there remains a need in the art for agents to boost the immune response to uncontrolled cell proliferation, such as tumor growth or cancer. 3. SUMMARY OF THE INVENTION [0005] In one aspect, the present disclosure provides a method of disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a subject having osteosarcoma, comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than NAI-1539756353v1 1 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M; and (b) a PD-1 antagonist. [0006] In another aspect, the present disclosure provides a method of disrupting, inhibiting, or blocking collagen-induced LAIR1 activity in a subject having osteosarcoma, comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M; and (b) a PD-1 antagonist. [0007] In another aspect, the present disclosure provides a method of disrupting, inhibiting, or blocking LAIR1-induced suppression of an immune cell or immune cell activity in a subject having osteosarcoma, comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M; and (b) a PD-1 antagonist, wherein the immune cell or immune cell activity is a myeloid cell or myeloid cell activity, a natural killer (NK) cell or NK cell activity, a T-cell or T-cell activity, a myeloid-derived suppressor cell (MDSC) or MDSC activity, a regulatory T-cell (Treg) or Treg activity. In certain embodiments, (i) the myeloid cell is a monocyte, a macrophage, a dendritic cell, or an APC; and/or (ii) the T-cell is a cytotoxic T-cell (CTL). [0008] In another aspect, the present disclosure provides a method of treating osteosarcoma in a subject, comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10- 8 M; and (b) a PD-1 antagonist. [0009] In another aspect, the present disclosure provides a method of (a) inhibiting tumor growth, (b) increasing or enhancing an immune response to a tumor or tumor cells, (c) activating or enhancing a persistent or long-term immune response to a tumor or tumor cells, (d) inhibiting tumor relapse or tumor regrowth, and/or (e) inducing a persistent or long-term immunity that inhibits tumor relapse or tumor regrowth, in a subject having osteosarcoma, the method comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human NAI-1539756353v1 2 LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10- 8 M; and (b) a PD-1 antagonist. [0010] In another aspect, the present disclosure provides a method of activating immune cells in the tumor microenvironment in a subject having osteosarcoma, comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M; and (b) a PD-1 antagonist, wherein the immune cells are myeloid cells, NK cells, and/or T-cells. In certain embodiments, (i) the myeloid cells are monocytes, macrophages, dendritic cells, or antigen presenting cells (APCs); and/or (ii) the T-cells are cytotoxic T-cells (CTLs). [0011] In another aspect, the present disclosure provides use of (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof and (b) a PD-1 antagonist for (a) treatment of osteosarcoma; (b) disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a subject having osteosarcoma; (c) disrupting, inhibiting, or blocking collagen- induced LAIR1 activity in a subject having osteosarcoma; (d) disrupting, inhibiting, or blocking LAIR1-induced suppression of an immune cell or immune cell activity in a subject having osteosarcoma; (e) inhibiting tumor growth, increasing or enhancing an immune response to a tumor or tumor cells, activating or enhancing a persistent or long-term immune response to a tumor or tumor cells, inhibiting tumor relapse or tumor regrowth, and/or inducing a persistent or long-term immunity that inhibits tumor relapse or tumor regrowth, in a subject having osteosarcoma; and/or (f) activating immune cells in the tumor microenvironment in a subject having osteosarcoma, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M. [0012] In another aspect, the present disclosure provides use of (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof and (b) a PD-1 antagonist in the manufacture of a medicament (a) treatment of osteosarcoma; (b) disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a subject having osteosarcoma; (c) disrupting, inhibiting, or blocking collagen-induced LAIR1 activity in a subject having osteosarcoma; (d) disrupting, inhibiting, or blocking LAIR1-induced suppression of an immune cell or immune cell activity in a subject having osteosarcoma; (e) inhibiting tumor growth, increasing or NAI-1539756353v1 3 enhancing an immune response to a tumor or tumor cells, activating or enhancing a persistent or long-term immune response to a tumor or tumor cells, inhibiting tumor relapse or tumor regrowth, and/or inducing a persistent or long-term immunity that inhibits tumor relapse or tumor regrowth, in a subject having osteosarcoma; and/or (f) activating immune cells in the tumor microenvironment in a subject having osteosarcoma, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M. [0013] In another aspect, the present disclosure provides a method of disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a cell mixture comprising osteosarcoma cells to enhance the immune response to the osteosarcoma cells, the method comprising contacting the cell mixture with (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M; and (b) a PD-1 antagonist. [0014] In certain embodiments, the cell mixture comprises at least one of myeloid cells, NK cells, T-cells, cytotoxic T-cells, MDSCs, and T-regs. In certain embodiments, the myeloid cells comprise at least one of monocytes, macrophages, dendritic cells, and APCs. [0015] In another aspect, the present disclosure provides a method of disrupting, inhibiting, or blocking LAIR1-induced suppression of an immune cell or immune cell activity to enhance the immune response to osteosarcoma cells, comprising contacting a cell mixture comprising the osteosarcoma cells and the immune cell with (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M; and (b) a PD-1 antagonist, wherein the immune cell or immune cell activity is a myeloid cell or myeloid cell activity, a NK cell or NK cell activity, a T-cell or T- cell activity, a MDSC or MDSC activity, a Treg or Treg activity, and wherein the immune cell is an intratumoral cell, and is or was present in osteosarcoma or a tumor microenvironment thereof. In certain embodiments, (i) the myeloid cell is a monocyte, a macrophage, a dendritic cell, or an APC; and/or (ii) the T-cell is a cytotoxic T-cell (CTL). [0016] In certain embodiments, the PD-1 antagonist is an antagonistic anti-PD-1 antibody. In certain embodiments, the antagonistic anti-PD-1 antibody is selected from the group NAI-1539756353v1 4 consisting of pembrolizumab, pidilizumab, nivolumab, durvalumab, budigalima, cemiplimab, tislelizumab, spartalizumab, and STI-A1110. In certain embodiments, the antagonistic anti- PD-1 antibody is administered to the subject prior to, concurrently, or subsequent to the administration of the antibody that binds to LAIR1. [0017] In certain embodiments, the antibody comprises: (i) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:119; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:120, (ii) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:117; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:118, (iii) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:115; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:116, (iv) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:121; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:122, (v) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:123; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:124, (vi) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:125; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:126, (vii) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:127; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:128, (viii) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:129; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:130, and/or (ix) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:131; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:132. [0018] In certain embodiments, the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:25, SEQ ID NO:31, SEQ ID NO:34, or SEQ ID NO:35; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:44, or SEQ ID NO:45; (3) the VH CDR3 comprising NAI-1539756353v1 5 the amino acid sequence of SEQ ID NO:27, or SEQ ID NO:37, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:28 or SEQ ID NO:38; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:42 or SEQ ID NO:39; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:30 or SEQ ID NO:40. [0019] In certain embodiments, the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:41, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27, the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:42, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:31, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:43, the VH CDR3 comprises the amino acid of SEQ ID NO:27; the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:42, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; (iii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:44, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:42, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; (iv) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:34, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:41, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:42, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; and (v) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:35, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:45, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:37; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:38, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:39, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:40. [0020] In certain embodiments, the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:119, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:120. In certain embodiments, the VH comprises the amino acid sequence of SEQ ID NO:119, and/or the VL comprises the amino acid sequence of SEQ ID NO:120. In certain embodiments, the antibody comprises a heavy chain having at NAI-1539756353v1 6 least 90% sequence identity to the amino acid sequence of SEQ ID NO:134 and a light chain having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:136. In certain embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:134 and a light chain comprising the amino acid sequence of SEQ ID NO:136. [0021] In certain embodiments, the antibody comprises: (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:25, SEQ ID NO:31, SEQ ID NO:34, or SEQ ID NO:35; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:26, SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:36; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:27 or SEQ ID NO:37, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:28 or SEQ ID NO:38; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:29 or SEQ ID NO:39; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:30 or SEQ ID NO:40. [0022] In certain embodiments, the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:26, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:31, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:32, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; (iii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:33, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; (iv) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:34, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:26, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; and (v) the VH CDR1 NAI-1539756353v1 7 comprises the amino acid sequence of SEQ ID NO:35, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:36, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:37; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:38, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:39, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:40. [0023] In certain embodiments, the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:117, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:118. In certain embodiments, the VH comprises the amino acid sequence of SEQ ID NO:117, and/or the VL comprises the amino acid sequence of SEQ ID NO:118. [0024] In certain embodiments, the antibody comprises: (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:9, SEQ ID NO:15, SEQ ID NO:18, or SEQ ID NO:19; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:10, SEQ ID NO:16, SEQ ID NO:17, or SEQ ID NO:20; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:11 or SEQ ID NO:21, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:12 or SEQ ID NO:22; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:13 or SEQ ID NO:23; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:14 or SEQ ID NO:24. [0025] In certain embodiments, the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:9, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:10, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:11; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:12, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:13, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:14; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:15, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:16, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:11; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:12, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:13, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:14; (iii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:9, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:17, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:11; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:12, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:13, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:14; (iv) the VH CDR1 comprises the NAI-1539756353v1 8 amino acid sequence of SEQ ID NO:18, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:10, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:11; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:12, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:13, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:14; and (v) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:19, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:20, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:21; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:22, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:23, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:24. [0026] In certain embodiments, the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:115, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:116. In certain embodiments, the VH comprises the amino acid sequence of SEQ ID NO:115, and/or the VL comprises the amino acid sequence of SEQ ID NO:116. [0027] In certain embodiments, the antibody comprises: (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:46, SEQ ID NO:52, SEQ ID NO:55, or SEQ ID NO:56; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:47, SEQ ID NO:53, SEQ ID NO:54 or SEQ ID NO:57; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:48 or SEQ ID NO:58, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:49 or SEQ ID NO:59; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:50 or SEQ ID NO:60; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:51 or SEQ ID NO:61. [0028] In certain embodiments, the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:46, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:47, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:48; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:49, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:50, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:51; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:52, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:53, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:48; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:49, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:50, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:51; (iii) the VH CDR1 comprises NAI-1539756353v1 9 the amino acid sequence of SEQ ID NO:46, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:54, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:48; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:49, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:50, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:51; (iv) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:55, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:47, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:48; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:49, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:50, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:51; and (v) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:56, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:57, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:58; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:59, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:60, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:61. [0029] In certain embodiments, the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:121, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:122. In certain embodiments, the VH comprises the amino acid sequence of SEQ ID NO:121, and/or the VL comprises the amino acid sequence of SEQ ID NO:122. [0030] In certain embodiments, the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:62, SEQ ID NO:68, SEQ ID NO:71, or SEQ ID NO:72; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:63, SEQ ID NO:69, SEQ ID NO:70, or SEQ ID NO:73; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:64 or SEQ ID NO:74, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:65 or SEQ ID NO:75; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:66 or SEQ ID NO:76; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:67 or SEQ ID NO:77. [0031] In certain embodiments, the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:62, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:63, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:64; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:65, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:66, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:67; (ii) the VH CDR1 NAI-1539756353v1 10 comprises the amino acid sequence of SEQ ID NO:68, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:69, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:64; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:65, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:66, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:67; (iii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:62, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:70, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:64; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:65, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:66, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:67; (iv) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:71, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:63, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:64; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:65, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:66, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:67; and (v) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:72, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:73, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:74; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:75, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:76, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:77. [0032] In certain embodiments, the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:123, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:124. In certain embodiments, the VH comprises the amino acid sequence of SEQ ID NO:123, and/or the VL comprises the amino acid sequence of SEQ ID NO:124. [0033] In certain embodiments, the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:25, SEQ ID NO:31, SEQ ID NO:34, or SEQ ID NO:35; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:78, SEQ ID NO:82, SEQ ID NO:83, or SEQ ID NO:84; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:79 or SEQ ID NO:85, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:80 or SEQ ID NO:86; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:29 or SEQ ID NO:39; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:81 or SEQ ID NO:87. NAI-1539756353v1 11 [0034] In certain embodiments, the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:78, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:79; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:80, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:81; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:31, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:82, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:79; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:80, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:81; (iii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:83, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:79; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:80, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:81; (iv) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:34, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:78, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:79; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:80, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:81; and (v) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:35, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:84, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:85; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:86, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:39, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:87. [0035] In certain embodiments, the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:125, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:126. In certain embodiments, the VH comprises the amino acid sequence of SEQ ID NO:125, and/or the VL comprises the amino acid sequence of SEQ ID NO:126. [0036] In certain embodiments, the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:127, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:128. In certain embodiments, the VH comprises the NAI-1539756353v1 12 amino acid sequence of SEQ ID NO:127, and/or the VL comprises the amino acid sequence of SEQ ID NO:128. In certain embodiments, the antibody comprises a heavy chain having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:138 and a light chain having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:140. In certain embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:138 and a light chain comprising the amino acid sequence of SEQ ID NO:140. [0037] In certain embodiments, the antibody comprises (a) a VH comprising(1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:25, SEQ ID NO:31, SEQ ID NO:34, or SEQ ID NO:35; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:88, SEQ ID NO:32, SEQ ID NO:93, or SEQ ID NO:94; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:89 or SEQ ID NO:95, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:90 or SEQ ID NO:96; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:91 or SEQ ID NO:97; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:92 or SEQ ID NO:98. [0038] In certain embodiments, the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:88, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:89; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:90, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:91, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:92; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:31, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:32, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:89; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:90, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:91, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:92; (iii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:93, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:89; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:90, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:91, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:92; (iv) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:34, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:88, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:89; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NAI-1539756353v1 13 NO:90, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:91, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:92; and (v) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:35, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:94, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:95; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:96, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:97, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:98. [0039] In certain embodiments, the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:129, and/or the light chain variable region has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:130. In certain embodiments, the VH comprises the amino acid sequence of SEQ ID NO:129, and/or the VL comprises the amino acid sequence of SEQ ID NO:130. [0040] In certain embodiments, the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:99, SEQ ID NO:105, SEQ ID NO:108, or SEQ ID NO:109; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:100, SEQ ID NO:106, SEQ ID NO:107 or SEQ ID NO:110; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:101 or SEQ ID NO:111, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:102 or SEQ ID NO:112; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:103 or SEQ ID NO:113; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:104 or SEQ ID NO:114. [0041] In certain embodiments, the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:99, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:100, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:101; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:102, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:103, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:104; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:105, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:106, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:101; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:102, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:103, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:104; (iii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:99, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:107, the VH CDR3 comprises the amino acid sequence of SEQ NAI-1539756353v1 14 ID NO:101; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:102, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:103, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:104; (iv) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:108, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:100, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:101; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:102, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:103, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:104; and (v) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:109, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:110, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:111; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:112, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:113, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:114. [0042] In certain embodiments, the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:131, and/or the light chain variable region has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:132. In certain embodiments, the VH comprises the amino acid sequence of SEQ ID NO:131, and/or the VL comprises the amino acid sequence of SEQ ID NO:132. [0043] In certain embodiments, the antibody is a recombinant antibody, a monoclonal antibody, a chimeric antibody, a humanized antibody, a bispecific antibody, or a multispecific antibody. In certain embodiments, the antibody is an IgG1 antibody, an IgG2 antibody, or an IgG4 antibody; optionally wherein the antibody is a human IgG1 antibody, a human IgG2 antibody, or a human IgG4 antibody. In certain embodiments, the antibody comprises a kappa light chain or a lambda light chain, optionally wherein the antibody comprises a human kappa light chain or a human lambda light chain. In certain embodiments, the antibody is attached to a half-life extending moiety. [0044] In certain embodiments, the antibody is an antibody fragment. In certain embodiments, the antibody fragment comprises at least one antigen binding site that binds to LAIR1. [0045] In certain embodiments, the antibody fragment is a Fab, a Fab’, a F(ab’)2, a Fv, a scFv, a (scFv)2, a single chain antibody, a dual variable region antibody, a diabody, or a nanobody. [0046] In certain embodiments, the antibody inhibits binding of LAIR-1 to one or more LAIR ligands and optionally has at least one of the following properties: (i) binding human NAI-1539756353v1 15 LAIR1; (ii) binding cyno LAIR1; (iii) not binding mouse LAIR1; (iv) not binding human LAIR-2; (v) being a LAIR1 antagonist; (vi) inhibiting LAIR1 activity; (vii) inhibiting LAIR1 signaling in cells that express LAIR1; (viii) inhibiting binding of LAIR1 to collagen; (ix) inhibiting binding of LAIR1 to MARCO; (x) inhibiting binding of LAIR1 to COLEC12; (xi) inhibiting LAIR1-induced suppression of myeloid cells; (xii) inhibiting LAIR1-induced suppression of myeloid cell activity; (xiii) restoring FcR activation in myeloid cells; (xiv) restoring cytokine and/or chemokine production in myeloid cells; (xv) inhibiting LAIR1- induced suppression of NK cells; (xvi) inhibiting LAIR1-induced suppression of NK activity; (xvii) inhibiting LAIR1-induced suppression of T-cell activity; and (xviii) inhibiting MDSC activity, optionally wherein the one or more LAIR ligands is selected from the group consisting of collagen, MARCO, COLEC12, MBL, SPD, and C1 complex. [0047] In certain embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. [0048] In certain embodiments, the antibody or the pharmaceutical composition is administered at a therapeutically effective amount. 4. BRIEF DESCRIPTION OF THE FIGURES [0049] Figures 1A & 1B provide representative images of immunostaining of LAIR1, IBA1 and CD163 in consecutive sections of a human osteosarcoma biopsy sample. Figure 1A shows low magnification images of IBA1 (left panel), LAIR1 (middle panel) and CD163 (right panel). Figure 1B shows high magnification images of LAIR1 (upper panel) and IBA1 (lower panel). [0050] Figure 2 provides representative images of OSCAR expression by in situ hybridization in consecutive sections of a human osteosarcoma biopsy sample. PPIB was used as a control. [0051] Figures 3A & 3B depict that collagen abundance was assessed in osteosarcoma resection specimens using immunohistochemistry. Figure 3A shows immunostaining of alpha-1 type I collagen (red) in osteosarcoma samples from six patients. Figure 3B shows percentage of area positive for picrosirius red (PSR) or alpha-1 type I collagen (COL1A1) in different cancer indications via immunostaining. Values presented are Mean +/- SD. [0052] Figure 4 shows the scores of a 58-gene set associated with cancer stroma shown in different cancer types. 5. DETAILED DESCRIPTION NAI-1539756353v1 16 [0053] The present disclosure provides methods of using LAIR1 binding agents (e.g., LAIR1 binding agents disclosed in Section 5.3) and compositions (e.g., pharmaceutical compositions, see Section 5.5) comprising thereof for treating osteosarcoma. The LAIR1 binding agents disclosed herein include antibodies (e.g., monospecific or multispecific, including bispecific) and fragments thereof that bind to LAIR1, including antibodies and fragments thereof that bind to human LAIR1. The LAIR1 binding agents disclosed herein inhibit the activity of LAIR1 (e.g., inhibit the LAIR1 suppressive activity, inhibit the binding of LAIR1 to at least one LAIR ligand, such as collagen, MARCO, COLEC12, MBL, SPD, and C1 complex). [0054] Section or subsection headings used herein are for organizational purposes only and should not be construed as limiting and/or separating the subject matter disclosed herein. For purposes of clarity of disclosure and not by way of limitation, the detailed description is divided into the following subsections: 5.1 Definitions; 5.2 LAIR1 Ligands; 5.3 LAIR1 Binding Agents; 5.4 Polynucleotides, Vectors, and Cells; 5.5 Pharmaceutical Compositions; 5.6 Methods of Treating Osteosarcoma; and 5.7 Kits. 5.1 Definitions [0055] Techniques and procedures described or referenced herein include those that are generally well understood and/or commonly employed using conventional methodology by those skilled in the art, such as, for example, the widely utilized methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual (3d ed.2001); Current Protocols in Molecular Biology (Ausubel et al. eds., 2003); Therapeutic Monoclonal Antibodies: From Bench to Clinic (An ed.2009); Monoclonal Antibodies: Methods and Protocols (Albitar ed. 2010); and Antibody Engineering Vols.1 and 2 (Kontermann and Dübel eds., 2d ed.2010). Unless otherwise defined herein, technical and scientific terms used in the present description have the meanings that are commonly understood by those of ordinary skill in the art. Whenever appropriate, terms used in the singular will also include the plural and vice versa. In the event that any description of a term set forth conflicts with any document incorporated herein by reference, the description of the term set forth below shall control. NAI-1539756353v1 17 [0056] The term “binding agent” as used herein refers to a molecule (e.g., an antibody) that binds an antigen (e.g., LAIR1). In certain embodiments, a binding agent is an antibody (including an antibody fragment, such as an antigen-binding fragment or an epitope-binding fragment) or other peptide-based molecule as well as a conjugate of an antibody, antibody fragment, or peptide-based molecule (e.g., an antibody-drug conjugate) that binds to an antigen (e.g., LAIR1). In certain embodiments, a binding agent comprises an alternative protein scaffold or artificial scaffold (e.g., a non-immunoglobulin backbone). In certain embodiments, a binding agent is a fusion protein comprising an antigen-binding site. In certain embodiments, a binding agent is a bispecific or multispecific molecule comprising at least one antigen-binding site. [0057] The terms “antibody,” “immunoglobulin,” and “Ig” are used interchangeably herein, and are used in the broadest sense and encompasses, for example polyclonal antibodies, recombinant antibodies, monoclonal antibodies (including agonist, antagonist, neutralizing antibodies, full-length monoclonal antibodies), synthetic antibodies, chimeric antibodies, humanized antibodies, human antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), antibody compositions having polyepitopic or monoepitopic specificity, single domain antibodies (e.g., VHH), or human versions of antibodies having full-length heavy and/or light chains. [0058] VHH refers to a domain antibody derived from a variable region of a heavy chain only antibody. Exemplary single domain antibodies include, but are not limited to, antibodies naturally devoid of light chains such as those from Camelidae species (e.g., llama), single domain antibodies derived from conventional 4-chain antibodies, engineered antibodies and single domain scaffolds other than those derived from antibodies. Single domain antibodies may be derived from any species including, but not limited to mouse, human, camel, llama, goat, rabbit, and bovine. VHH can also be derived from other species besides Camelidae that may produce heavy chain antibodies naturally devoid of light chain. [0059] Antibodies also include antibody fragments (and/or polypeptides that comprise antibody fragments) that retain antigen (e.g., LAIR1) binding characteristics. Non-limiting examples of antibody fragments include antigen-binding regions and/or effector regions of the antibody, e.g., Fab, Fab’, F(ab’)2, Fv, scFv, (scFv)2, single chain antibody molecule, dual variable domain antibody, single variable domain, linear antibody, V region, a multispecific antibody formed from antibody fragments, F(ab)2, Fd, Fc, diabody, di-diabody, disulfide- linked Fvs (dsFv), single-domain antibody (e.g., nanobody) or other fragments (e.g., fragments consisting of the variable regions of the heavy and light chains that are non- NAI-1539756353v1 18 covalently coupled). A variable (V) region domain may be any suitable arrangement of immunoglobulin heavy (VH) and/or light (VL) variable domains. For example, antibodies also include tetrameric antibodies comprising two heavy chain and two light chain molecules, an antibody light chain monomer, and an antibody heavy chain monomer. In certain embodiments, the VH and VL may be covalently coupled directly or through a linker to form a single chain Fv (scFv). As used herein, scFv proteins are included in the category “antibody fragments.” An antibody fragment can also be a peptide comprising one or more complementarity determining regions (CDRs) of an antibody. CDRs (also termed “minimal recognition units” or “hypervariable regions”) can be obtained by constructing polynucleotides that encode one or more CDRs of interest. Such polynucleotides are prepared, for example, by using the polymerase chain reaction to synthesize the variable region using mRNA of antibody-producing cells as a template (see, for example, Larrick et al., Methods: A Companion to Methods in Enzymology, 2:106 (1991); Courtenay-Luck, “Genetic Manipulation of Monoclonal Antibodies,” in Monoclonal Antibodies Production, Engineering and Clinical Application, Ritter et al. (eds.), page 166, Cambridge University Press (1995); and Ward et al., “Genetic Manipulation and Expression of Antibodies,” in Monoclonal Antibodies: Principles and Applications, Birch et al., (eds.), page 137, Wiley- Liss, Inc. (1995)). Antibody fragments may be incorporated, for example, into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, variable domains of new antigen receptors (v-NAR), and bis-single chain Fv regions (see, e.g., Hollinger and Hudson, Nature Biotechnology, 23(9):1126-1136, 2005). [0060] The terms “antigen-binding fragment,” “antigen-binding domain,” “antigen-binding region,” and similar terms refer to that portion of an antibody, which comprises the amino acid residues that interact with an antigen and confer on the binding fragment, domain, or region its specificity and affinity for the antigen (e.g., the CDRs). “Antigen-binding fragment” as used herein includes “antibody fragment,” which comprises a portion of an antibody including one or more CDRs, such as the antigen-binding or variable region of the antibody. [0061] In certain embodiments, antibodies comprising a VH and/or VL further contain a light chain and/or a heavy chain constant region, such as one or more constant regions, including one or more IgG1, IgG2, IgG3 and/or IgG4 constant regions. In certain embodiments, antibodies can include epitope-binding fragments of any of the above. The antibodies disclosed herein can be of any class (e.g., IgG, IgE, IgM, IgD, and IgA) or any subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) of immunoglobulin molecule. NAI-1539756353v1 19 [0062] The term “monospecific” when used in reference to a binding agent (e.g., an antibody) means that the binding agent (e.g., an antibody) having one or more binding sites, each of which binds to the same epitope of the same antigen. [0063] The term “multispecific” when used in reference to a binding agent (e.g., an antibody) means that the binding agent can specifically bind to at least two distinct epitopes, for example two binding sites each formed by a pair of an antibody heavy chain variable domain (VH) and an antibody light chain variable domain (VL) or each formed by a pair of VHH domains binding to different antigens or to different epitopes on the same antigen. When a bispecific binding agent (e.g., an antibody) comprises two antigen-binding sites, each may bind to a different epitope. Such a bispecific binding agent (e.g., an antibody) may bind to two different epitopes on the same antigen (e.g., epitopes on LAIR1 or MARCO). [0064] The term “monoclonal antibody” as used herein refers to a substantially homogenous antibody population involved in the highly specific recognition and binding of a single antigenic determinant or epitope. Furthermore, “monoclonal antibody” refers to such antibodies made by any kind of techniques, including but not limited to, hybridoma production, phage library display, recombinant expression, and transgenic animals. [0065] The term “chimeric antibody” refers to an antibody in which a portion of the heavy and/or light chain is derived from a first source or species, while the remainder of the heavy and/or light chain is derived from a different source or species. [0066] The term “humanized antibody” as used herein refers to an antibody that comprises a human heavy chain variable region and a light chain variable region wherein the native CDR amino acid residues are replaced by residues from corresponding CDRs from a non- human antibody (e.g., mouse, rat, rabbit, or non-human primate), and the non-human antibody has the desired specificity, affinity, and/or activity. In certain embodiments, one or more framework region amino acid residues of the human heavy chain or light chain variable regions are replaced by corresponding residues from the non-human antibody. Furthermore, humanized antibodies can comprise amino acid residues that are not found in the human antibody or non-human antibody. In certain embodiments, these modifications are made to further refine and/or optimize antibody characteristics. In certain embodiments, the humanized antibody comprises at least a portion of a human immunoglobulin constant region (e.g., CH1, CH2, CH3, Fc, and/or hinge region). [0067] The term “human antibody” as used herein refers to an antibody that possesses an amino acid sequence that corresponds to an antibody produced by a human and/or an antibody that has been made using any of the techniques that are known to those of skill in NAI-1539756353v1 20 the art for making human antibodies. These techniques include, but not limited to, phage display libraries, yeast display libraries, transgenic animals, recombinant protein production, and B-cell hybridoma technology. [0068] The terms “identical” or percent “identity” as used herein in the context of two or more nucleic acids or polypeptides, refer to two or more sequences or subsequences that are the same or have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned (introducing gaps, if necessary) for maximum correspondence, not considering any conservative amino acid substitutions as part of the sequence identity. The percent identity can be measured by sequence comparison software or algorithms, or visual inspection. Algorithms and software known in the art that can align amino acid or nucleotide sequences include, but are not limited to, BLAST, ALIGN, Megalign, BestFit, GCG Wisconsin Package, and variants thereof. In certain embodiments, two nucleic acids or polypeptides are substantially identical, meaning that they have at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% (e.g., at least 95%, 96%, 97%, 98%, or 99%) nucleotide or amino acid residue identity, when compared and aligned for maximum correspondence, as measured using a sequence comparison algorithm or by visual inspection. In certain embodiments, identity exists over a region of the amino acid sequences that is at least about 10 residues, at least about 20 residues, at least about 40 residues, at least about 60 residues, or at least about 80 residues in length. In certain embodiments, identity exists over a region longer than 60 residues, such as at least about 100 residues. In certain embodiments, the sequences are substantially identical over the full length of the sequences being compared, such as the region of a target protein or an antibody. In certain embodiments, identity exists over a region of the nucleotide sequences that is at least about 100 bases, at least about 200 bases, at least about 400 bases, at least about 600 bases in length, or at least about 800 base in length. In certain embodiments, identity exists over a longer region than 600 bases, such as at least about 1000 bases or more. In certain embodiments the sequences are substantially identical over the full-length of the sequences being compared, such as a nucleotide sequence encoding a protein of interest. [0069] A “conservative amino acid substitution” is one in which one amino acid residue is replaced with another amino acid residue having a side chain with similar chemical characteristics. Families of amino acid residues having similar side chains include basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, NAI-1539756353v1 21 phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Generally, conservative substitutions do not abrogate the binding of the polypeptide, soluble protein, or antibody containing the amino acid sequence, to the target binding site. Methods of identifying amino acid conservative substitutions that do not eliminate binding are well- known in the art. [0070] As used herein, an “antigen” is a moiety or molecule that contains an epitope to which a binding agent (e.g., an antibody) can bind. In certain embodiments, the antigen, to which a binding agent (e.g., an antibody) disclosed herein binds, is LAIR1 (e.g., human LAIR1), or a fragment thereof, including a fragment that comprises one or more domains of LAIR1. [0071] As used herein, an “epitope” refers to a localized region of an antigen to which an antibody can bind. An epitope can be a linear epitope or a conformational, non-linear, or discontinuous, epitope. In the case of a polypeptide antigen, for example, an epitope can be contiguous amino acids of the polypeptide (a “linear” epitope) or an epitope can comprise amino acids from two or more non-contiguous regions of the polypeptide (a “conformational,” “non-linear” or “discontinuous” epitope). It will be appreciated by one of skill in the art that a linear epitope may or may not be dependent on secondary, tertiary, or quaternary structure. In certain embodiments, an antibody binds to a group of amino acids regardless of whether they are folded in a natural three-dimensional protein structure. In certain embodiments, an antibody requires amino acid residues making up the epitope to exhibit a particular conformation (e.g., bend, twist, turn, or fold) in order to recognize and bind the epitope. [0072] “Epitope binning” is the process of grouping antibodies based on the epitopes they recognize. Particularly, epitope binning comprises methods and systems for discriminating the epitope recognition properties of different antibodies, using competition assays combined with computational processes for clustering antibodies based on their epitope recognition properties and identifying antibodies having distinct binding specificities. [0073] An antibody binds “an epitope” or “essentially the same epitope” or “the same epitope” as a reference antibody, when the two antibodies recognize identical, overlapping or adjacent epitopes in a three-dimensional space. Competition assays can be used for determining whether two antibodies bind to identical, overlapping or adjacent epitopes in a three-dimensional space, using labeled antigen or labeled antibody. The antigen can immobilized on a 96-well plate, or expressed on a cell surface, and the ability of unlabeled NAI-1539756353v1 22 antibodies to block the binding of labeled antibodies is measured using radioactive, fluorescent, or enzymatic labels. [0074] As used herein, the terms “specifically binds,” “specifically recognizes,” “immunospecifically binds,” “selectively binds,” “immunospecifically recognizes” and “immunospecific” are analogous terms in the context of antibodies and refer to molecules that bind to an antigen (e.g., epitope) as such binding is understood by one skilled in the art. In certain embodiments, “specifically binds” means, for instance that a polypeptide or molecule interacts more frequently, more rapidly, with greater duration, with greater affinity, or with some combination of the above to the epitope, protein, or target molecule than with alternative substances, including related and unrelated proteins. For example, a molecule that specifically binds to an antigen may bind to other peptides or polypeptides, generally with lower affinity as determined by immunoassays, BIACORE™, KinExA 3000 instrument (Sapidyne Instruments, Boise, ID), the OctetQK384 system (ForteBio, Menlo Park, CA), or other assays known in the art. In certain embodiments, an antibody or antigen-binding domain binds to or specifically binds to an antigen when it binds to the antigen with higher affinity than to any cross-reactive antigen as determined using experimental techniques, such as radioimmunoassays (RIAs) and enzyme linked immunosorbent assays (ELISAs). Typically a specific or selective reaction will be at least twice background signal or noise and may be more than 10 times background. See, e.g., Fundamental Immunology 332-36 (Paul ed., 2d ed.1989) for a discussion regarding binding specificity. In certain embodiments, the extent of binding of an antibody or antigen-binding domain to a “non-target” protein is less than about 10% of the binding of the antibody or antigen-binding domain to its particular target antigen, for example, as determined by fluorescence activated cell sorting (FACS) analysis or RIAs. In certain embodiments, molecules that specifically bind to an antigen bind to the antigen with a Ka that is at least 2 logs, 2.5 logs, 3 logs, 4 logs or greater than the Ka when the molecules bind to another antigen. In certain embodiments, molecules that specifically bind to an antigen do not cross react with other proteins. In certain embodiments “specifically binds” means, for instance, that a polypeptide or molecule binds a protein or target with a KD of about 0.1mM or less, but more usually less than about 1µM. In certain embodiments, “specifically binds” means that a polypeptide or molecule binds a target with a KD of at least about 0.1µM or less, at least about 0.01µM or less, or at least about 1nM or less. Because of the sequence identity between homologous proteins in different species, specific binding can include a polypeptide or molecule that recognizes a protein or target in more than one species. Likewise, because of homology within certain regions of polypeptide NAI-1539756353v1 23 sequences of different proteins, specific binding can include a polypeptide or molecule that recognizes more than one protein or target. It is understood that, in certain embodiments, a polypeptide or molecule that specifically binds a first target may or may not specifically bind a second target. As such, “specific binding” does not necessarily require (although it can include) exclusive binding, e.g., binding to a single target. Thus, a polypeptide or molecule can, in certain embodiments, specifically bind more than one target. In certain embodiments, multiple targets can be bound by the same antigen-binding site on the polypeptide or molecule. For example, an antibody can, in certain instances, comprise two identical antigen- binding sites, each of which specifically binds the same epitope on two or more proteins. In certain alternative embodiments, an antibody can be bispecific and comprise at least two antigen-binding sites with differing specificities. Generally, but not necessarily, reference to “binding” means “specific binding”. [0075] “Binding affinity” generally refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., a binding agent such as an antibody) and its binding partner (e.g., an antigen such as LAIR1). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a binding molecule X for its binding partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including those disclosed herein. Low-affinity antibodies generally bind antigen slowly and tend to dissociate readily, whereas high-affinity antibodies generally bind antigen faster and tend to remain bound longer. A variety of methods of measuring binding affinity are known in the art, any of which can be used for purposes of the present disclosure. In one embodiment, the “KD” or “KD value” may be measured by biolayer interferometry (BLI) using, for example, the OctetQK384 system (ForteBio, Menlo Park, CA). Alternatively, the KD may also be measured in a radiolabeled antigen-binding assay (RIA), for example, performed with the Fab version of an antibody of interest and its antigen (Chen, et al., (1999) J. Mol Biol 293:865-881) or using surface plasmon resonance (SPR) assays by BIACORE™, using, for example, a BIACORE™-2000 or a BIACORE™-3000 (BIACORE™, Inc., Piscataway, NJ). An “on-rate” or “rate of association” or “association rate” or “kon,” as well as an “off-rate” or “rate of dissociation” or “dissociation rate” or “koff,” can also be determined with the same SPR or BLI techniques described above using, for example, the OctetQK384 system (ForteBio, Menlo Park, CA) or a BIACORE™-2000 or a BIACORE™- 3000 (BIACORE™, Inc., Piscataway, NJ), respectively. NAI-1539756353v1 24 [0076] The term “compete” or any grammatical variation thereof when used in the context of LAIR1 binding agents (e.g., antibodies) means binding agents that compete for the same epitope or binding site on a target, which includes competition between such binding agents as determined by an assay in which the binding agent under study prevents or inhibits the specific binding of a reference molecule (e.g., a reference ligand, or reference antigen- binding protein, such as a reference antibody) to a common antigen (e.g., LAIR1). Suitable types of competitive binding assays can be used to determine if a test binding agent competes with a reference molecule for binding to LAIR1 (e.g., human LAIR1). Examples of assays include solid phase direct or indirect radioimmunoassay (RIA); solid phase direct or indirect enzyme immunoassay (EIA), sandwich competition assay (see, e.g., Stahli et al., (1983) Methods in Enzymology 9:242-253); solid phase direct biotin-avidin EIA (see, e.g., Kirkland et al., (1986) J. Immunol.137:3614-3619 or Cheung, et al., (1990) Virology 176:546-552); solid phase direct labeled assay; solid phase direct labeled sandwich assay (see, e.g., Harlow and Lane, (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Press); solid phase direct label RIA using I-125 label (see, e.g., Morel et al., (1988) Molec. Immunol.25:7-15); and direct labeled RIA (Moldenhauer et al., (1990) Scand. J. Immunol.32:77-82). Typically, such an assay involves the use of a purified antigen (e.g., LAIR1, such as human LAIR1) bound to a solid surface or cells bearing either of an unlabeled test antigen-binding protein (e.g., test LAIR1 antibody) or a labeled reference antigen-binding protein (e.g., reference LAIR1 antibody). Competitive inhibition may be measured by determining the amount of label bound to the solid surface or cells in the presence of the test antigen-binding protein. Usually, the test antigen-binding protein is present in excess. Antibodies identified by competition assay (competing antibodies) include antibodies binding to the same epitope as the reference antibody and/or antibodies binding to an adjacent epitope sufficiently proximal to the epitope bound by the reference antibodies for steric hindrance to occur (e.g., similar epitope or overlapping epitope). Usually, when a competing antibody is present in excess, it will inhibit specific binding of a reference antibody to a common antigen by at least 20%, for example, at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more. [0077] The term “constant region” or “constant domain” as understood in the art refers to an antibody portion, for example, a carboxyl terminal portion of a light and/or heavy chain which is not directly involved in binding of an antibody to an antigen but can exhibit various effector functions, such as interaction with an Fc receptor. The term includes the portions of NAI-1539756353v1 25 an immunoglobulin molecule having a generally more conserved amino acid sequence relative to an immunoglobulin variable domain. [0078] Antibody “effector functions” refer to those biological activities attributable to the Fc region (e.g., a native sequence Fc region or amino acid sequence variant Fc region) of an antibody, and vary with the antibody isotype. Examples of antibody effector functions include: C1q binding and complement-dependent cytotoxicity; Fc receptor binding; antibody- dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B-cell receptor); and B-cell activation. [0079] The term “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain, including, for example, native sequence Fc regions, recombinant Fc regions, and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is often defined to stretch from an amino acid residue at position Cys226 (according to the EU numbering system), or from Pro230 (according to the EU numbering system), to the carboxyl-terminus thereof. The C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody. [0080] As used herein, the term “heavy chain” when used in reference to an antibody refers to a polypeptide chain of about 50-70 kDa, wherein the amino-terminal portion includes a variable region of about 120 to 130 or more amino acids, and a carboxy-terminal portion includes one or more constant regions. The “heavy chain” can refer to any distinct types, e.g., for example, alpha (α), delta (δ), epsilon (ε), gamma (γ) and mu (µ), based on the amino acid sequence of the constant domain, which give rise to IgA, IgD, IgE, IgG and IgM classes of antibodies, respectively, including subclasses of IgG, e.g., IgG1, IgG2, IgG3 and IgG4. [0081] As used herein, the term “light chain” when used in reference to an antibody can refer to a polypeptide chain of about 25 kDa, wherein the amino-terminal portion includes a variable region of about 100 to about 110 or more amino acids, and a carboxy-terminal portion includes a constant region. The approximate length of a light chain is 211 to 217 amino acids. There are two distinct types, e.g., kappa (κ) or lambda (λ) based on the amino acid sequence of the constant domains. [0082] In certain embodiments, an antibody is a 4-chain antibody unit comprising two heavy (H) chain / light (L) chain pairs. The amino acid sequences of the H chains are identical or different and the amino acid sequences of the L chains are identical or different. NAI-1539756353v1 26 For example, an antibody comprises a first H / L chain pair and a second H / L chain pair, wherein the first H / L chain pair binds to an LAIR1 antigen and the second H/ L chain pair binds to another LAIR1 antigen or a non-LAIR1 antigen. In certain embodiments, an antibody is a 2-chain antibody unit comprising a VHH-VHH pair. In further embodiments, the amino acid sequences of the VHH are identical. In other embodiments, the amino acid sequence of the VHH are different from each other. For example, an antibody comprises a first VHH and a second VHH, wherein the first VHH binds to an LAIR1 antigen and the second VHH binds to another LAIR1 antigen or a non-LAIR1 antigen. In certain embodiments, the H and/or L chains comprise constant regions, for example, human constant regions. In certain embodiments, the L chain constant region of such antibodies is a kappa or lambda light chain constant region, for example, a human kappa or lambda light chain constant region. In certain embodiments, the H chain constant region of such antibodies comprises a gamma heavy chain constant region, for example, a human gamma heavy chain constant region. In certain embodiments, such antibodies comprise IgG constant regions, for example, human IgG constant regions (e.g., IgG1, IgG2, IgG3, and/or IgG4 constant regions). [0083] The term “variable region” or “variable domain” refers to a portion of the light or heavy chains of an antibody that is generally located at the amino-terminal of the light or heavy chain, has a length of about 120 to 130 amino acids in the heavy chain and about 100 to 110 amino acids in the light chain, and is used in the binding and specificity of each particular antibody for its particular antigen. The variable region of the heavy chain may be referred to as “VH.” The variable region of the light chain may be referred to as “VL.” The term “variable” refers to the fact that certain segments of the variable regions differ extensively in sequence among antibodies. The V region mediates antigen binding and defines specificity of a particular antibody for its particular antigen. However, the variability is not evenly distributed across the 110-amino acid span of the variable regions. Instead, the V regions consist of less variable (e.g., relatively invariant) stretches called framework regions (FRs) of about 15-30 amino acids separated by shorter regions of greater variability (e.g., extreme variability) called “hypervariable regions” or alternatively called “complementarity determining regions (CDRs).” The variable regions of heavy and light chains each comprise four frameworks (FR1, FR2, FR3 and FR4), largely adopting a β sheet configuration, connected by three hypervariable regions, which form loops connecting, and in some cases forming part of, the β sheet structure. The hypervariable regions in each chain are held together in close proximity by the frameworks and, with the hypervariable regions from the other chain, contribute to the formation of the antigen-binding site of antibodies (see, e.g., NAI-1539756353v1 27 Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, (1991)). The constant regions are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular-cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). The variable regions differ extensively in sequence between different antibodies. The variability in sequence is concentrated in the CDRs while the less variable portions in the variable region are referred to as framework regions (FR). The CDRs of the light and heavy chains are primarily responsible for the interaction of the antibody with its antigen. In specific embodiments, the variable region is a human variable region. [0084] The term “hypervariable region,” “HVR,” “HV,” “complementarity determining region,” or “CDR” when used herein refers to the regions of an antibody variable region that are hypervariable in sequence and/or form structurally defined loops. Generally, antibodies comprise six hypervariable regions: three in the VH (H1 or VH CDR1, H2 or VH CDR2, and H3 or VH CDR3), and three in the VL (L1 or VL CDR1, L2 or VL CDR2, and L3 or VL CDR3). A number of hypervariable region delineations are in use and are encompassed herein. The Kabat CDRs are based on sequence variability and are the most commonly used (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). Chothia refers instead to the location of the structural loops (see, e.g., Chothia and Lesk, J. Mol. Biol.196:901-917 (1987)). The end of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34). The AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular’s AbM antibody modeling software (see, e.g., Martin, in Antibody Engineering, Vol.2, Chapter 3, Springer Verlag). The “contact” hypervariable regions are based on an analysis of the available complex crystal structures. The residues from each of these hypervariable regions or CDRs are noted below. [0085] A universal numbering system has been developed and widely adopted, ImMunoGeneTics (IMGT®) Information System (Lefranc et al., Dev. Comp. Immunol. 27(1):55-77 (2003)). IMGT is an integrated information system specializing in immunoglobulins (IG), T-cell receptors (TR) and major histocompatibility complex (MHC) NAI-1539756353v1 28 of human and other vertebrates. Herein, the CDRs are referred to in terms of both the amino acid sequence and the location within the light or heavy chain. As the “location” of the CDRs within the structure of the immunoglobulin variable domain is conserved between species and present in structures called loops, by using numbering systems that align variable domain sequences according to structural features, CDR and framework residues and are readily identified. This information can be used in grafting and replacement of CDR residues from immunoglobulins of one species into an acceptor framework from, typically, a human antibody. An additional numbering system (AHon) has been developed by Honegger and Plückthun, J. Mol. Biol.309: 657-670 (2001). Correspondence between the numbering system, including, for example, the Kabat numbering and the IMGT unique numbering system, is well known to one skilled in the art (see, e.g., Kabat, supra; Chothia and Lesk, supra; Martin, supra; Lefranc et al., supra) and is also illustrated below. Various systems known in the art or disclosed herein represent different ways of delineating CDRs, and when they are used to define the same antibody, they are often considered equivalent. An Exemplary system, shown herein, combines Kabat and Chothia. The residues from each of these hypervariable regions or CDRs are exemplified in the table below. [0086] The specific CDR sequences defined herein are generally based on a combination of Kabat and Chothia definitions (Exemplary definition). However, it will be understood that reference to a heavy chain variable region CDR or CDRs and/or a light chain variable region CDR or CDRs of a specific antibody will encompass all CDR definitions as known to those of skill in the art. Exemplary CDRs According to Various Numbering Systems
Figure imgf000030_0001
[0087] Hypervariable regions may comprise “extended hypervariable regions” as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2) and 89-97 or 89-96 (L3) in the VL and 26-35 or 26- 35A (H1), 50-65 or 49-65 (H2) and 93-102, 94-102, or 95-102 (H3) in the VH. As used herein, the terms “hypervariable region,” “HVR,” “HV,” “complementarity determining region,” or “CDR” are used interchangeably. NAI-1539756353v1 29 [0088] The term "immune response" as used herein includes responses from both the innate immune system and the adaptive immune system. It includes both cell-mediated and/or humoral immune responses. It includes both T-cell and B-cell responses, as well as responses from other cells of the immune system such as NK cells, monocytes, macrophages, dendritic cells, etc. [0089] The term “pharmaceutically acceptable” as used herein means being approved by a regulatory agency of the federal or a state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia or other generally recognized Pharmacopeia for use in animals, and more particularly in humans. [0090] “Excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, carriers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof. The term “excipient” can also refer to a diluent, adjuvant (e.g., Freunds’ adjuvant (complete or incomplete)) or vehicle. In certain embodiments, excipients are pharmaceutically acceptable excipients. Examples of pharmaceutically acceptable excipients include buffers, such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid; low molecular weight (e.g., fewer than about 10 amino acid residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugar alcohols, such as mannitol or sorbitol; salt-forming counterions, such as sodium; and/or nonionic surfactants, such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™. Other examples of pharmaceutically acceptable excipients are described in Remington and Gennaro, Remington’s Pharmaceutical Sciences (18th ed.1990). In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press NAI-1539756353v1 30 and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009. In certain embodiments, pharmaceutically acceptable excipients are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. In certain embodiments, a pharmaceutically acceptable excipient is an aqueous pH buffered solution. In certain embodiments, excipients are sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water is an exemplary excipient when a composition (e.g., a pharmaceutical composition) is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions. An excipient can also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. Compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations, and the like. Oral compositions, including formulations, can include standard excipients such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Compositions, including pharmaceutical compounds, may contain a prophylactically or therapeutically effective amount of an LAIR1 binding agent (e.g., an antibody), for example, in isolated or purified form, together with a suitable amount of excipient so as to provide the form for proper administration to the subject (e.g., patient). The formulation should suit the mode of administration. [0091] An “effective amount” is generally an amount sufficient to reduce the severity and/or frequency of symptoms, eliminate the symptoms and/or underlying cause, prevent or delay the occurrence of symptoms and/or their underlying cause, and/or improve or remediate the damage that results from or is associated with a disease, disorder, or condition. In certain embodiments, the effective amount is a therapeutically effective amount or a prophylactically effective amount. [0092] The term “therapeutically effective amount” as used herein refers to the amount of an agent (e.g., an antibody disclosed herein or any other agent disclosed herein) that is sufficient to reduce and/or ameliorate the severity and/or duration of a given disease, disorder or condition, and/or a symptom related thereto. A therapeutically effective amount of an NAI-1539756353v1 31 agent, including a therapeutic agent, can be an amount necessary for (i) reduction, delay or amelioration of the advancement or progression of a given disease, disorder, or condition, (ii) reduction, delay or amelioration of the recurrence, development or onset of a given disease, disorder or conditions, and/or (iii) to improve or enhance the prophylactic or therapeutic effect of another therapy (e.g., a therapy other than the administration of an agent disclosed herein). A “therapeutically effective amount” of a substance/molecule/agent of the present disclosure (e.g., an LAIR1 antibody) may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance/molecule/agent, to elicit a desired response in the individual. A therapeutically effective amount encompasses an amount in which any toxic or detrimental effects of the substance/molecule/agent are outweighed by the therapeutically beneficial effects. In certain embodiments, the term “therapeutically effective amount” refers to an amount of an agent effective to “treat” a disease, disorder, or condition, in a subject or mammal. [0093] The term “treating” or any grammatical variation thereof refers to reducing and/or ameliorating the severity and/or duration of a given disease, disorder or condition, and/or a symptom related thereto, such as (i) reduction, delay or amelioration of the advancement or progression of a given disease, disorder, or condition, (ii) reduction, delay or amelioration of the recurrence, development or onset of a given disease, disorder or conditions, and/or (iii) to improve or enhance the prophylactic or therapeutic effect of another therapy (e.g., a therapy other than the administration of an agent disclosed herein). [0094] The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically or prophylactically effective amount may be administered in one or more administrations. [0095] The terms “about” and “approximately” mean within 20%, within 15%, within 10%, within 9%, within 8%, within 7%, within 6%, within 5%, within 4%, within 3%, within 2%, within 1%, or less variation of a given value or range. [0096] As used herein, comparative terms, such as reduce, decrease, increase, or any grammatical variation thereof, can refer to certain variation from the reference. In certain embodiments, such variation can refer to about 10%, or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 1 fold, or about 2 fold, or about 3 fold, or about 4 fold, or about 5 fold, or about 10 fold, or about 20 fold, or about 30 fold, or about 40 fold, or about 100 fold or higher than the reference. In certain embodiments, such variation can refer to about 1%, or about 2%, or about 3%, or about 4%, or about 5%, or about 6%, or about 7%, or about 8%, or about 9%, or NAI-1539756353v1 32 about 10%, or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% of the reference. [0097] As used in the present disclosure and claims, the singular forms “a”, “an” and “the” include plural forms unless the context clearly dictates otherwise. [0098] It is understood that wherever embodiments are disclosed herein with the term “comprising” otherwise analogous embodiments described in terms of “consisting of” and/or “consisting essentially of” are also provided. It is also understood that wherever embodiments are disclosed herein with the phrase “consisting essentially of” otherwise analogous embodiments described in terms of “consisting of” are also provided. [0099] The term “between” as used in a phrase as such “between A and B” or “between A- B” refers to a range including both A and B. [00100] The term “and/or” as used in a phrase such as “A and/or B” herein is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone). [00101] The term “optional” or “optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances wherein the circumstance occurs, and the instances wherein the circumstance does not occur. 5.2 LAIR1 Ligands [00102] Collagens are known high affinity ligands for LAIR1 (see, e.g., Lebbink et al., 2006, Journal of Exp. Med., 203:1419-1425). MARCO and COLEC12 have also been identified as ligands for LAIR1. [00103] In certain embodiments, LAIR1 binds MARCO. In certain embodiments, LAIR1 binds SEQ ID NO:154. In certain embodiments, LAIR1 binds the extracellular domain of MARCO. In certain embodiments, LAIR1 binds within amino acid 65-520 of SEQ ID NO:154. In certain embodiments, LAIR1 binds within SEQ ID NO:155. In certain embodiments, LAIR1 binds within the collagen-like domain of MARCO. In certain embodiments, LAIR1 binds within amino acids 147-419 of SEQ ID NO:154. In certain embodiments, LAIR1 binds within SEQ ID NO:156. In certain embodiments, LAIR1 binds within the SRCR domain of MARCO. In certain embodiments, LAIR1 binds within amino acids 424-519 of SEQ ID NO:154. In certain embodiments, LAIR1 binds within SEQ ID NO:157. NAI-1539756353v1 33 [00104] In certain embodiments, the LAIR1 binding agent disclosed herein inhibits, disrupts, or blocks binding of LAIR1 to collagen. In certain embodiments, the LAIR1 binding agent disclosed herein blocks the interaction of LAIR1 to collagen. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits binding of LAIR1 to collagen. In certain embodiments, the LAIR1 binding agent disclosed herein blocks or inhibits a functional interaction between LAIR1 to collagen. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits, disrupts, or blocks binding of LAIR1 to MARCO. In certain embodiments, the LAIR1 binding agent disclosed herein blocks the interaction of LAIR1 to MARCO. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits binding of LAIR1 to MARCO. In certain embodiments, the LAIR1 binding agent disclosed herein blocks or inhibits a functional interaction between LAIR1 to MARCO. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits, disrupts, or blocks binding of LAIR1 to COLEC12. In certain embodiments, the LAIR1 binding agent disclosed herein blocks the interaction of LAIR1 to COLEC12. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits binding of LAIR1 to COLEC12. In certain embodiments, the LAIR1 binding agent disclosed herein blocks or inhibits a functional interaction between LAIR1 to COLEC12. [00105] In certain embodiments, the LAIR1 binding agent disclosed herein inhibits collagen-induced LAIR1 activity. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits collagen-induced LAIR1 suppressive activity. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits collagen-induced LAIR1 suppression of myeloid cells. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits collagen-induced LAIR1 suppression of myeloid cell activity. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits collagen-induced LAIR1 suppression of APCs. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits collagen-induced LAIR1 suppression of APC activity. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits collagen-induced LAIR1 suppression of dendritic cells. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits collagen-induced LAIR1 suppression of dendritic cell activity. In certain embodiments, the myeloid cells, dendritic cells, or APCs are tumor-associated cells. In certain embodiments, the myeloid cells, dendritic cells, or APCs are residing in the tumor microenvironment. In certain embodiments, the myeloid cells, dendritic cells, or APCs are residing within a tumor. [00106] In certain embodiments, the LAIR1 binding agent disclosed herein inhibits MARCO-induced LAIR1 activity. In certain embodiments, the LAIR1 binding agent NAI-1539756353v1 34 disclosed herein inhibits MARCO-induced LAIR1 suppressive activity. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits MARCO-induced LAIR1 suppression of myeloid cells. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits MARCO-induced LAIR1 suppression of myeloid cell activity. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits MARCO-induced LAIR1 suppression of APCs. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits MARCO-induced LAIR1 suppression of APC activity. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits MARCO-induced LAIR1 suppression of dendritic cells. In certain embodiments, the LAIR1 binding agent disclosed herein inhibits MARCO-induced LAIR1 suppression of dendritic cell activity. In certain embodiments, the myeloid cells, dendritic cells, or APCs are tumor-associated cells. In certain embodiments, the myeloid cells, dendritic cells, or APCs are residing in the tumor microenvironment. In certain embodiments, the myeloid cells, dendritic cells, or APCs are residing within a tumor. 5.3 LAIR1 Binding Agents [00107] Amino acid (aa) sequences for human LAIR1 (UniProtKB No. Q6GTX8), cynomolgus monkey (“cyno”) LAIR1 (UniProtKB No. A0A2K5TN26), and mouse LAIR1 (UniProtKB No. Q8BG84) are provided herein as SEQ ID NO:1, SEQ ID NO:5, and SEQ ID NO:149, respectively. As used herein, reference to amino acid positions of LAIR1 refer to the numbering of amino acid sequences including the signal sequence. [00108] LAIR1 is a single pass type I transmembrane protein with a predicted molecular weight of approximately 32 kDa. As characterized within UniProtKB, human LAIR1 is a protein of 287 amino acids (aa) - the signal sequence is aa 1-21, the extracellular domain is aa 22-165, the transmembrane region is aa 166-186, and the cytoplasmic domain is aa 187-287. Within the extracellular domain, the Ig-like C2-type domain is aa 29-117 and the “stem region” is aa 118-165. Within the cytoplasmic domain, immunoreceptor tyrosine-based inhibitory motifs (ITIMs) are positioned at aa 249-254 and 279-284. LAIR1 is expressed on almost all immune cells, including NK cells, T-cells, B-cells, monocytes, dendritic cells, eosinophils, basophils, and mast cells. LAIR1 is characterized by an extracellular domain comprising one Ig-like C2 type domain, a transmembrane domain, and a cytoplasmic domain containing 2 ITIM domains (see, e.g., Meyaard et al., 1997, Immunity, 7:283-290; Meyaard et al., 2008, J. Leuk. Biol., 83:799-803). LAIR1 is known to bind to multiple transmembrane and extracellular matrix collagens. MARCO and COLEC12 were identified as ligands for LAIR1. NAI-1539756353v1 35 [00109] Cyno LAIR1 has an amino acid sequence identity to human LAIR1 of 88%. As characterized within UniProtKB, cyno LAIR1 is a protein of 287 amino acids and it is believed that the structural characteristics of cyno LAIR1 are similar to human LAIR1. Thus, for cyno LAIR1 the signal sequence is predicted to be aa 1-21, the extracellular domain is predicted to be aa 22-165, the transmembrane region is predicted to be aa 166-186, and the cytoplasmic domain is predicted to be aa 187-287. Within the extracellular domain, the Ig- like C2-type domain is predicted to be aa 29-117 and the “stem region” is predicted to be aa 118-165. Within the cytoplasmic domain, ITIMs are positioned at aa 249-254 and 279-284. [00110] Mouse LAIR1 has an amino acid sequence identity to human LAIR1 of 42%. As characterized within UniProtKB, mouse LAIR1 is a protein of 263 amino acids and has structural characteristics similar to human LAIR1. Thus, for mouse LAIR1 the signal sequence is aa 1-21, the extracellular domain is aa 22-144, the transmembrane region is aa 145-165, and the cytoplasmic domain is aa 166-263. Within the extracellular domain, the Ig- like C2-type domain is aa 27-114 and the “stem region” is aa 115-144. Within the cytoplasmic domain, ITIMs are positioned at aa 226-231 and 255-260. [00111] In certain embodiments, the LAIR1 binding agent disclosed herein binds LAIR1 or a LAIR1 fragment. In certain embodiments, the LAIR1 fragment comprises the extracellular domain of LAIR1. In certain embodiments, the LAIR1 fragment comprises the Ig-like C2 type domain (D1). In certain embodiments, the LAIR1 fragment comprises the Ig-like C2 type domain and the stem region (D1-stem). In certain embodiments, the extracellular domain of human LAIR1 comprises amino acids 22-165 of SEQ ID NO:1. In certain embodiments, D1 of human LAIR1 comprises amino acids 29-117 of SEQ ID NO:1. In certain embodiments, D1-stem of human LAIR1 comprises amino acids 29-165 of SEQ ID NO:1. In certain embodiments, a human LAIR1 fragment comprises the amino acid sequence of SEQ ID NO:3. In certain embodiments, a human LAIR1 fragment comprises the amino acid sequence of SEQ ID NO:4. In certain embodiments, the extracellular domain of cyno LAIR1 comprises amino acids 22-165 of SEQ ID NO:5. In certain embodiments, D1 of cyno LAIR1 comprises amino acids 29-117 of SEQ ID NO:5. In certain embodiments, D1- stem of cyno LAIR1 comprises amino acids 29-165 of SEQ ID NO:5. In certain embodiments, a fragment of cyno LAIR1 comprises the amino acid sequence of SEQ ID NO:7. In certain embodiments, a fragment of cyno LAIR1 comprises the amino acid sequence of SEQ ID NO:8. In certain embodiments, the extracellular domain of mouse LAIR1 comprises amino acids 22-144 of SEQ ID NO:149. In certain embodiments, D1 of mouse LAIR1 comprises amino acids 27-114 of SEQ ID NO:149. In certain embodiments, NAI-1539756353v1 36 D1-stem of mouse LAIR1 comprises amino acids 27-144 of SEQ ID NO:149. In certain embodiments, a fragment of mouse LAIR1 comprises the amino acid sequence of SEQ ID NO:151. In certain embodiments, a fragment of mouse LAIR1 comprises the amino acid sequence of SEQ ID NO:152. [00112] It is understood that the regions and/or domains of LAIR1 (e.g., human LAIR1, cyno LAIR1, or mouse LAIR1) may be defined differently by those of skill in the art, therefore the N-terminal amino acids and the C-terminal amino acids of any LAIR1 domain or region may vary by 1, 2, 3, 4, 5, or more amino acid residues. [00113] In one aspect, the present disclosure provides LAIR1 binding agents. In certain embodiments, the LAIR1 binding agent disclosed herein binds a fragment of LAIR1. In certain embodiments, the LAIR1 binding agent binds within a specific region of LAIR1. In certain embodiments, the LAIR1 binding agent binds within the extracellular domain of LAIR1. In certain embodiments, the LAIR1 binding agent binds within the D1 domain of LAIR1. In certain embodiments, the LAIR1 binding agent binds within the D1-stem domain of LAIR1. In certain embodiments, the LAIR1 binding agent binds an epitope on LAIR1. In certain embodiments, the LAIR1 binding agent binds a conformational epitope on LAIR1. [00114] In certain embodiments, the LAIR1 binding agent binds human LAIR1. In certain embodiments, the LAIR1 binding agent binds cyno LAIR1. In certain embodiments, the LAIR1 binding agent binds mouse LAIR1. In certain embodiments, the LAIR1 binding agent binds human LAIR1 and cyno LAIR1. In certain embodiments, the LAIR1 binding agent binds human LAIR1 and cyno LAIR1, but does not bind mouse LAIR1. In certain embodiments, the LAIR1 binding agent binds SEQ ID NO:1. In certain embodiments, the LAIR1 binding agent binds SEQ ID NO:2. In certain embodiments, the LAIR1 binding agent binds within amino acids 22-165 of SEQ ID NO:1. In certain embodiments, the LAIR1 binding agent binds within amino acids 29-117 of SEQ ID NO:1. In certain embodiments, the LAIR1 binding agent binds within amino acids 29-165 of SEQ ID NO:1. In certain embodiments, the LAIR1 binding agent binds SEQ ID NO:3. In certain embodiments, the LAIR1 binding agent binds SEQ ID NO:4. In certain embodiments, the LAIR1 binding agent binds SEQ ID NO:5. In certain embodiments, the LAIR1 binding agent binds SEQ ID NO:6. In certain embodiments, the LAIR1 binding agent binds within amino acids 22-165 of SEQ ID NO:5. In certain embodiments, the LAIR1 binding agent binds within amino acids 29-117 of SEQ ID NO:5. In certain embodiments, the LAIR1 binding agent binds within amino acids 29-165 of SEQ ID NO:5. In certain embodiments, the LAIR1 binding agent binds SEQ ID NO:7. In certain embodiments, the LAIR1 binding agent binds SEQ ID NO:8. In certain NAI-1539756353v1 37 embodiments, the LAIR1 binding agent binds SEQ ID NO:149. In certain embodiments, the LAIR1 binding agent binds SEQ ID NO:150. In certain embodiments, the LAIR1 binding agent binds within amino acids 22-144 of SEQ ID NO:149. In certain embodiments, the LAIR1 binding agent binds within amino acids 27-114 of SEQ ID NO:149. In certain embodiments, the LAIR1 binding agent binds within amino acids 27-144 of SEQ ID NO:149. In certain embodiments, the LAIR1 binding agent binds SEQ ID NO:151. In certain embodiments, the LAIR1 binding agent binds SEQ ID NO:152. [00115] In certain embodiments, the LAIR1 binding agent binds a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:2. In certain embodiments, the LAIR1 binding agent binds a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:3. In certain embodiments, the LAIR1 binding agent binds a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:4. In certain embodiments, the LAIR1 binding agent binds a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:6. In certain embodiments, the LAIR1 binding agent binds a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:7. In certain embodiments, the LAIR1 binding agent binds a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:8. In certain embodiments, the LAIR1 binding agent binds a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:150. In certain embodiments, the LAIR1 binding agent binds a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:151. In certain embodiments, the LAIR1 binding agent binds a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:152. [00116] In certain embodiments, the LAIR1 binding agent binds an epitope comprising amino acids within SEQ ID NO:2. In certain embodiments, the LAIR1 binding agent binds an epitope comprising amino acids within SEQ ID NO:3. In certain embodiments, the LAIR1 binding agent binds an epitope comprising amino acids within SEQ ID NO:4. In certain embodiments, the LAIR1 binding agent binds an epitope comprising at least one amino acid within amino acids 70-80 of SEQ ID NO:1. In certain embodiments, the LAIR1 binding agent binds an epitope comprising at least one amino acid within amino acids 61-80 of SEQ ID NO:1. In certain embodiments, the LAIR1 binding agent binds an epitope comprising amino acids within SEQ ID NO:6. In certain embodiments, the LAIR1 binding agent binds an epitope comprising amino acids within SEQ ID NO:7. In certain embodiments, the LAIR1 binding agent binds an epitope comprising amino acids within SEQ ID NO:8. In certain embodiments, the LAIR1 binding agent binds an epitope comprising NAI-1539756353v1 38 amino acids within SEQ ID NO:150. In certain embodiments, the LAIR1 binding agent binds an epitope comprising amino acids within SEQ ID NO:151. In certain embodiments, the LAIR1 binding agent binds an epitope comprising amino acids within SEQ ID NO:152. [00117] A variety of methods of measuring binding affinity are known in the art, any of which can be used for purposes of the present disclosure, including by RIA, for example, performed with the Fab version of an antibody of interest and its antigen (Chen et al., 1999, J. Mol Biol 293:865-81); by biolayer interferometry (BLI) or surface plasmon resonance (SPR) assays by OCTET®, using, for example, an OCTET®Red96 system, or by BIACORE®, using, for example, a BIACORE®TM-2000 or a BIACORE®TM-3000. An “on-rate” or “rate of association” or “association rate” or “kon” may also be determined with the same biolayer interferometry (BLI) or surface plasmon resonance (SPR) techniques described above using, for example, the OCTET®Red96, the BIACORE®TM-2000, the BIACORE®TM-3000 system, the BIACORE®TM-8K, or the BIACORE®TM-8K+ system. [00118] In certain embodiments, the LAIR1 binding agent (e.g., an anti-LAIR1 antibody) provided herein binds to LAIR1 (e.g., human LAIR1) with a dissociation constant (KD) of 1 μM or less, 100 nM or less, 40 nM or less, 20 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 50 pM or less, 10 pM or less, or 1 pM or less. In certain embodiments, the LAIR1 binding agent binds LAIR1 with a KD of about 20 nM or less, 10 nM or less, 5 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.5 nM or less, 0.1 nM or less, 50 pM or less, 25 pM or less, 10 pM or less, 1 pM or less. In certain embodiments, the LAIR1 binding agent binds LAIR1 with a KD of from 0.01 nM to 2.5 nM, from 0.1 nM to 5 nM, or from 1 nM to 5 nM. In certain embodiments, the KD of the LAIR1 binding agent is determined using an LAIR1 protein immobilized on a Biacore chip and the binding agent flowed over the chip. In certain embodiments, the KD of the LAIR1 binding agent is determined using the binding agent captured by an anti-human IgG antibody on a Biacore chip and soluble LAIR1 flowed over the chip. [00119] In certain embodiments, the LAIR1 binding agent (e.g., an anti-LAIR1 antibody) binds LAIR1 with a half maximal effective concentration (EC50) of 1 μM or less, 100 nM or less, 40 nM or less, 20 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less. In certain embodiments, the LAIR1 binding agent binds human LAIR1 with an EC50 of 1 μM or less, 100 nM or less, 40 nM or less, 20 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less. In certain embodiments, the LAIR1 binding agent binds cyno LAIR1 and/or human LAIR1 with an EC50 of 40 nM or less, 20 nM or less, 10 nM or less, 1 nM or less or 0.1 nM or less. In certain embodiments, the LAIR1 binding agent binds LAIR1 with an EC50 of 0.1 nM to NAI-1539756353v1 39 about 3 nM, 0.1 nM to 2 nM, 0.1 nM to 1 nM, 0.5 nM to 3 nM, 0.5 nM to 2 nM, or 0.5 nM to 1 nM. [00120] In certain embodiments, the LAIR1 binding agent disclosed herein (e.g., an anti- LAIR1 antibody) has at least one of the following properties: (i) binding human LAIR1; (ii) binding cyno LAIR1; (iii) not binding mouse LAIR1; (iv) not binding human LAIR-2; (v) being a LAIR1 antagonist; (vi) inhibiting LAIR1 activity; (vii) inhibiting LAIR1 signaling in cells that express LAIR1; (viii) inhibiting binding of LAIR1 to collagen; (ix) inhibiting binding of LAIR1 to MARCO; (x) inhibiting binding of LAIR1 to COLEC12; (xi) inhibiting LAIR1-induced suppression of myeloid cells; (xii) inhibiting LAIR1-induced suppression of myeloid cell activity; (xiii) restoring FcR activation in myeloid cells; (xiv) restoring cytokine and/or chemokine production in myeloid cells; (xv) inhibiting LAIR1-induced suppression of NK cells; (xvi) inhibiting LAIR1-induced suppression of NK activity; (xvii) inhibiting LAIR1-induced suppression of T-cell activity; and (xviii) inhibiting MDSC activity. In certain embodiments, the myeloid cells are monocytes, macrophages, dendritic cells, antigen- presenting cells (APCs), or any combination thereof. [00121] In certain embodiments, the LAIR1 binding agent is an anti-LAIR1 antibody. In certain embodiments, the anti-LAIR1 antibody is a recombinant antibody, a monoclonal antibody, a chimeric antibody, a humanized antibody, or a human antibody. In certain embodiments, the anti-LAIR1 antibody is an IgG antibody (e.g., an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody). In certain embodiments, the antibody comprises an IgG heavy chain (e.g., an IgG1 heavy chain, an IgG2 heavy chain, or an IgG4 heavy chain). In certain embodiments, the antibody comprises a human IgG1 heavy chain, a human IgG2 heavy chain, or a human IgG4 heavy chain. In certain embodiments, the anti- LAIR1 antibody comprises a kappa light chain. In certain embodiments, the anti-LAIR1 antibody comprises a kappa light chain constant region. In certain embodiments, the anti- LAIR1 antibody comprises a human kappa light chain constant region. In certain embodiments, the anti-LAIR1 antibody comprises a lambda light chain. In certain embodiments, the anti-LAIR1 antibody comprises a lambda light chain constant region. In certain embodiments, the anti-LAIR1 antibody comprises a human lambda light chain constant region. In certain embodiments, the human kappa light chain constant region comprises the amino acid sequence set forth in SEQ ID NO:147. In certain embodiments, the human lambda light chain constant region comprises the amino acid sequence set forth in SEQ ID NO:148. NAI-1539756353v1 40 [00122] In certain embodiments, the antibody is a monospecific antibody. In certain embodiments, the antibody is a bispecific antibody. In certain embodiments, the antibody is a multispecific antibody. In certain embodiments, the antibody is a monovalent antibody. In certain embodiments, the antibody is a bivalent antibody. In certain embodiments, the antibody is a tetravalent antibody. [00123] In certain embodiments, the antibody is isolated. In certain embodiments, the antibody is substantially pure. [00124] In certain embodiments, the LAIR1 binding agent is a polyclonal antibody. Polyclonal antibodies can be prepared by any methods known to those of skill in the art. In certain embodiments, the polyclonal antibodies are produced by immunizing an animal (e.g., a rabbit, rat, mouse, goat, donkey) with an antigen of interest (e.g., a purified peptide fragment, a recombinant protein, or a fusion protein) using multiple subcutaneous or intraperitoneal injections. In certain embodiments, the antigen is conjugated to a carrier such as keyhole limpet hemocyanin (KLH), serum albumin, bovine thyroglobulin, or soybean trypsin inhibitor. The antigen (with or without a carrier protein) is diluted in sterile saline and usually combined with an adjuvant (e.g., complete or incomplete Freund’s adjuvant) to form a stable emulsion. After a period of time, polyclonal antibodies are recovered from the immunized animal (e.g., from blood or ascites). In certain embodiments, the polyclonal antibodies are purified from serum or ascites according to standard methods in the art including, but not limited to, affinity chromatography, ion-exchange chromatography, gel electrophoresis, and/or dialysis. [00125] In certain embodiments, the LAIR1 binding agent is a monoclonal antibody. Monoclonal antibodies can be prepared by any method known to those of skill in the art. In certain embodiments, monoclonal antibodies are prepared using hybridoma methods known to one of skill in the art. For example, using a hybridoma method, a mouse, rat, rabbit, hamster, or other appropriate host animal, is immunized as described above. In certain embodiments, lymphocytes are immunized in vitro. In certain embodiments, the immunizing antigen is a human protein or a fragment thereof. In certain embodiments, the immunizing antigen is a mouse protein or a fragment thereof. In certain embodiments, the immunizing antigen is a cyno protein or a fragment thereof. In certain embodiments, the immunizing antigen is a combination of two or more (e.g., 2, 3, 4) related proteins or fragments thereof. [00126] Following immunization, lymphocytes are isolated and fused with a suitable myeloma cell line using, for example, polyethylene glycol or electrofusion. The hybridoma cells are selected using specialized media as known in the art and unfused lymphocytes and NAI-1539756353v1 41 myeloma cells do not survive the selection process. Hybridomas that produce monoclonal antibodies directed specifically against a chosen antigen can be identified by a variety of methods including, but not limited to, immunoprecipitation, immunoblotting, and in vitro binding assays (e.g., flow cytometry, FACS, ELISA, SPR (e.g., Biacore), and radioimmunoassay). Once hybridoma cells that produce antibodies of the desired specificity, affinity, and/or activity are identified, the clones may be subcloned by limiting dilution techniques. In certain embodiments, high-throughput methods are used to distribute single cell hybridoma cells into plates. In certain embodiments, high-throughput methods are used to directly distribute single cells from original fusion into plates. The hybridomas can be propagated either in in vitro culture using standard methods or in vivo as ascites tumors in an animal. The monoclonal antibodies can be purified from the culture medium or ascites fluid according to standard methods in the art including, but not limited to, affinity chromatography, ion-exchange chromatography, gel electrophoresis, and dialysis. [00127] In certain embodiments, monoclonal antibodies are made using recombinant DNA techniques as known to one skilled in the art. For example, the polynucleotides encoding an antibody are isolated from mature B-cells or hybridoma cells, such as by RT-PCR using oligonucleotide primers that specifically amplify the genes encoding the heavy and light chains of the antibody, and their sequence is determined using standard techniques. The isolated polynucleotides encoding the heavy and light chains are then cloned into suitable expression vectors which produce the monoclonal antibodies when transfected into host cells such as E. coli, simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin proteins. [00128] In certain embodiments, recombinant monoclonal antibodies are isolated from phage display libraries expressing variable domains or CDRs of a desired species. Screening of phage libraries can be accomplished by various techniques known in the art. [00129] In certain embodiments, a monoclonal antibody is modified by using recombinant DNA technology to generate alternative antibodies. In certain embodiments, the constant domains of the light chain and heavy chain of a mouse monoclonal antibody are substituted for constant regions of a human antibody to generate a chimeric antibody. In certain embodiments, the constant regions are truncated or removed to generate a desired antibody fragment of a monoclonal antibody. In certain embodiments, site-directed or high-density mutagenesis of the variable region(s) is used to optimize specificity and affinity of a monoclonal antibody. NAI-1539756353v1 42 [00130] In certain embodiments, the LAIR1 binding agent is a humanized antibody. Various methods for generating humanized antibodies are known in the art. In certain embodiments, a humanized antibody comprises one or more amino acid residues that have been introduced into it from a source that is non-human. In certain embodiments, humanization is performed by substituting one or more non-human CDR sequences for the corresponding CDR sequences of a human antibody. In certain embodiments, the humanized antibodies are constructed by substituting all six CDRs of a non-human antibody (e.g., a mouse antibody) for the corresponding CDRs of a human antibody. [00131] The choice of which human heavy chain variable region and/or light chain variable region to use for generating humanized antibodies can be made based on a variety of factors and by a variety of methods known in the art. In certain embodiments, the “best-fit” method is used where the sequence of the variable region of a non-human (e.g., rodent) antibody is screened against the entire library of known human variable region sequences. The human sequence that is most similar to that of the non-human sequence is selected as the human variable region framework for the humanized antibody. In certain embodiments, a particular variable region framework derived from a consensus sequence of all human antibodies of a particular subgroup of light or heavy chains is selected as the variable region framework. In certain embodiments, the variable region framework sequence is derived from the consensus sequences of the most abundant human subclasses. In certain embodiments, human germline genes are used as the source of the variable region framework sequences. [00132] Other methods for humanization include, but not limited to, a method called “superhumanization” which is described as the direct transfer of CDRs to a human germline framework, a method termed Human String Content (HSC) which is based on a metric of “antibody humanness”, methods based on generation of large libraries of humanized variants (including phage, ribosomal, and yeast display libraries), and methods based on framework region shuffling. [00133] In certain embodiments, the LAIR1 binding agent is a human antibody. Human antibodies can be prepared using various techniques known in the art. In certain embodiments, human antibodies are generated from immortalized human B lymphocytes immunized in vitro. In certain embodiments, human antibodies are generated from lymphocytes isolated from an immunized individual. In any case, cells that produce an antibody directed against a target antigen can be generated and isolated. In certain embodiments, a human antibody is selected from a phage library, where that phage library expresses human antibodies. Alternatively, phage display technology may be used to NAI-1539756353v1 43 produce human antibodies and antibody fragments in vitro, from immunoglobulin variable region gene repertoires from unimmunized human donors. Techniques for the generation and use of antibody phage libraries are well known in the art. Once antibodies are identified, affinity maturation strategies known in the art, including but not limited to, chain shuffling and site-directed mutagenesis, may be employed to generate higher affinity human antibodies. In certain embodiments, human antibodies are produced in transgenic mice that contain human immunoglobulin loci. Upon immunization these mice are capable of producing the full repertoire of human antibodies in the absence of endogenous immunoglobulin production. [00134] In certain embodiments, the LAIR1 binding agent is an antibody fragment comprising an antigen-binding site that bind to LAIR1. In certain embodiments, the antibody fragment is Fab, Fab’, F(ab’)2, Fv, scFv, (scFv)2, single chain antibody molecule, dual variable domain antibody, single variable domain, linear antibody, V region, a multispecific antibody formed from antibody fragments, F(ab)2, Fd, Fc, diabody, di-diabody, disulfide- linked Fvs (dsFv), single-domain antibody (e.g., nanobody) or other fragments (e.g., fragments consisting of the variable regions of the heavy and light chains that are non- covalently coupled). In certain embodiments, the LAIR1 binding agent is a scFv. In certain embodiments, the scFv is a disulfide-linked scFv (dsscFv). DsscFv antibodies comprise an engineered disulfide bond between the light chain variable region and heavy chain variable region of the scFv. In certain embodiments, the disulfide bond increases stability and/or thermostability of the scFv molecule. In certain embodiments, the LAIR1 binding agent is a Fv. In certain embodiments, the LAIR1 binding agent is a Fab. In certain embodiments, the LAIR1 binding agent is a F(ab’)2. In certain embodiments, the LAIR1 binding agent is a Fab’. [00135] Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody. In certain embodiments, the antibody fragment disclosed herein is produced using recombinant technologies known in the art (e.g., E.coli or phage expression). [00136] In certain embodiments, the LAIR1 binding agent is a bispecific antibody. Bispecific antibodies are capable of recognizing and binding at least two different antigens or epitopes. The different epitopes can either be within the same molecule (e.g., two epitopes on LAIR1) or on different molecules (e.g., one epitope on LAIR1 and one epitope on a different target). In certain embodiments, the bispecific antibody has enhanced potency as compared to an individual antibody or to a combination of more than one antibody. In NAI-1539756353v1 44 certain embodiments, the bispecific antibody has reduced toxicity as compared to an individual antibody or to a combination of more than one antibody. It is known to those of skill in the art that any therapeutic agent may have unique pharmacokinetics (PK) (e.g., circulating half-life). In certain embodiments, the bispecific antibody has the ability to synchronize the PK of two active binding agents wherein the two individual binding agents have different PK profiles. In certain embodiments, the bispecific antibody has the ability to concentrate the actions of two agents in a common area (e.g., tissue) in a subject. In certain embodiments, the bispecific antibody has the ability to concentrate the actions of two agents to a common target (e.g., a specific cell type). In certain embodiments, the bispecific antibody has the ability to target the actions of two agents to more than one biological pathway or function. In certain embodiments, the bispecific antibody has the ability to target two different cells and bring them closer together. [00137] In certain embodiments, the bispecific antibody has decreased toxicity and/or side effects. In certain embodiments, the bispecific antibody has decreased toxicity and/or side effects as compared to a mixture of the two individual antibodies or the antibodies as single agents. In certain embodiments, the bispecific antibody has an increased therapeutic index. In certain embodiments, the bispecific antibody has an increased therapeutic index as compared to a mixture of the two individual antibodies or the antibodies as single agents. [00138] Many techniques for making bispecific antibodies are known to those skilled in the art. In certain embodiments, the bispecific antibody comprises heavy chain constant regions with modifications in the amino acids that are part of the interface between the two heavy chains. These modifications are made to enhance heterodimer formation and generally reduce or eliminate homodimer formation. In certain embodiments, the bispecific antibody is generated using a knobs-into-holes (KIH) strategy. In certain embodiments, the bispecific antibody comprises variant hinge regions incapable of forming disulfide linkages between identical heavy chains (e.g., reduce homodimer formation). In certain embodiments, the bispecific antibody comprises heavy chains with changes in amino acids that result in altered electrostatic interactions. In certain embodiments, the bispecific antibodies comprise heavy chains with changes in amino acids that result in altered hydrophobic/hydrophilic interactions. [00139] Bispecific antibodies can be intact antibodies or antibody fragments comprising antigen-binding sites. [00140] In certain embodiments, the LAIR1 binding agent disclosed herein is an antibody that binds LAIR1. In certain embodiments, the anti-LAIR1 antibody binds human LAIR1. NAI-1539756353v1 45 In certain embodiments, the anti-LAIR1 antibody binds cyno LAIR1. In certain embodiments, the anti-LAIR1 antibody binds mouse LAIR1. In certain embodiments, the anti-LAIR1 antibody binds human LAIR1 and cyno LAIR1. In certain embodiments, the anti-LAIR1 antibody binds human LAIR1 and cyno LAIR1, and does not bind mouse LAIR1. In certain embodiments, the anti-LAIR1 antibody binds an LAIR1 epitope. In certain embodiments, the anti-LAIR1 antibody binds an LAIR1 epitope within the extracellular domain of human LAIR1. In certain embodiments, the anti-LAIR1 antibody binds an LAIR1 epitope within the extracellular domain of cyno LAIR1. [00141] In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising at least one amino acid (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9) within amino acids 22-165 of SEQ ID NO:1. In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising at least one amino acid within amino acids 22-117 of SEQ ID NO:1. In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising at least one amino acid within amino acids 29-117 of SEQ ID NO:1. In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising amino acids within SEQ ID NO:3. In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising amino acids within SEQ ID NO:4. [00142] In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising at least one amino acid (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9) within amino acids 22-165 of SEQ ID NO:5. In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising at least one amino acid within amino acids 22-117 of SEQ ID NO:5. In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising at least one amino acid within amino acids 29-117 of SEQ ID NO:5. In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising amino acids within SEQ ID NO:7. In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising amino acids within SEQ ID NO:8. [00143] In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising at least one amino acid (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9) within amino acids 22-144 of SEQ ID NO:149. In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising at least one amino acid within amino acids 22-114 of SEQ ID NO:149. In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising at least one amino acid within amino acids 27-114 of SEQ ID NO:149. In certain embodiments, the anti-LAIR1 antibody binds an epitope comprising amino acids within SEQ ID NO:151. In certain embodiments, the anti- LAIR1 antibody binds an epitope comprising amino acids within SEQ ID NO:152. [00144] In certain embodiments, the epitope is a conformational epitope. In certain embodiments, the epitope is a linear epitope. NAI-1539756353v1 46 [00145] In certain embodiments, the anti-LAIR1 antibody competes with a second agent for binding within the extracellular domain of human LAIR1. In certain embodiments, the anti- LAIR1 antibody competes with a second agent for binding within the extracellular domain of cyno LAIR1. In certain embodiments, the anti-LAIR1 antibody competes with a second agent for binding within amino acids 22-165 of SEQ ID NO:1. In certain embodiments, the anti-LAIR1 antibody competes with a second agent for binding within amino acids 22-117 of SEQ ID NO:1. In certain embodiments, the anti-LAIR1 antibody competes with a second agent for binding within amino acid sequence SEQ ID NO:3. In certain embodiments, the anti-LAIR1 antibody competes with a second agent for binding within amino acid sequence SEQ ID NO:4. [00146] In certain embodiments, the LAIR1 binding agent is a variant of the anti-LAIR1 antibody disclosed herein. In certain embodiments, the anti-LAIR1 antibody variant comprises from 1 to 30, from 1 to 25, from 1 to 20, from 1 to 15, from 1 to 10, from 1 to 5, or from 1 to 3 amino acid substitutions. In certain embodiments, the amino acid substitution(s) is in a CDR of the antibody. In certain embodiments, the amino acid substitution(s) is not in a CDR of the antibody. In certain embodiments, the amino acid substitution(s) is in a framework region of the antibody. In certain embodiments, the amino acid substitution(s) is a conservative amino acid substitution. [00147] In certain embodiments, the anti-LAIR1 antibody disclosed herein comprises the six CDRs of antibody designated as 47A1, 47H1, Hz47H1.v4, 57D12, 61H4, 62G10, 108D10, or 43H2 based on the Kabat definition as set forth in Tables 1-7. In certain embodiments, the anti-LAIR1 antibody disclosed herein comprises the six CDRs of antibody designated as 47A1, 47H1, Hz47H1.v4, 57D12, 61H4, 62G10, 108D10, or 43H2 based on the Chothia definition as set forth in Tables 1-7. In certain embodiments, the anti-LAIR1 antibody disclosed herein comprises the six CDRs of antibody designated as 47A1, 47H1, Hz47H1.v4, 57D12, 61H4, 62G10, 108D10, or 43H2 based on the AbM definition as set forth in Tables 1- 7. In certain embodiments, the anti-LAIR1 antibody disclosed herein comprises the six CDRs of antibody designated as 47A1, 47H1, Hz47H1.v4, 57D12, 61H4, 62G10, 108D10, or 43H2 based on the IMGT definition as set forth in Tables 1-7. In certain embodiments, the anti-LAIR1 antibody disclosed herein comprises the six CDRs of antibody designated as 47A1, 47H1, Hz47H1.v4, 57D12, 61H4, 62G10, 108D10, or 43H2 based on the Contact definition as set forth in Tables 1-7. In certain embodiments, the anti-LAIR1 antibody disclosed herein comprises the six CDRs of antibody designated as 47A1, 47H1, Hz47H1.v4, NAI-1539756353v1 47 57D12, 61H4, 62G10, 108D10, or 43H2 based on the Exemplary definition as set forth in Tables 1-7. [00148] In certain embodiments, the LAIR1 binding agent is an anti-LAIR1 antibody that comprises one, two, three, four, five, and/or six CDRs of any one of the antibodies disclosed herein. In certain embodiments, the anti-LAIR1 antibody comprises (i) a VH comprising one, two, and/or three VH CDRs from Table 1, and/or (ii) a VL comprising one, two, and/or three VL CDRs from Table 1. In certain embodiments, the anti-LAIR1 antibody comprises (i) a VH comprising one, two, and/or three VH CDRs from Table 2A, and/or (ii) a VL comprising one, two, and/or three VL CDRs from Table 2A. In certain embodiments, the anti-LAIR1 antibody comprises (i) a VH comprising one, two, and/or three VH CDRs from Table 2B, and/or (ii) a VL comprising one, two, and/or three VL CDRs from Table 2B. In certain embodiments, the anti-LAIR1 antibody comprises (i) a VH comprising one, two, and/or three VH CDRs from Table 3, and/or (ii) a VL comprising one, two, and/or three VL CDRs from Table 3. In certain embodiments, the anti-LAIR1 antibody comprises (i) a VH comprising one, two, and/or three VH CDRs from Table 4, and/or (ii) a VL comprising one, two, and/or three VL CDRs from Table 4. In certain embodiments, the anti-LAIR1 antibody comprises (i) a VH comprising one, two, and/or three VH CDRs from Table 5, and/or (ii) a VL comprising one, two, and/or three VL CDRs from Table 5. In certain embodiments, the anti-LAIR1 antibody comprises (i) a heavy chain variable region comprising one, two, and/or three VH CDRs from Table 6, and/or (ii) a VL comprising one, two, and/or three VL CDRs from Table 6. In certain embodiments, the anti-LAIR1 antibody comprises (i) a VH comprising one, two, and/or three VH CDRs from Table 7, and/or (ii) a VL comprising one, two, and/or three VL CDRs from Table 7. [00149] In certain embodiments, the LAIR1 binding agent is an anti-LAIR1 antibody that comprises (i) a VH comprising three VH CDRs from Table 1, and (ii) a VL comprising three VL CDRs from Table 1. In certain embodiments, the anti-LAIR1 antibody comprises (i) a VH comprising three VH CDRs from Table 2A, and (ii) a VL comprising three VL CDRs from Table 2A. In certain embodiments, the anti-LAIR1 antibody comprises (i) a VH comprising three VH CDRs from Table 2B, and (ii) a VL comprising three VL CDRs from Table 2B. In certain embodiments, the anti-LAIR1 antibody comprises (i) a VH comprising three VH CDRs from Table 3, and (ii) a VL comprising three VL CDRs from Table 3. In certain embodiments, the anti-LAIR1 antibody comprises (i) a VH comprising three VH CDRs from Table 4, and (ii) a VL comprising three VL CDRs from Table 4. In certain embodiments, the anti-LAIR1 antibody comprises (i) a VH comprising three VH CDRs from NAI-1539756353v1 48 Table 5, and (ii) a VL comprising three VL CDRs from Table 5. In certain embodiments, the anti-LAIR1 antibody comprises (i) a VH comprising three VH CDRs from Table 6, and (ii) a VL comprising three VL CDRs from Table 6. In certain embodiments, the anti-LAIR1 antibody comprises (i) a VH comprising three VH CDRs from Table 7, and (ii) a VL comprising three VL CDRs from Table 7. NAI-1539756353v1 49 Table 1: Antibody 47A1
Figure imgf000051_0001
NAI-1539756353v1 50 Table 2A: Antibody 47H1
Figure imgf000052_0001
NAI-1539756353v1 51 Table 2B: Antibody Hz47H1.v4
Figure imgf000053_0001
NAI-1539756353v1 52 Table 3: Antibody 57D12
Figure imgf000054_0001
NAI-1539756353v1 53 Table 4: Antibody 61H4
Figure imgf000055_0001
NAI-1539756353v1 54 Table 5: Antibodies 62G10 and Hz62G10.v1
Figure imgf000056_0001
NAI-1539756353v1 55 Table 6: Antibody 108D10
Figure imgf000057_0001
NAI-1539756353v1 56 Table 7: Antibody 43H2
Figure imgf000058_0001
NAI-1539756353v1 57 [00150] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from an antibody disclosed herein (e.g., an antibody disclosed in Tables 1-7). In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises: (a) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from an antibody disclosed herein (e.g., an antibody disclosed in Tables 1-7). [00151] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) is a variant of the LAIR1 binding agent (e.g., an antibody) disclosed herein. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) variant comprises amino acid substitutions in the VH and/or the VL as compared to the LAIR1 binding agent disclosed herein. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) variant comprises amino acid substitutions in the VH CDR1, VH CDR2, and/or VH CDR3 and/or the VL CDR1, VL CDR2, and/or VL CDR3 as compared to the LAIR1 binding agent (e.g., an antibody) disclosed herein (e.g., an antibody disclosed in Tables 1-7). In certain embodiments, the LAIR1 binding agent variant comprises one or more (e.g., 1, 2, 3, 4, etc.) amino acid substitutions in a CDR of an antibody disclosed herein (e.g., an antibody disclosed in Tables 1-7). In certain embodiments, the amino acid substitutions are conservative substitutions. In certain embodiments, a CDR comprises one amino acid substitution. In certain embodiments, a CDR comprises two amino acid substitutions. In certain embodiments, a CDR comprises three amino acid substitutions. In certain embodiments, a CDR comprises four amino acid substitutions. In certain embodiments, the CDR is a VH CDR1. In certain embodiments, the CDR is a VH CDR2. In some embodiment, the CDR is a VH CDR3. In certain embodiments, the CDR is a VL CDR1. In certain embodiments, the CDR is a VL CDR2. In certain embodiments, the CDR is a VL CDR3. In certain embodiments, the substitutions are made as part of a humanization process. In certain embodiments, the substitutions are made as part of a germline humanization process. In certain embodiments, the substitutions are made as part of an affinity maturation process. In certain embodiments, the substitutions are made as part of an optimization process. [00152] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises one or more VH CDRs or VL CDRs that have been modified to reduce deamidation within the CDR sequence. Deamidation is a chemical reaction in which an amide functional group in the side chain of the amino acids asparagine (Asn or N) or glutamine (Gln or Q) is removed or converted to another functional group. Generally, asparagine is converted to aspartic acid NAI-1539756353v1 58 or isoaspartic acid and glutamine is converted to glutamic acid or polyglutamic acid. In some situations, deamidation may change the structure, function, and/or stability of a polypeptide, potentially resulting in decreased biological activity. In certain embodiments, the VH CDR1, VH CDR2, and/or VH CDR3 of an antibody disclosed herein is modified to reduce deamidation. In certain embodiments, the VL CDR1, VL CDR2, and/or VL CDR3 of an antibody disclosed herein is modified to reduce deamidation. [00153] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises one or more VH CDRs or VL CDRs that have been modified to reduce isomerization. Isomerization is a chemical process by which a compound is transformed into any of its isomeric forms, i.e., forms with the same chemical composition but with different structure or configuration and, potentially with different physical and chemical properties. Studies have shown that aspartate (Asp or D) isomerization within a CDR can impact antibody binding and/or stability. In certain embodiments, the VH CDR1, VH CDR2, and/or VH CDR3 of an antibody disclosed herein is modified to reduce isomerization. In certain embodiments, the VL CDR1, VL CDR2, and/or VL CDR3 is modified to reduce isomerization. [00154] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises one or more VH CDRs or VL CDRs that have been modified to reduce oxidation. Oxidation is a chemical process by which an oxygen is added to an atom, for example, methionine is converted to methionine sulfoxide by addition of an oxygen to the sulfur atom. Oxidation of one or more amino acids can potentially affect the physical and chemical properties of a protein. Studies have shown that oxidation of methionine (Met or M) within a CDR has the potential to impact antibody binding and/or stability. In certain embodiments, the VH CDR1, VH CDR2, and/or VH CDR3 of an antibody disclosed herein is modified to reduce oxidation. In certain embodiments, the VL CDR1, VL CDR2, and/or VL CDR3 of an antibody disclosed herein is modified to reduce oxidation. [00155] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH and/or a VL that comprises a modification within the amino acid sequence wherein the modification eliminates a glycosylation site. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises one or more VH CDRs or VL CDRs that have been modified to eliminate a glycosylation site. The consensus glycosylation site for N-linked glycans is N-X-S/T, wherein X can be any amino acid except proline. Generally, a glycosylation site within a variable region and/or within a CDR will impact antibody structure, binding, and/or stability. NAI-1539756353v1 59 [00156] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 47A1 (Table 1), a humanized version thereof, or variants thereof. In certain embodiments, the LAIR1 binding agent (e.g., antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from antibody 47A1 (Table 1). In certain embodiments, the LAIR1 binding agent (e.g., antibody) comprises a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 47A1 (Table 1). In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises: (a) a VH comprising a VH CDR1, a VH CDR2, a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 47A1 (Table 1). [00157] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:115; and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:116. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:115; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:116. [00158] CDR sequences can be determined according to well-known numbering systems or a combination thereof. In certain embodiments, the CDRs are according to Kabat numbering. In certain embodiments, the CDRs are according to AbM numbering. In certain embodiments, the CDRs are according to Chothia numbering. In certain embodiments, the CDRs are according to Contact numbering. In certain embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia. Various exemplary CDR numbering systems are described and illustrated above in Section 5.1. [00159] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:9, 15, 18, and 19; a VH CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:10, 16, 17, and 20; and a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:11 and 21; and/or (b) a VL region comprising a VL CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:12 and 22; a VL CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NAI-1539756353v1 60 NOs:13 and 23; and a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:14 and 24. [00160] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:11; and/or (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:14. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises: (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:11; and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:14. [00161] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:15, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:16, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:11; and/or (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:14. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:15, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:16, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:11; and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:14. [00162] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:17, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:11; and/or (b) a VL NAI-1539756353v1 61 comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:14. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:17, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:11, and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:14. [00163] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:18, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, and VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:11, and/or (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:14. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:18, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, and VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:11; and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:14. [00164] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:19, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:20, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:21; and/or (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:22, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:24. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:19, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:20, and a VH CDR3 comprising the amino acid NAI-1539756353v1 62 sequence set forth in SEQ ID NO:21; and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:22, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:24. [00165] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:115; and/or a VL having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:116. In certain embodiments, the binding of the LAIR1 binding agent (e.g., an antibody) thereof to LAIR1 (e.g., human LAIR1) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:115 and/or a VL comprising an amino acid sequence of SEQ ID NO:116. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:115 and a VL comprising an amino acid sequence of SEQ ID NO:116. [00166] In certain embodiments, the LAIR1-binding agent is antibody 47A1 (Table 1). In certain embodiments, the LAIR1-binding agent is a humanized version of antibody 47A1 (Table 1). In certain embodiments, the LAIR1-binding agent is a variant of antibody 47A1 (Table 1) or a variant of a humanized version of 47A1. [00167] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 47H1 (Table 2A), humanized versions thereof (e.g., Hz47H1.v4, Table 2B), or variants thereof. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from antibody 47H1 (Table 2A). In certain embodiments, the LAIR1 binding agent comprises a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 47H1 (Table 2A). In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises: (a) a VH comprising a VH CDR1, a VH CDR2, a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 47H1 (Table 2A). NAI-1539756353v1 63 [00168] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:117; and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:118. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:117; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:118. [00169] CDR sequences can be determined according to well-known numbering systems or a combination thereof. In certain embodiments, the CDRs are according to Kabat numbering. In certain embodiments, the CDRs are according to AbM numbering. In certain embodiments, the CDRs are according to Chothia numbering. In certain embodiments, the CDRs are according to Contact numbering. In certain embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia. [00170] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 25, 31, 34, and 35; a VH CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 32, 33, and 36; and a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 27 and 37; and/or (b) a VL region comprising a VL CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 28 and 38; a VL CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 29 and 39; and a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 30 and 40. [00171] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:26, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:26, a VH NAI-1539756353v1 64 CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30. [00172] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:31, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:32, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:31, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:32, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30. [00173] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:33, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:33, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30. [00174] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:34, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:26, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and/or (b) a VL CDR1 comprising the NAI-1539756353v1 65 amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:34, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:26, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30. [00175] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:36 or set forth in SEQ ID NO:45, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:37; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:38, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:39, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:40. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:36, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:37; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:38, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:39, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:40. [00176] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises: (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:26, or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27, or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30, or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions. NAI-1539756353v1 66 [00177] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:117; and/or a VL having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:118. In certain embodiments, the binding of the LAIR1 binding agent (e.g., an antibody) thereof to LAIR1 (e.g., human LAIR1) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:117, and/or a VL comprising an amino acid sequence of SEQ ID NO:118. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:117, and a VL comprising an amino acid sequence of SEQ ID NO:118. [00178] In certain embodiments, the LAIR1-binding agent (e.g., an antibody) comprises: (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:26, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and (b) a VL comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:118. In certain embodiments, the LAIR1-binding agent (e.g., an antibody) comprises: (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:26, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27, wherein the VH comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:117, and (b) a VL comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:118. In certain embodiments, the LAIR1-binding agent (e.g., an antibody) comprises: (a) a VH comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:117, and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid NAI-1539756353v1 67 sequence set forth in SEQ ID NO:30. In certain embodiments, the LAIR1-binding agent (e.g., an antibody) comprises: (a) a VH comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:117, and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30, wherein the VL comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:118. [00179] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody Hz47H1.v4 (Table 2B), or variants thereof. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from antibody Hz47H1.v4 (Table 2B). In other embodiments, the LAIR1 binding agent comprises a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody Hz47H1.v4 (Table 2B). In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises: (a) a VH comprising a VH CDR1, a VH CDR2, a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody Hz47H1.v4 (Table 2B). [00180] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:119; and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:120. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:119; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:120. [00181] CDR sequences can be determined according to well-known numbering systems or a combination thereof. In certain embodiments, the CDRs are according to Kabat numbering. In certain embodiments, the CDRs are according to AbM numbering. In certain embodiments, the CDRs are according to Chothia numbering. In certain embodiments, the CDRs are according to Contact numbering. In certain embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia. NAI-1539756353v1 68 [00182] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 25, 31, 34, and 35; a VH CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 41, 43, 44 and 45; and a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 27 and 37; and/or (b) a VL region comprising a VL CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 28 and 38; a VL CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 42 and 39; and a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 30 and 40. [00183] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:41, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:41, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30. [00184] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:31, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:43, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:31, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:43, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the NAI-1539756353v1 69 amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30. [00185] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:44, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:44, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30. [00186] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:34, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:41, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:34, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:41, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30. [00187] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:45 or set forth in SEQ ID NO:45, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:37, and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:38, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:39, and a VL CDR3 comprising NAI-1539756353v1 70 the amino acid sequence set forth in SEQ ID NO:40. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:45, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:37; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:38, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:39, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:40. [00188] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:119; and/or a VL having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:120. In certain embodiments, the binding of the LAIR1 binding agent (e.g., an antibody) thereof to LAIR1 (e.g., human LAIR1) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:119, and/or a VL comprising an amino acid sequence of SEQ ID NO:120. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:119, and a VL comprising an amino acid sequence of SEQ ID NO:120. [00189] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises: (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:41, or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27, or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30, or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions. NAI-1539756353v1 71 [00190] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises one or more VH CDRs or VL CDRs that have been modified to reduce deamidation within the CDR sequence. In certain embodiments, the VH CDR2 of antibody 47H1 or Hz47H1.v4 is modified to reduce deamidation. [00191] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises one or more VH CDRs or VL CDRs that have been modified to reduce isomerization. In certain embodiments, the VL CDR2 of antibody 47H1 or Hz47H1.v4 is modified to reduce isomerization. [00192] In certain embodiments, the LAIR1-binding agent (e.g., an antibody) comprises: (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:41, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27, and (b) a VL comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:120. In certain embodiments, the LAIR1-binding agent (e.g., an antibody) comprises: (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:41, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27, wherein the VH comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:119, and (b) a VL comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:120. In certain embodiments, the LAIR1-binding agent (e.g., an antibody) comprises: (a) a VH comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:119, and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30. In certain embodiments, the LAIR1-binding agent (e.g., an antibody) comprises: (a) a VH comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:119, and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30, wherein the VL comprises at least 80%, at least 85%, at least 90%, at least NAI-1539756353v1 72 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:120. [00193] In certain embodiments, the LAIR1-binding agent (e.g., an antibody) comprises: (a) a heavy chain comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:41, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27, and (b) a light chain comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30, wherein the heavy chain comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:134, and wherein the light chain comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:136. In certain embodiments, the LAIR1- binding agent (e.g., an antibody) comprises: (a) a heavy chain comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:41, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27, and (b) a light chain comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30, wherein the heavy chain comprises at least 95% sequence identity to the amino acid sequence of SEQ ID NO:134, and wherein the light chain comprises at least 95% sequence identity to the amino acid sequence of SEQ ID NO:136. In certain embodiments, the LAIR1-binding agent (e.g., an antibody) comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:134 and (b) a light chain comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30, wherein the light chain comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to the amino acid sequence of SEQ ID NO:136. In certain embodiments, the LAIR1-binding agent (e.g., an antibody) comprises: (a) a heavy chain comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:41, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27, NAI-1539756353v1 73 wherein the heavy chain comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to the amino acid sequence of SEQ ID NO:134, and (b) a light chain comprising the amino acid sequence of SEQ ID NO:136. In certain embodiments, the LAIR1-binding agent is an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:134 and a light chain comprising the amino acid sequence of SEQ ID NO:136. [00194] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) is antibody 47H1. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) is a humanized version of antibody 47H1 (e.g., Hz47H1.v4). In certain embodiments, the LAIR1 binding agent is a variant of antibody 47H1 or a variant of a humanized version of 47H1 (e.g., Hz47H1.v4). In certain embodiments, the LAIR1 binding agent is antibody Hz47H1.v4. [00195] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 57D12 (Table 3), a humanized version thereof, or variants thereof. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from antibody 57D12 (Table 3). In other embodiments, the LAIR1 binding agent comprises a VL comprising a VL CDR1, VL CDR2, and a VL CDR3 from antibody 57D12 (Table 3). In certain embodiments, the LAIR1 binding agent comprises: (a) a VH comprising a VH CDR1, a VH CDR2, a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 57D12 (Table 3). [00196] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:121; and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:122. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:121; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:122. [00197] CDR sequences can be determined according to well-known numbering systems or a combination thereof. In certain embodiments, the CDRs are according to Kabat numbering. In certain embodiments, the CDRs are according to AbM numbering. In certain embodiments, the CDRs are according to Chothia numbering. In certain embodiments, the CDRs are according to Contact numbering. In certain embodiments, the CDR sequences are NAI-1539756353v1 74 determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia. [00198] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) provided herein comprises (a) a VH comprising a VH CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 46, 52, 55 and 56; a VH CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 47, 53, 54 and 57; and a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 48 and 58; and/or (b) a VL region comprising a VL CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 49 and 59; a VL CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 50 and 60; and a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 51 and 61. [00199] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:46, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:47, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:48; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:49, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:50, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:51. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:46, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:47, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:48; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:49, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:50, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:51. [00200] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:52, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:53, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:48; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:49, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:50, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:51. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:52, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:53, a VH NAI-1539756353v1 75 CDR3 comprising the amino acid sequence set forth in SEQ ID NO:48; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:49, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:50, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:51. [00201] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:46, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:54, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:48; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:49, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:50, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:51. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:46, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:54, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:48; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:49, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:50, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:51. [00202] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:55, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:47, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:48, and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:49, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:50, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:51. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:55, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:47, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:48; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:49, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:50, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:51. [00203] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:56, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:57, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:58; and/or (b) a VL CDR1 comprising the NAI-1539756353v1 76 amino acid sequence set forth in SEQ ID NO:59, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:60, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:61. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:56, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:57, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:58; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:59, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:60, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:61. [00204] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:121, and/or a VL having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:122. In certain embodiments, the binding of the LAIR1 binding agent (e.g., an antibody) thereof to LAIR1 (e.g., human LAIR1) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:121, and/or a VL comprising an amino acid sequence of SEQ ID NO:122. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:121, and a VL comprising an amino acid sequence of SEQ ID NO:122. [00205] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) is antibody 57D12 (Table 3). In certain embodiments, the LAIR1 binding agent (e.g., an antibody) is a humanized version of antibody 57D12 (Table 3). In certain embodiments, the LAIR1 binding agent (e.g., an antibody) is a variant of antibody 57D12 (Table 3) or a variant of a humanized version of antibody 57D12 (Table 3). [00206] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 and/or a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 61H4 (Table 4), a humanized version thereof, or variants thereof. In certain embodiments, the LAIR1 binding agent comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from antibody 61H4 (Table 4). In other embodiments, the LAIR1 NAI-1539756353v1 77 binding agent comprises a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 61H4 (Table 4). In certain embodiments, the LAIR1 binding agent comprises: (a) a VH comprising a VH CDR1, a VH CDR2, a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 61H4 (Table 4). [00207] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2; and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:123 and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:124. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:123; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:124. [00208] CDR sequences can be determined according to well-known numbering systems or a combination thereof. In certain embodiments, the CDRs are according to Kabat numbering. In certain embodiments, the CDRs are according to AbM numbering. In certain embodiments, the CDRs are according to Chothia numbering. In certain embodiments, the CDRs are according to Contact numbering. In certain embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia. [00209] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 62, 68, 71, and 72; a VH CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 63, 69, 70, and 73; and a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 64 and 74; and/or (b) a VL region comprising a VL CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 65 and 75; a VL CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 66 and 76; and a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 67 and 77. [00210] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:62, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:63, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:64; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:65, a VL CDR2 comprising the amino acid NAI-1539756353v1 78 sequence set forth in SEQ ID NO:66, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:67. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:62, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:63, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:64; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:65, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:66, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:67. [00211] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:68, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:69, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:64; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:65, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:66, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:67. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:68, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:69, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:64; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:65, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:66, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:67. [00212] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:62, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:70, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:64; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:65, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:66, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:67. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:62, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:70, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:64; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:65, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:66, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:67. NAI-1539756353v1 79 [00213] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:71, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:63, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:64; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:65, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:66, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:67. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:71, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:63, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:64; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:65, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:66, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:67. [00214] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:72, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:73, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:74; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:75, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:76, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:77. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:72, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:73, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:74; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:75, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:76, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:77. [00215] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:123, and/or a VL having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:124. In certain embodiments, the binding of the LAIR1 binding agent (e.g., an antibody) thereof to LAIR1 (e.g., human LAIR1) is NAI-1539756353v1 80 maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:123 and/or a VL comprising an amino acid sequence of SEQ ID NO:124. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:123 and a VL comprising an amino acid sequence of SEQ ID NO:124. [00216] In certain embodiments, the LAIR1-binding agent is antibody 61H4 (Table 4). In certain embodiments, the LAIR1-binding agent is a humanized version of antibody 61H4 (Table 4). In certain embodiments, the LAIR1-binding agent is a variant of antibody 61H4 (Table 4) or a variant of a humanized antibody 61H4 (Table 4). [00217] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 and/or a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 62G10 or Hz62G10.v1 (Table 5), a humanized version thereof, or variants thereof. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from antibody 62G10 or Hz62G10.v1 (Table 5). In other embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 62G10 or Hz62G10.v1 (Table 5). In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises: (a) a VH comprising a VH CDR1, a VH CDR2, a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 62G10 or Hz62G10.v1 (Table 5). [00218] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:125; and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:126. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:125; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:126. [00219] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:127; and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NAI-1539756353v1 81 NO:128. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:127; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:128. [00220] CDR sequences can be determined according to well-known numbering systems or a combination thereof. In certain embodiments, the CDRs are according to Kabat numbering. In certain embodiments, the CDRs are according to AbM numbering. In certain embodiments, the CDRs are according to Chothia numbering. In certain embodiments, the CDRs are according to Contact numbering. In certain embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia. [00221] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 25, 31, 34, and 35; a VH CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 78, 82, 83, and 84; and a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 79 and 85; and/or (b) a VL region comprising a VL CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 80 and 86; a VL CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 29 and 39; and a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 81 and 87. [00222] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:78, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:78, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81. NAI-1539756353v1 82 [00223] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:31, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:82, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:31, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:82, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81. [00224] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:83, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:83, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81. [00225] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:34, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:78, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NAI-1539756353v1 83 NO:34, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:78, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81. [00226] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:84, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:85; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:86, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:39, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:87. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:84, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:85; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:86, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:39, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:87. [00227] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:125, and/or a VL having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:126. In certain embodiments, the binding of the LAIR1 binding agent (e.g., an antibody) thereof to LAIR1 (e.g., human LAIR1) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:125 and a VL region comprising the amino acid sequence of SEQ ID NO:126. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:125 and/or a VL region comprising the amino acid sequence of SEQ ID NO:126. NAI-1539756353v1 84 [00228] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:127, and/or a VL having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:128. In certain embodiments, the binding of the LAIR1 binding agent (e.g., an antibody) thereof to LAIR1 (e.g., human LAIR1) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:127, and/or a VL comprising the amino acid sequence of SEQ ID NO:128. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:127, and a VL comprising the amino acid sequence of SEQ ID NO:128. [00229] In certain embodiments, the LAIR1-binding agent comprises: (a) a heavy chain comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:78, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79, and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81, wherein the heavy chain comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:138, and wherein the light chain comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:140. In certain embodiments, the LAIR1-binding agent comprises: (a) a heavy chain comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:78, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79, and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81, wherein the heavy chain comprises at least 95% sequence identity to the amino acid sequence of SEQ ID NAI-1539756353v1 85 NO:138, and wherein the light chain comprises at least 95% sequence identity to the amino acid sequence of SEQ ID NO:140. In certain embodiments, the LAIR1-binding agent comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:138 and (b) a light chain comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81, wherein the light chain comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to the amino acid sequence of SEQ ID NO:140. In certain embodiments, the LAIR1-binding agent comprises: (a) a heavy chain comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:78, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79, wherein the heavy chain comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to the amino acid sequence of SEQ ID NO:138, and (b) a light chain comprising the amino acid sequence of SEQ ID NO:140. In certain embodiments, the LAIR1-binding agent is an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:138 and a light chain comprising the amino acid sequence of SEQ ID NO:140. [00230] In certain embodiments, the LAIR1-binding agent (e.g., an antibody) is antibody 62G10 (Table 5). In certain embodiments, the LAIR1-binding agent is a humanized version of antibody 62G10 (e.g., Hz62G10.v1) (Table 5). In certain embodiments, the LAIR1- binding agent (e.g., an antibody) is a variant of antibody 62G10 (Table 5) or a variant of humanized antibody 62G10 (Table 5). In certain embodiments, the LAIR1-binding agent (e.g., an antibody) is antibody Hz62G10.v1 (Table 5). [00231] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 and/or a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 108D10 (Table 6), a humanized version thereof, or variants thereof. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from antibody 108D10 (Table 6). In other embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 108D10 (Table 6). In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises: (a) a comprising a VH CDR1, a VH CDR2, a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 108D10 (Table 6). NAI-1539756353v1 86 [00232] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) provided herein comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:129; and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:130. In certain embodiments, the LAIR1 binding agent provided (e.g., an antibody) herein comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:129; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:130. [00233] CDR sequences can be determined according to well-known numbering systems or a combination thereof. In certain embodiments, the CDRs are according to Kabat numbering. In certain embodiments, the CDRs are according to AbM numbering. In certain embodiments, the CDRs are according to Chothia numbering. In certain embodiments, the CDRs are according to Contact numbering. In certain embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia. [00234] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 25, 31, 34, and 35; a VH CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 88, 32, 93, and 94; and a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 89 and 95; and/or (b) a VL region comprising a VL CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 90 and 96; a VL CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 91 and 97; and a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 92 and 98. [00235] In certain embodiments, the LAIR1 binding (e.g., an antibody) agent comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:88, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:89; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:90, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:91, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:92. In certain embodiments, the LAIR1 binding (e.g., an antibody) agent comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:88, a VH NAI-1539756353v1 87 CDR3 comprising the amino acid sequence set forth in SEQ ID NO:89; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:90, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:91, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:92. [00236] In certain embodiments, the LAIR1 binding (e.g., an antibody) agent comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:31, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:32, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:89; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:90, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:91, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:92. In certain embodiments, the LAIR1 binding (e.g., an antibody) agent comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:31, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:32, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:89; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:90, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:91, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:92. [00237] In certain embodiments, the LAIR1 binding (e.g., an antibody) agent comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:93, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:89; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:90, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:91, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:92. In certain embodiments, the LAIR1 binding (e.g., an antibody) agent comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:93, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:89; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:90, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:91, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:92. [00238] In certain embodiments, the LAIR1 binding (e.g., an antibody) agent comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:34, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:88, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:89; and/or (b) a VL CDR1 comprising the NAI-1539756353v1 88 amino acid sequence set forth in SEQ ID NO:90, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:91, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:92. In certain embodiments, the LAIR1 binding (e.g., an antibody) agent comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:34, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:88, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:89; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:90, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:91, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:92. [00239] In certain embodiments, the LAIR1 binding (e.g., an antibody) agent comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:94, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:95; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:96, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:97), and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:98). In certain embodiments, the LAIR1 binding (e.g., an antibody) agent comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:94, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:95; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:96, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:97), and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:98). [00240] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:129; and/or a VL having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:130. In certain embodiments, the binding of the LAIR1 binding agent (e.g., an antibody) thereof to LAIR1 (e.g., human LAIR1) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:129 and/or a VL comprising an amino acid sequence of SEQ ID NO:130. In certain NAI-1539756353v1 89 embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:129 and a VL comprising an amino acid sequence of SEQ ID NO:130. [00241] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) is antibody 108D10 (Table 6). In certain embodiments, the LAIR1 binding agent (e.g., an antibody) is a humanized version of antibody 108D10 (Table 6). In certain embodiments, the LAIR1 binding agent (e.g., an antibody) is a variant of antibody 108D10 (Table 6) or a variant of humanized antibody 108D10 (Table 6). [00242] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) binds mouse LAIR1. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 43H2 (Table 7) or variants thereof. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from antibody 43H2 (Table 7). In other embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 43H2 (Table 7). In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises: (a) a VH comprising a VH CDR1, a VH CDR2, a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 43H2 (Table 7). [00243] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:131; and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:132. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:131; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:132. [00244] CDR sequences can be determined according to well-known numbering systems or a combination thereof. In certain embodiments, the CDRs are according to Kabat numbering. In certain embodiments, the CDRs are according to AbM numbering. In certain embodiments, the CDRs are according to Chothia numbering. In certain embodiments, the CDRs are according to Contact numbering. In certain embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia. NAI-1539756353v1 90 [00245] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 99, 105, 108, and 109; a VH CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 100, 106, 107, and 110; and a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 101 and 111; and/or (b) a VL region comprising a VL CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 102 and 112; a VL CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 103 and 113; and a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 104 and 114. [00246] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:99, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:100, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:101; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:102, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:103, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:104. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:99, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:100, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:101; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:102, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:103, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:104. [00247] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:105, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:106, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:101; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:102, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:103, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:104. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:105, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:106, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:101; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:102, a VL CDR2 comprising the NAI-1539756353v1 91 amino acid sequence set forth in SEQ ID NO:103, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:104. [00248] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:99, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:107, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:101; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:102, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:103, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:104. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:99, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:107, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:101; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:102, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:103, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:104. [00249] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:108, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:100, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:101; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:102, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:103, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:104. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:108, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:100, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:101; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:102, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:103, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:104. [00250] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:109, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:110, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:111; and/or (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:112, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:113, and a VL CDR3 comprising the amino acid sequence NAI-1539756353v1 92 set forth in SEQ ID NO:114. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises (a) a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:109, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:110, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:111; and (b) a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:112, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:113, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:114. [00251] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:131; and/or a VL having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:132. In certain embodiments, the binding of the LAIR1 binding agent (e.g., an antibody) thereof to LAIR1 (e.g., human LAIR1) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:131 and/or a VL comprising an amino acid sequence of SEQ ID NO:132. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:131 and a VL comprising an amino acid sequence of SEQ ID NO:132. [00252] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) is antibody 43H2 (Table 7). In certain embodiments, the LAIR1 binding agent (e.g., an antibody) is a humanized version of antibody 43H2 (Table 7). In certain embodiments, the LAIR1 binding agent (e.g., an antibody) is a variant of antibody 43H2 (Table 7) or a variant of humanized antibody 43H2 (Table 7). [00253] Provided herein are LAIR1 binding agents that compete with one or more of the LAIR1 binding agents disclosed herein for binding to LAIR1. In certain embodiments, the LAIR1 binding agent competes with one or more of the LAIR1 binding agents disclosed herein for binding to human LAIR1. In certain embodiments, the LAIR1 binding agent that competes with one or more of the LAIR1 binding agents disclosed herein is an antibody. [00254] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti- NAI-1539756353v1 93 LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:115 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:116. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti-LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:115, and a VL comprising the amino acid sequence of SEQ ID NO:116. [00255] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:117 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:118. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti-LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:117, and a VL comprising the amino acid sequence of SEQ ID NO:118. [00256] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:119 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:120. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti-LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:119, and a VL comprising the amino acid sequence of SEQ ID NO:120. [00257] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:121 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:122. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti-LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:121, and a VL comprising the amino acid sequence of SEQ ID NO:122. NAI-1539756353v1 94 [00258] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:123 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:124. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti-LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:123, and a VL comprising the amino acid sequence of SEQ ID NO:124. [00259] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:125 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:126. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti-LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:125, and a VL comprising the amino acid sequence of SEQ ID NO:126. [00260] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:127 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:128. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti-LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:127, and a VL comprising the amino acid sequence of SEQ ID NO:128. [00261] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:129 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:130. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) specifically binds to LAIR1 (e.g., human LAIR1) competitively with an anti-LAIR1 antibody NAI-1539756353v1 95 comprising a VH comprising the amino acid sequence of SEQ ID NO:129, and a VL comprising the amino acid sequence of SEQ ID NO:130. [00262] In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) specifically binds to LAIR1 (e.g., mouse LAIR1) competitively with an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:131 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:132. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) specifically binds to LAIR1 (e.g., mouse LAIR1) competitively with an anti-LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:131, and a VL comprising the amino acid sequence of SEQ ID NO:132. [00263] In certain embodiments, functional epitopes can be mapped, e.g., by combinatorial alanine scanning, to identify amino acids in the LAIR1 protein that are necessary for interaction with LAIR1 binding agents (such as antibodies) provided herein. In certain embodiments, conformational and crystal structure of LAIR1 binding agents (such as antibodies) bound to LAIR1 may be employed to identify the epitopes. In certain embodiments, the present disclosure provides an antibody that specifically binds to the same epitope as any of the LAIR1 binding agents (such as antibodies or fragments thereof) provided herein. [00264] For example, in certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:115 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:116. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti- LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:115, and a VL comprising the amino acid sequence of SEQ ID NO:116. [00265] For example, in certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:117 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:118. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti- NAI-1539756353v1 96 LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:117, and a VL comprising the amino acid sequence of SEQ ID NO:118. [00266] For example, in certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:119 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:120. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti- LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:119, and a VL comprising the amino acid sequence of SEQ ID NO:120. [00267] For example, in certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:121 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:122. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti- LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:121, and a VL comprising the amino acid sequence of SEQ ID NO:122. [00268] For example, in certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:123 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:124. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti- LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:123, and a VL comprising the amino acid sequence of SEQ ID NO:124. [00269] For example, in certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:125 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:126. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti- LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:125, and a VL comprising the amino acid sequence of SEQ ID NO:126. NAI-1539756353v1 97 [00270] For example, in certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:127 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:128. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti- LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:127, and a VL comprising the amino acid sequence of SEQ ID NO:128. [00271] For example, in certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:129 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:130. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti- LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:129, and a VL comprising the amino acid sequence of SEQ ID NO:130. [00272] For example, in certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti- LAIR1 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:131 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:132. In certain embodiments, the LAIR1 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti- LAIR1 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:131, and a VL comprising the amino acid sequence of SEQ ID NO:132. [00273] In certain embodiments, the LAIR1 binding agent disclosed herein comprises an antibody in which at least one or more of the constant regions of the antibody has been modified or deleted. In certain embodiments, an antibody comprises one or more modifications to one or more of the heavy chain constant regions (CH1, CH2, CH3, or CH4) and/or to the light chain constant region (CL). In certain embodiments, an antibody comprises one or more modifications to the hinge region. In certain embodiments, the heavy chain constant region of the modified antibody comprises at least one human constant region. In certain embodiments, the heavy chain constant region of the modified antibody comprises more than one human constant region. In certain embodiments, modifications to the constant region comprise additions, deletions, or substitutions of one or more amino acids in one or NAI-1539756353v1 98 more regions. In certain embodiments, one or more regions are partially or entirely deleted from the constant regions of a modified antibody. In certain embodiments, the entire CH2 domain has been removed from an antibody (ΔCH2 constructs). In certain embodiments, one or more regions are partially or entirely deleted from the hinge region of a modified antibody. In certain embodiments, a deleted constant region is replaced by a short amino acid spacer that provides some of the molecular flexibility typically imparted by the absent constant region. In certain embodiments, a deleted hinge region is replaced by a short amino acid spacer that provides some of the molecular flexibility typically imparted by the absent hinge region. In certain embodiments, a modified antibody comprises a CH3 domain directly fused to the hinge region of the antibody. In certain embodiments, a modified antibody comprises a peptide spacer inserted between the hinge region and modified CH2 and/or CH3 domains. [00274] It is known in the art that the constant region(s) of an antibody mediates several effector functions and these effector functions can vary depending on the isotype of the antibody. For example, binding of the C1q component of complement to the Fc region of IgG or IgM antibodies when the antibodies are bound to antigen activates the complement system. Activation of complement is important in the opsonization and lysis of cell pathogens. The activation of complement also stimulates the inflammatory immune response and can be involved in autoimmune hypersensitivity. In addition, the Fc region of an antibody can bind a cell expressing a Fc receptor (FcR). There are a number of Fc receptors that are specific for different classes of antibody, including IgG (gamma receptors), IgE (epsilon receptors), IgA (alpha receptors) and IgM (mu receptors). Binding of antibody to Fc receptors on cell surfaces triggers a number of important and diverse biological responses including, but not limited to, engulfment and destruction of antibody-coated particles, clearance of immune complexes, lysis of antibody-coated target cells by killer cells (i.e., antibody-dependent cell cytotoxicity or ADCC), release of inflammatory mediators, placental transfer, and control of immunoglobulin production. [00275] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) comprises a variant constant region or Fc region. The amino acid sequences of the constant region or Fc region of human IgG1, IgG2, IgG3, and IgG4 are known to those of ordinary skill in the art (e.g., a representative human IgG1 constant region is SEQ ID NO:141). In some cases, constant regions or Fc regions with amino acid variations have been identified in native antibodies. In certain embodiments, a variant constant region or Fc region is engineered with substitutions at specific amino acid positions as compared to a native constant region or Fc region. Variant constant region or Fc regions are well-known in the art and include, but are NAI-1539756353v1 99 not limited to, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:158, and SEQ ID NO:159. [00276] In certain embodiments, a modified antibody provides for altered effector functions that, in turn, affect the biological profile of the antibody. For example, in certain embodiments, the deletion or inactivation (through point mutations or other means) of a constant region reduces binding of a modified antibody to a Fc receptor. In certain embodiments, constant region modifications increase the serum half-life of an antibody. In certain embodiments, constant region modifications reduce the serum half-life of an antibody. In certain embodiments, constant region modifications decrease or remove ADCC and/or complement-dependent cytotoxicity (CDC) of an antibody. In certain embodiments, a human IgG1 Fc region with specific amino acid substitutions corresponding to IgG2 or IgG4 residues reduce effector functions (e.g., ADCC and CDC) in a modified antibody. In certain embodiments, a modified antibody does not have one or more effector functions. In certain embodiments, a modified antibody has no ADCC activity and/or no CDC activity. In certain embodiments, a modified antibody does not bind an Fc receptor and/or complement factors. In certain embodiments, a modified antibody does not have any detectable effector functions (e.g., an “effectorless” antibody). In certain embodiments, constant region modifications increase or enhance ADCC and/or CDC of an antibody. In certain embodiments, the constant region is modified to eliminate disulfide linkages or oligosaccharide moieties. In certain embodiments, the constant region is modified to add/substitute one or more amino acids to provide one or more cytotoxin, oligosaccharide, or carbohydrate attachment sites. [00277] Modifications to the constant region of antibodies disclosed herein may be made using well-known biochemical or molecular engineering techniques. In certain embodiments, antibody variants are prepared by introducing appropriate nucleotide changes into the encoding DNA, and/or by synthesis of the desired antibody or polypeptide. Using these engineering techniques to modify an antibody it may be possible to disrupt the activity or effector function provided by a specific sequence or region while substantially maintaining the structure, binding activity, and other desired characteristics of the modified antibody. [00278] The present disclosure further embraces additional variants and equivalents that are substantially homologous to the recombinant, monoclonal, chimeric, humanized, and human antibodies, or antibody fragments thereof, disclosed herein. In certain embodiments, it is desirable to improve the binding affinity of the antibody. In certain embodiments, it is desirable to modulate biological properties of the antibody, including but not limited to, specificity, thermostability, expression level, effector function(s), glycosylation, NAI-1539756353v1 100 immunogenicity, and/or solubility. Those skilled in the art will appreciate that amino acid changes may alter post-translational processes of an antibody, such as changing the number or position of glycosylation sites or altering membrane anchoring characteristics. [00279] Variations may be a substitution, deletion, or insertion of one or more nucleotides encoding the antibody or polypeptide that results in a change in the amino acid sequence as compared with the native antibody or polypeptide sequence. In certain embodiments, amino acid substitutions are the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, such as the replacement of a leucine with a serine (i.e., conservative amino acid replacements). In certain embodiments, the substitution, deletion, or insertion includes less than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid substitutions, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less than 4 amino acid substitutions, less than 3 amino acid substitutions, or less than 2 amino acid substitutions relative to the parent molecule. In certain embodiments, variations in the amino acid sequence that are biologically useful and/or relevant are determined by systematically making insertions, deletions, or substitutions in the sequence and testing the resulting variant proteins for activity as compared to the parental antibody. [00280] In certain embodiments, variants may include addition of amino acid residues at the amino- and/or carboxyl-terminal end of the antibody or polypeptide. The length of additional amino acids residues may range from one residue to a hundred or more residues. In certain embodiments, a variant comprises an N-terminal methionyl residue. In certain embodiments, the variant comprises an additional polypeptide/protein to create a fusion protein. In certain embodiments, a variant is engineered to be detectable and may comprise a detectable label and/or protein (e.g., a fluorescent tag, a fluorescent protein, or an enzyme). [00281] In certain embodiments, a cysteine residue not involved in maintaining the proper conformation of an antibody is substituted or deleted to modulate the antibody’s characteristics, for example, to improve oxidative stability and/or prevent aberrant disulfide crosslinking. Conversely, in certain embodiments, one or more cysteine residues are added to create disulfide bond(s) to improve stability. [00282] In certain embodiments, an antibody of the present disclosure is “deimmunized”. The deimmunization of antibodies generally consists of introducing specific amino acid mutations (e.g., substitutions, deletions, additions) that result in removal of T-cell epitopes (known or predicted) without significantly reducing the binding affinity or other desired activities of the antibody. NAI-1539756353v1 101 [00283] The variant antibodies or polypeptides disclosed herein may be generated using methods known in the art, including but not limited to, site-directed mutagenesis, alanine scanning mutagenesis, and PCR mutagenesis. [00284] In certain embodiments, the LAIR1 binding agent disclosed herein is chemically modified. In certain embodiments, the LAIR1 binding agent is the anti-LAIR1 antibody that is chemically modified by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, and/or linkage to a cellular ligand or other protein. Any of numerous chemical modifications may be carried out by known techniques. In certain embodiments, the LAIR1 binding agent is attached (either directly or indirectly) to a half-life extending moiety including, but not limited to, polyethylene glycol (PEG), a PEG mimetic, XTEN®, serum albumin, polysialic acid, N-(2- hydroxypropyl)methacrylamide, or dextran. In certain embodiments, the LAIR1 binding agent is an antibody, wherein the antibody is attached (either directly or indirectly) to a half- life extending moiety including, but not limited to, polyethylene glycol (PEG), a PEG mimetic, XTEN®, serum albumin, polysialic acid, N-(2-hydroxypropyl)methacrylamide, or dextran. In certain embodiments, the LAIR1 binding agent is an antibody fragment (e.g., scFv, Fv, Fab, F(ab′)2, or F(ab′)), wherein the antibody fragment is attached (either directly or indirectly) to a half-life extending moiety including, but not limited to, polyethylene glycol (PEG), a PEG mimetic, XTEN®, serum albumin, polysialic acid, N-(2- hydroxypropyl)methacrylamide, or dextran. [00285] The present disclosure encompasses LAIR1 binding agents built upon non- immunoglobulin backbones, wherein the agents bind the same epitope or essentially the same epitope as the anti-LAIR1 antibody disclosed herein. In certain embodiments, a non- immunoglobulin-based binding agent is an agent that competes with the LAIR1 binding agent disclosed herein in a competitive binding assay. In certain embodiments, alternative LAIR1 binding agents comprise a scaffold protein. Generally, scaffold proteins can be assigned to one of three groups based on the architecture of their backbone (1) scaffolds consisting of α- helices; (2) small scaffolds with few secondary structures or an irregular architecture of α- helices and β-sheets; and (3) scaffolds consisting of predominantly β-sheets. Scaffold proteins include, but are not limited to, (i) anticalins, which are based upon the lipocalin scaffold; (ii) adnectins, which are based on the 10th domain of human fibronectin type 3; (iii) affibodies, which are based on the B-domain in the Ig-binding region of Staphylococcus aureus protein A; (iv) darpins, which are based on ankyrin repeat domain proteins; (v) fynomers, which are based on the SH3 domain of the human Fyn protein kinase; (vi) affitins, NAI-1539756353v1 102 which are based on Sac7d from Sulfolobus acidocaldarius; (vii) affilins, which are based on human γ-B-crystallin or human ubiquitin; (viii) avimers, which are based on the A-domains of membrane receptor proteins; (ix) knottins (cysteine knot miniproteins), which are based upon a stable 30-amino acid anti-parallel β-strand protein fold; and (x) Kunitz domain inhibitor scaffolds, which are based upon a structure that contains three disulfide bonds and three loops. [00286] In certain embodiments, the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 shown in Table 1. In certain embodiments, the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:11, a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:14. In certain embodiments, the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3 and/or a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 47A1. [00287] In certain embodiments, the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 shown in Tables 2A or 2B. In certain embodiments, the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:26 or set forth in SEQ ID NO:41, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27, a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29 or set forth in SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30. In certain embodiments, the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 47H1 or Hz47H1.v4. [00288] In certain embodiments, the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 shown in Table 3. In certain embodiments, the LAIR1 binding agent NAI-1539756353v1 103 comprises an engineered scaffold protein comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:46, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:47, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:48, a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:49, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:50, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:51. In certain embodiments, the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 57D12. [00289] In certain embodiments, the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 shown in Table 4. In certain embodiments, the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:62, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:63, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:64, a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:65, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:66, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:67. In certain embodiments, the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 61H4. [00290] In certain embodiments, the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 shown in Table 5. In certain embodiments, the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:78, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:79, a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:80, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81. In certain embodiments, the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 62G10 or Hz62G10.v1. NAI-1539756353v1 104 [00291] In certain embodiments, the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 shown in Table 6. In certain embodiments, the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:88, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:89, a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:90, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:91, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:92. In certain embodiments, the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 108D10. [00292] In certain embodiments, the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL CDR1, a VL CDR2, and a VL CDR3 shown in Table 7. In certain embodiments, the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:99, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:100, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:101, a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:102, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:103, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:104. In certain embodiments, the LAIR1 binding agent comprises an engineered scaffold protein comprising a VH CDR1, a VH CDR2, and a VH CDR3; and a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 43H2. [00293] The present disclosure further provides a composition comprising a LAIR1 binding agent (e.g., an antibody) disclosed herein. In certain embodiments, the composition comprises an anti-LAIR1 antibody disclosed herein. In certain embodiments, the composition comprises a monoclonal anti-LAIR1 antibody disclosed herein. In certain embodiments, the composition comprises an antibody selected from the group consisting of: antibody 47A1, antibody 47H1, antibody 57D12, antibody 61H4, antibody 62G10, antibody 108D10, and humanized versions thereof. In certain embodiments, the composition comprises an antibody selected from the group consisting of: antibody 47A1, antibody 47H1, antibody Hz47H1.v4, antibody 57D12, antibody 61H4, antibody 62G10, antibody Hz62G10.v1, antibody 108D10, and any combinations thereof. NAI-1539756353v1 105 [00294] The present disclosure further provides a pharmaceutical composition comprising a LAIR1 binding agent (e.g., an antibody) disclosed herein and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises an anti-LAIR1 antibody disclosed herein and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a monoclonal anti-LAIR1 antibody disclosed herein and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises an antibody selected from the group consisting of: antibody 47A1, antibody 47H1, antibody 57D12, antibody 61H4, antibody 62G10, antibody 108D10, and humanized versions thereof and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises an antibody selected from the group consisting of: antibody 47A1, antibody 47H1, antibody Hz47H1.v4, antibody 57D12, antibody 61H4, antibody 62G10, antibody Hz62G10.v1, antibody 108D10, and any combinations thereof; and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises antibody Hz47H1.v4 and a pharmaceutically acceptable carrier. In certain embodiments,the pharmaceutical composition comprises antibody Hz62G10.v1 and a pharmaceutically acceptable carrier. [00295] In certain embodiments, the LAIR1 binding agent (e.g., an antibody) is isolated. In certain embodiments, the LAIR1 binding agent (e.g., an antibody) is substantially pure. [00296] The LAIR1 binding agents disclosed herein can be produced by any suitable method known in the art. Such methods range from direct protein synthesis methods to constructing a DNA sequence encoding polypeptide sequences and expressing those sequences in a suitable host. In certain embodiments, a DNA sequence is constructed using recombinant technology by isolating or synthesizing a DNA sequence encoding a wild-type protein of interest. Optionally, the sequence can be mutagenized by site-specific mutagenesis to provide functional variants thereof. In certain embodiments, a DNA sequence encoding a polypeptide of interest is constructed by chemical synthesis using an oligonucleotide synthesizer. Oligonucleotides can be designed based on the amino acid sequence of the desired polypeptide and selecting those codons that are favored in the host cell in which the recombinant polypeptide of interest will be produced. Standard methods can be applied to synthesize a polynucleotide sequence encoding an isolated polypeptide of interest. For example, a complete amino acid sequence can be used to construct a back-translated gene. Further, a DNA oligomer containing a nucleotide sequence coding for the particular isolated polypeptide can be synthesized. For example, several oligonucleotides coding for portions of NAI-1539756353v1 106 the desired polypeptide can be synthesized and then ligated. The individual oligonucleotides typically contain 5′ or 3′ overhangs for complementary assembly. [00297] Once assembled (by synthesis, site-directed mutagenesis, or another method), the polynucleotide sequences encoding a particular polypeptide of interest can be inserted into an expression vector and operatively linked to an expression control sequence appropriate for expression of the protein in a desired host. Proper assembly can be confirmed by nucleotide sequencing, restriction enzyme mapping, and/or expression of a biologically active polypeptide in a suitable host. [00298] In certain embodiments, recombinant expression vectors are used to amplify and express DNA encoding the LAIR1 binding agents disclosed herein. For example, recombinant expression vectors can be replicable DNA constructs which have synthetic or cDNA-derived DNA fragments encoding a polypeptide chain of a LAIR1 binding agent, such as an anti-LAIR1 antibody, or antigen-binding fragment thereof, operatively linked to suitable transcriptional and/or translational regulatory elements derived from mammalian, microbial, viral or insect genes. A transcriptional unit generally comprises an assembly of: (i) a genetic element or elements having a regulatory role in gene expression, for example, transcriptional promoters or enhancers, (ii) a structural or coding sequence that is transcribed into mRNA and translated into protein, and (iii) appropriate transcription and translation initiation and termination sequences. Regulatory elements can include an operator sequence to control transcription. The ability to replicate in a host, usually conferred by an origin of replication, and a selection gene to facilitate recognition of transformants can additionally be incorporated. DNA regions are “operatively linked” when they are functionally related to each other. For example, DNA for a signal peptide (secretory leader) is operatively linked to DNA for a polypeptide if it is expressed as a precursor that participates in the secretion of the polypeptide; a promoter is operatively linked to a coding sequence if it controls the transcription of the sequence; or a ribosome binding site is operatively linked to a coding sequence if it is positioned so as to permit translation. In certain embodiments, structural elements intended for use in yeast expression systems include a leader sequence enabling extracellular secretion of translated protein by a host cell. In certain embodiments, in situations where recombinant protein is expressed without a leader or transport sequence, a polypeptide may include an N-terminal methionine residue. This residue can optionally be subsequently cleaved from the expressed recombinant protein to provide a final product. [00299] The choice of an expression control sequence and an expression vector generally depends upon the choice of host. A wide variety of expression host/vector combinations can NAI-1539756353v1 107 be employed. Useful expression vectors for eukaryotic hosts include, for example, vectors comprising expression control sequences from SV40, bovine papilloma virus, adenovirus, and cytomegalovirus. Useful expression vectors for bacterial hosts include known bacterial plasmids, such as plasmids from E. coli, including pCR1, pBR322, pMB9 and their derivatives, and wider host range plasmids, such as M13 and other filamentous single- stranded DNA phages. [00300] Suitable host cells for expression of the LAIR1 binding agent or a LAIR1 protein or fragment thereof to use as an antigen or immunogen include prokaryotes, yeast cells, insect cells, or higher eukaryotic cells under the control of appropriate promoters. Prokaryotes include gram-negative or gram-positive organisms, for example E. coli or Bacillus. Higher eukaryotic cells include established cell lines of mammalian origin as disclosed herein. Cell- free translation systems may also be employed. Appropriate cloning vectors and expression vectors for use with bacterial, fungal, yeast, and mammalian cellular hosts, as well as methods of protein production, including antibody production are well known in the art. [00301] Various mammalian culture systems may be used to express recombinant polypeptides. Expression of recombinant proteins in mammalian cells may be desirable because these proteins are generally correctly folded, appropriately modified, and biologically functional. Examples of suitable mammalian host cell lines include, but are not limited to, COS-7 (monkey kidney-derived), L-929 (murine fibroblast-derived), C127 (murine mammary tumor-derived), 3T3 (murine fibroblast-derived), CHO (Chinese hamster ovary-derived), HeLa (human cervical cancer-derived), BHK (hamster kidney fibroblast- derived), HEK-293 (human embryonic kidney-derived) cell lines and variants thereof. Mammalian expression vectors can comprise non-transcribed elements such as an origin of replication, a suitable promoter and enhancer linked to the gene to be expressed, and other 5’or 3’ flanking non-transcribed sequences, and 5’ or 3’non-translated sequences, such as necessary ribosome binding sites, a polyadenylation site, splice donor and acceptor sites, and transcriptional termination sequences. [00302] Expression of recombinant proteins in insect cell culture systems (e.g., baculovirus) also offers a robust method for producing correctly folded and biologically functional proteins. Baculovirus systems for production of heterologous proteins in insect cells are well-known to those of skill in the art. [00303] Proteins produced by a host cell can be purified according to any suitable method. Standard methods include chromatography (e.g., ion exchange, affinity, and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique NAI-1539756353v1 108 for protein purification. Affinity tags such as hexahistidine (His6; SEQ ID NO:153), maltose binding domain, influenza coat sequence, and glutathione-S-transferase can be attached to the protein to allow easy purification by passage over an appropriate affinity column. Affinity chromatography methods used for purifying immunoglobulins can include, but are not limited to, Protein A, Protein G, and Protein L chromatography. Isolated proteins can be physically characterized using techniques that include, but are not limited to, proteolysis, size exclusion chromatography (SEC), mass spectrometry (MS), nuclear magnetic resonance (NMR), isoelectric focusing (IEF), high performance liquid chromatography (HPLC), and x- ray crystallography. The purity of isolated proteins can be determined using techniques known to those of skill in the art, including but not limited to, SDS-PAGE, SEC, capillary gel electrophoresis, IEF, and capillary isoelectric focusing (cIEF). [00304] In certain embodiments, supernatants from expression systems that secrete recombinant protein into culture media are first concentrated using a commercially available protein concentration filter, for example, an Amicon® or Millipore Pellicon® ultrafiltration unit. Following the concentration step, the concentrate can be applied to a suitable purification matrix. In certain embodiments, an anion exchange resin is employed, for example, a matrix or substrate having pendant diethylaminoethyl (DEAE) groups. The matrices can be acrylamide, agarose, dextran, cellulose, or other types commonly employed in protein purification. In certain embodiments, a cation exchange step is employed. Suitable cation exchangers include various insoluble matrices comprising sulfopropyl or carboxymethyl groups. In certain embodiments, a hydroxyapatite media is employed, including but not limited to, ceramic hydroxyapatite (CHT). In certain embodiments, one or more reverse-phase HPLC steps employing hydrophobic RP-HPLC media, e.g., silica gel having pendant methyl or other aliphatic groups, are employed to further purify a recombinant protein. In certain embodiments, hydrophobic interaction chromatography (HIC) is used to separate recombinant proteins based on their hydrophobicity. HIC is a useful separation technique for purifying proteins while maintaining biological activity due to the use of conditions and matrices that operate under less denaturing conditions than some other techniques. Some or all of the foregoing purification steps, in various combinations, can be employed to provide a homogeneous recombinant protein. [00305] LAIR1 binding agents of the present disclosure may be analyzed for their physical/chemical properties and/or biological activities by various assays known in the art. In certain embodiments, the LAIR1 binding agent is tested for its ability to bind LAIR1. Binding assays include, but are not limited to, SPR (e.g., Biacore), ELISA, and FACS. In NAI-1539756353v1 109 certain embodiments, the LAIR1 binding agent is tested for its ability to inhibit, reduce, or block binding to collagen, MARCO, and/or COLEC12. In addition, binding agents may be evaluated for solubility, stability, thermostability, viscosity, expression levels, expression quality, and/or purification efficiency. [00306] In certain embodiments, monoclonal antibodies generated against LAIR1 are grouped based upon the epitope each individual antibody recognizes, a process known as “epitope binning”. Generally, antibodies are tested in a pairwise combinatorial manner and antibodies that compete with each other are grouped together into bins. For example, in a premix binning assay, a first antibody is immobilized on a surface and a premixed solution of a second antibody and antigen is flowed over the immobilized first antibody. In tandem, the antigen is immobilized on a surface and the two antibodies are flowed over the immobilized antigen and compete to bind. Using these techniques, antibodies that block one another can be identified. A competitive blocking profile is created for each antibody relative to the other antibodies. The blocking results determine which bin each antibody is placed in. High- throughput methods of epitope binning are known in the art and allow for screening and characterization of large numbers of antibodies within a short period of time. Antibodies that bind similar epitopes often share similar functions and/or capabilities. Conversely, antibodies that bind different epitopes may have different functional activities. [00307] In certain embodiments, an epitope bin comprises at least one antibody from the group consisting of: 47A1, 47H1, 57D12, 61H4, 62G10, and 108D10. In certain embodiments, an epitope bin comprises at least antibodies 47A1, 57D12, and 61H4. In certain embodiments, an epitope bin comprises antibodies 47A1, 57D12, and 61H4. In certain embodiments, an epitope bin comprises at least antibodies 47H1, 62G10, and 108D10. In certain embodiments, an epitope bin comprises antibodies 47H1, 62G10, and 108D10. [00308] Epitope mapping is the process of identifying the binding site, or epitope on a target protein/antigen where an antibody (or other binding agent) binds. A variety of methods are known in the art for mapping epitopes on target proteins. These methods include (i) mutagenesis, including but not limited to, shotgun mutagenesis, site-directed mutagenesis, and alanine scanning; (ii) domain or fragment scanning; (iii) peptide scanning (e.g., Pepscan technology); (iv) display methods, including but not limited to, phage display, microbial display, and ribosome/mRNA display; (v) methods involving proteolysis and mass spectroscopy; (vi) methods involving amide hydrogen/deuterium exchange; and (vii) structural determination, including but not limited to, x-ray crystallography and NMR. NAI-1539756353v1 110 [00309] In certain embodiments, purified anti-LAIR1 antibodies are characterized by assays including, but not limited to, N-terminal sequencing, amino acid analysis, HPLC, mass spectrometry, differential scanning fluorimetry (DSF), nanoDSF, capillary isoelectric focusing (cIEF), ion exchange chromatography, and papain digestion. [00310] In certain embodiments, assays are provided for identifying LAIR1 binding agents that affect LAIR1 activity. In certain embodiments, assays are provided for identifying the anti-LAIR1 antibody that affects LAIR1 activity. These assays may include, but are not limited to, cell activation assays (e.g., cell proliferation assays), cytotoxic T-cell (CTL) assays, NK cell assays, mixed lymphocyte reaction (MLR) assays, cytokine/chemokine production assays, FcR binding assays, and cell migration assays. “Affect or affecting LAIR1 activity” may include, for example, inhibiting, reducing, blocking, antagonizing, suppressing, and/or interfering with LAIR1 activity. As LAIR1 generally acts as a negative regulator/inhibitory molecule, in certain embodiments, inhibiting, reducing, blocking, antagonizing, suppressing, and/or interfering with LAIR1 activity results in a release of LAIR1-induced suppression of a biological function (e.g., an activation signal). As disclosed herein, LAIR1 is expressed on T-cells, B-cells, NK cells, and myeloid cells. Myeloid cells include, but may not be limited to, monocytes, macrophages, dendritic cells, and APCs. LAIR1 activity or LAIR1 signaling activity includes, but is not limited to, suppression of myeloid cells, suppression of myeloid cell activity, suppression of tumor-associated myeloid cells, suppression of NK cells, suppression of NK cell activity, suppression of T-cells, and suppression of T-cell activity. In certain embodiments, inhibiting, reducing, blocking, antagonizing, suppressing, and/or interfering with LAIR1 activity results in a release of LAIR1-induced suppression of an activation signal. In certain embodiments, the anti-LAIR1 antibody inhibits LAIR1 signaling. In certain embodiments, the anti-LAIR1 antibody inhibits LAIR1 signaling thereby reversing an LAIR1-induced suppressive effect. In certain embodiments, the anti-LAIR1 antibody inhibits an LAIR1-induced extinction signal. [00311] In certain embodiments, the anti-LAIR1 antibody disrupts the LAIR1 signaling pathway. In certain embodiments, the anti-LAIR1 antibody disrupts the LAIR1 signaling pathway and activates myeloid cells. In certain embodiments, the anti-LAIR1 antibody disrupts the LAIR1 signaling pathway and activates APCs. In certain embodiments, the anti- LAIR1 antibody disrupts the LAIR1 signaling pathway and activates dendritic cells. In certain embodiments, the anti-LAIR1 antibody disrupts the LAIR1 signaling pathway and activates NK cells. In certain embodiments, the anti-LAIR1 antibody disrupts the LAIR1 signaling pathway and activates T-cells. In certain embodiments, the anti-LAIR1 antibody NAI-1539756353v1 111 disrupts the LAIR1 signaling pathway and activates CTLs. In certain embodiments, the anti- LAIR1 antibody disrupts the LAIR1 signaling pathway and activates tumor-associated T- cells. [00312] In certain embodiments, the terms “inhibiting”, “reducing”, “blocking”, “antagonizing”, “suppressing”, and “interfering” are relative to levels and/or activity in the absence of treatment with the LAIR1 binding agent. In certain embodiments, the terms “inhibiting”, “reducing”, “blocking”, “antagonizing”, “suppressing”, and “interfering” are relative to levels and/or activity prior to treatment with the LAIR1 binding agent. [00313] In certain embodiments, the LAIR1 binding agent inhibits human LAIR1 activity. In certain embodiments, the anti-LAIR1 antibody inhibits human LAIR1 activity. In certain embodiments, the anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody 47A1. In certain embodiments, the anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody 47H1. In certain embodiments, the anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody Hz47H1.v4. In certain embodiments, the anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody 57D12. In certain embodiments, the anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody 61H4. In certain embodiments, the anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody 62G10. In certain embodiments, the anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody Hz62H10.v1. In certain embodiments, the anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody 108D10. [00314] In certain embodiments, the LAIR1 binding agent inhibits mouse LAIR1 activity. In certain embodiments, the anti-LAIR1 antibody inhibits mouse LAIR1 activity. In certain embodiments, the anti-LAIR1 antibody that inhibits mouse LAIR1 activity is antibody 43H2. [00315] The present disclosure also provides conjugates comprising the LAIR1 binding agent disclosed herein. In certain embodiments, a conjugate comprises the anti-LAIR1 antibody disclosed herein. In certain embodiments, the antibody is attached to a second molecule. In certain embodiments, the antibody is conjugated to a cytotoxic agent or moiety. In certain embodiments, the antibody is conjugated to a cytotoxic agent to form an antibody- drug conjugate (ADC). In certain embodiments, the cytotoxic agent is a chemotherapeutic agent including, but not limited to, methotrexate, adriamycin/doxorubicin, melphalan, mitomycin C, chlorambucil, duocarmycin, daunorubicin, pyrrolobenzodiazepines (PBDs), or other intercalating agents. In certain embodiments, the cytotoxic agent is a microtubule inhibitor including, but not limited to, auristatins, maytansinoids (e.g., DM1 and DM4), and tubulysins. In certain embodiments, the cytotoxic agent is an enzymatically active toxin of NAI-1539756353v1 112 bacterial, fungal, plant, or animal origin, or fragments thereof, including, but not limited to, diphtheria A chain, non-binding active fragments of diphtheria toxin, exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), Momordica charantia inhibitor, curcin, crotin, Sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. In certain embodiments, an antibody is conjugated to one or more small molecule toxins, such as calicheamicins, maytansinoids, trichothenes, and CC1065. A derivative of any one of these toxins may be used as long as the derivative retains the cytotoxic activity of the parent molecule. [00316] Conjugates comprising the LAIR1 binding agent (e.g., the anti-LAIR1 antibody disclosed herein) may be made using any suitable method known in the art. In certain embodiments, conjugates are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyidithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCl), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis(p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p- diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). [00317] In certain embodiments, the LAIR1 binding agent disclosed herein is conjugated to a detectable substance or molecule that allows the agent to be used for diagnosis and/or detection. In certain embodiments, the anti-LAIR1 antibody disclosed herein is conjugated to a detectable substance or molecule that allows the antibody to be used for diagnosis and/or detection. In certain embodiments, a labeled anti-LAIR1 antibody is used to monitor immune cells in a tumor or in the microenvironment of a tumor. In certain embodiments, a labeled anti-LAIR1 antibody is used to monitor immune cells in a tumor or in the microenvironment of a tumor after treatment. A detectable substance can include but is not limited to, enzymes, such as horseradish peroxidase, alkaline phosphatase, beta-galactosidase, and acetylcholinesterase; prosthetic groups, such as biotin and flavine(s); fluorescent materials, such as, umbelliferone, fluorescein, fluorescein isothiocyanate (FITC), rhodamine, tetramethylrhodamine isothiocyanate (TRITC), dichlorotriazinylamine fluorescein, dansyl chloride, cyanine (Cy3), and phycoerythrin; bioluminescent materials, such as luciferase; radioactive materials, such as 212Bi, 14C, 57Co, 51Cr, 67Cu, 18F, 68Ga, 67Ga, 153Gd, 159Gd, 68Ge, 3H, 166Ho, 131I, 125I, 123I, 121I, 115In, 113In, 112In, 111In, 140La, 177Lu, 54Mn, 99Mo, 32P, 103Pd, NAI-1539756353v1 113 149Pm, 142Pr, 186Re, 188Re, 105Rh, 97Ru, 35S, 47Sc, 75Se, 153Sm, 113Sn, 117Sn, 85Sr, 99mTc, 201Ti, 133Xe, 90Y, 69Yb, 175Yb, 65Zn; positron emitting metals; and magnetic metal ions. [00318] The anti-LAIR1 antibody disclosed herein can also be conjugated to a second antibody to form an antibody heteroconjugate. [00319] The LAIR1 binding agent as disclosed herein may be attached to a solid support. In certain embodiments, the anti-LAIR1 antibody as disclosed herein is attached to a solid support. Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride, or polypropylene. In certain embodiments, an immobilized anti-LAIR1 antibody is used in an immunoassay. In certain embodiments, an immobilized anti-LAIR1 antibody is used in purification of the target antigen. [00320] In certain embodiments, the anti-LAIR1 antibody disclosed herein is used in an immunoassay. Immunoassays are known to those of skill in the art and include, but are not limited to, ELISA, SPR (e.g., Biacore), FACS, and immunohistochemistry (IHC). In certain embodiments, the anti-LAIR1 antibody disclosed herein is used on a tissue sample or a tumor sample. 5.4 Polynucleotides, Vectors, and Cells [00321] The present disclosure further encompasses polynucleotides comprising polynucleotides that encode a polypeptide (e.g., the LAIR1 binding agent (see Section 5.3) disclosed herein). In certain embodiments, the disclosure encompasses one or more polynucleotides that encode a binding agent (e.g., the LAIR1 binding agent (see Section 5.3)) disclosed herein. The term “polynucleotides that encode a polypeptide” encompasses a polynucleotide that includes only coding sequences for the polypeptide as well as a polynucleotide that includes additional coding and/or non-coding sequences. The polynucleotides of the disclosure can be in the form of RNA or in the form of DNA. DNA includes cDNA, genomic DNA, and synthetic DNA; and can be double-stranded or single- stranded, and if single stranded can be the coding strand or non-coding (anti-sense) strand. [00322] In certain embodiments, a polynucleotide comprises a polynucleotide encoding a heavy chain variable region and/or a light chain variable region of the LAIR1 binding agent disclosed herein. In certain embodiments, a polynucleotide comprises a polynucleotide encoding a heavy chain variable region of the LAIR1 binding agent disclosed herein. In certain embodiments, a polynucleotide comprises a polynucleotide encoding a light chain variable region of the LAIR1 binding agent disclosed herein. In certain embodiments, a polynucleotide comprises a polynucleotide encoding a heavy chain variable region of the NAI-1539756353v1 114 LAIR1 binding agent disclosed herein and a polynucleotide encoding a light chain variable region of the LAIR1 binding agent. [00323] In certain embodiments, a polynucleotide comprises a polynucleotide encoding a heavy chain and/or a light chain of the LAIR1 binding agent disclosed herein. In certain embodiments, a polynucleotide comprises a polynucleotide encoding a heavy chain of the LAIR1 binding agent disclosed herein. In certain embodiments, a polynucleotide comprises a polynucleotide encoding a light chain of the LAIR1 binding agent disclosed herein. In certain embodiments, a polynucleotide comprises a polynucleotide encoding a heavy chain of the LAIR1 binding agent disclosed herein and a polynucleotide encoding a light chain of the LAIR1 binding agent. [00324] In certain embodiments, the polynucleotide comprises a polynucleotide encoding a polypeptide comprising an amino acid sequence selected from the group consisting of: SEQ ID NOs:115-140. [00325] In certain embodiments, the polynucleotide comprises a polynucleotide encoding a polypeptide comprising more than one amino acid sequence selected from the group consisting of: SEQ ID NOs:115-132. In certain embodiments, the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:115 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:116. In certain embodiments, the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:117 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:118. In certain embodiments, the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:119 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:120. In certain embodiments, the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:121 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:122. In certain embodiments, the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:123 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:124. In certain embodiments, the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:125 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:126. In certain embodiments, the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:127 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:128. In certain NAI-1539756353v1 115 embodiments, the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:129 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:130. In certain embodiments, the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:131 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:132. [00326] In certain embodiments, the polynucleotide comprises a polynucleotide encoding a polypeptide comprising more than one amino acid sequence selected from the group consisting of: SEQ ID NOs:133-140. In certain embodiments, the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:133 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:135. In certain embodiments, the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:134 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:136. In certain embodiments, the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:137 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:139. In certain embodiments, the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO:138 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO:140. [00327] The present disclosure also provides variants of the polynucleotides disclosed herein, wherein the variant encodes, for example, fragments, analogs, and/or derivatives of a polypeptide. In certain embodiments, the present disclosure provides a polynucleotide comprising a polynucleotide having a nucleotide sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, and in certain embodiments, at least 96%, at least 97%, at least 98%, or at least 99% identical to a polynucleotide encoding a polypeptide disclosed herein. [00328] In certain embodiments, a polynucleotide comprises a polynucleotide having a nucleotide sequence at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, and in certain embodiments, at least 96%, at least 97%, at least 98%, or at least 99% identical to a polynucleotide encoding an amino acid sequence selected from the group consisting of: SEQ ID NOs:115-140. Also provided is a polynucleotide that comprises a polynucleotide that hybridizes to a polynucleotide encoding an amino acid sequence selected from the group consisting of: SEQ ID NOs:115-140. In certain embodiments, the hybridization is under conditions of high stringency as is known to those skilled in the art. NAI-1539756353v1 116 [00329] As used herein, the phrase “a polynucleotide having a nucleotide sequence at least 95% identical to a polynucleotide sequence” is intended to mean that the nucleotide sequence of the polynucleotide is identical to a reference sequence except that the polynucleotide sequence can include up to five point mutations per each 100 nucleotides of the reference nucleotide sequence. In other words, to obtain a polynucleotide having a nucleotide sequence at least 95% identical to a reference nucleotide sequence, up to 5% of the nucleotides in the reference sequence can be deleted or substituted with another nucleotide, or a number of nucleotides up to 5% of the total nucleotides in the reference sequence can be inserted into the reference sequence. It is understood by those of skill in the art that an appropriate calculation would be made for other “% identical” statements, for example, 90% identical or 85% identical. Mutations of the reference sequence can occur at the 5’ or 3’ terminal positions of the reference nucleotide sequence or anywhere between those terminal positions, interspersed either individually among nucleotides in the reference sequence or in one or more contiguous groups within the reference sequence. [00330] The polynucleotide variants can contain alterations in the coding regions, non- coding regions, or both. In certain embodiments, a polynucleotide variant contains alterations that produce silent substitutions, additions, or deletions, but does not alter the properties or activities of the encoded polypeptide. In certain embodiments, a polynucleotide variant comprises silent substitutions that results in no change to the amino acid sequence of the polypeptide (due to the degeneracy of the genetic code). In certain embodiments, a polynucleotide variant comprises one or more mutated codons comprising one or more (e.g., 1, 2, or 3) substitutions to the codon that change the amino acid encoded by that codon. Methods for introducing one or more substitutions into a codon are known in the art, including but not limited to, PCR mutagenesis and site-directed mutagenesis. Polynucleotide variants can be produced for a variety of reasons, for example, to optimize codon expression for a particular host (e.g., change codons in the human mRNA to those preferred by a bacterial host such as E. coli). In certain embodiments, a polynucleotide variant comprises at least one silent mutation in a non-coding or a coding region of the sequence. [00331] In certain embodiments, a polynucleotide variant is produced to modulate or alter expression (or expression levels) of the encoded polypeptide. In certain embodiments, a polynucleotide variant is produced to increase expression of the encoded polypeptide. In certain embodiments, a polynucleotide variant is produced to decrease expression of the encoded polypeptide. In certain embodiments, a polynucleotide variant has increased expression of the encoded polypeptide as compared to a parental polynucleotide sequence. In NAI-1539756353v1 117 certain embodiments, a polynucleotide variant has decreased expression of the encoded polypeptide as compared to a parental polynucleotide sequence. [00332] In certain embodiments, a polynucleotide comprises the coding sequence for a polypeptide fused in the same reading frame to a polynucleotide that aids in expression and secretion of a polypeptide from a host cell. In certain embodiments, the polynucleotide that aids in expression and secretion is a leader sequence that functions as a secretory sequence for controlling transport of a polypeptide. In certain embodiments, the polypeptide has a leader sequence cleaved by the host cell to form a “mature” form of the polypeptide. [00333] In certain embodiments, a polynucleotide comprises the coding sequence for a polypeptide fused in the same reading frame to a marker or tag sequence. For example, In certain embodiments, a marker sequence is a hexa-histidine tag (HIS-tag; SEQ ID NO:153) that allows for efficient purification of the polypeptide fused to the marker. In certain embodiments, a marker sequence is a hemagglutinin (HA) tag derived from the influenza hemagglutinin protein when a mammalian host is used. In certain embodiments, the marker sequence is a FLAG™ tag. In certain embodiments, a marker may be used in conjunction with other markers or tags. [00334] In certain embodiments, a polynucleotide is isolated. In certain embodiments, a polynucleotide is substantially pure. [00335] Vectors comprising any of the polynucleotides disclosed herein are also provided. In certain embodiments, a vector comprises a polynucleotide encoding the LAIR1 binding agent disclosed herein. In certain embodiments, a vector comprises a polynucleotide encoding a polypeptide that is part of the LAIR1 binding agent disclosed herein. In certain embodiments, a vector comprises a polynucleotide encoding the anti-LAIR1 antibody disclosed herein. In certain embodiments, a vector comprises a polynucleotide encoding a heavy chain variable region disclosed herein. In certain embodiments, a vector comprises a polynucleotide encoding a light chain variable region disclosed herein. In certain embodiments, a vector comprises a first polynucleotide encoding a heavy chain variable region and a second polynucleotide encoding a light chain variable region disclosed herein. In certain embodiments, a vector comprises a polynucleotide encoding a heavy chain of an anti-LAIR antibody disclosed herein. In certain embodiments, a vector comprises a polynucleotide encoding a light chain of an anti-LAIR antibody disclosed herein. In certain embodiments, a vector comprises a polynucleotide encoding a heavy chain and a polynucleotide encoding a light chain of an anti-LAIR antibody disclosed herein. NAI-1539756353v1 118 [00336] Cells comprising any of the polynucleotides disclosed herein are provided. In certain embodiments, a cell comprises one or more polynucleotides encoding the LAIR1 binding agent disclosed herein. In certain embodiments, a cell comprises one or more polynucleotides encoding a polypeptide that is part of the LAIR1 binding agent disclosed herein. In certain embodiments, a cell comprises one or more polynucleotides encoding the anti-LAIR1 antibody disclosed herein. In certain embodiments, a cell comprises a polynucleotide encoding a heavy chain variable region disclosed herein. In certain embodiments, a cell comprises a polynucleotide encoding a light chain variable region disclosed herein. In certain embodiments, a cell comprises a first polynucleotide encoding a heavy chain variable region and a second polynucleotide encoding a light chain variable region disclosed herein. In certain embodiments, a cell comprises a single polynucleotide encoding a heavy chain variable region and a light chain variable region disclosed herein. In certain embodiments, a cell comprises a polynucleotide encoding a heavy chain of an anti- LAIR antibody disclosed herein. In certain embodiments, a cell comprises a polynucleotide encoding a light chain of an anti-LAIR antibody disclosed herein. In certain embodiments, a cell comprises a first polynucleotide encoding a heavy chain and a second polynucleotide encoding a light chain of an anti-LAIR antibody disclosed herein. In certain embodiments, a cell comprises a single polynucleotide encoding a heavy chain and a light chain of an anti- LAIR antibody disclosed herein. [00337] In addition, cells comprising the vectors disclosed herein are provided. In certain embodiments, a cell comprises one or more vectors expressing the LAIR1 binding agent disclosed herein. In certain embodiments, a cell comprises one or more vectors expressing a polypeptide that is part of the LAIR1 binding agent disclosed herein. In certain embodiments, a cell comprises one or more vectors expressing the anti-LAIR1 antibody disclosed herein. In certain embodiments, a cell comprises a vector encoding the LAIR1 binding agent disclosed herein. In certain embodiments, a cell comprises a first vector expressing a heavy chain variable region disclosed herein and a second vector expressing a light chain variable region disclosed herein. In certain embodiments, a cell comprises a single vector expressing a heavy chain variable region and a light chain variable region disclosed herein. In certain embodiments, a cell comprises a first vector expressing a heavy chain of the anti-LAIR1 antibody disclosed herein and a second vector expressing a light chain of the anti-LAIR1 antibody disclosed herein. In certain embodiments, a cell comprises a single vector expressing a heavy chain and a light chain of the anti-LAIR1 antibody disclosed herein. NAI-1539756353v1 119 [00338] In certain embodiments, a cell produces the LAIR1 binding agent disclosed herein. In certain embodiments, a cell produces the anti-LAIR1 antibody disclosed herein. In certain embodiments, a cell produces an antibody selected from the group consisting of: 47A1, 47H1, Hz47H1.v4, 57D12, 61H4, 62G10, Hz62G10.v1, 108D10, and 43H2. In certain embodiments, the cell is a prokaryotic cell. In certain embodiments, the cell is a eukaryotic cell. In certain embodiments, the cell is a mammalian cell. In certain embodiments, the cell is isolated. In certain embodiments, the cell is a hybridoma. In certain embodiments, a hybridoma produces an antibody selected from the group consisting of: 47A1, 47H1, Hz47H1.v4, 57D12, 61H4, 62G10, Hz62G10.v1, 108D10, and 43H2. [00339] It is understood that modifications which do not substantially affect the activity of the various embodiments disclosed herein are also provided within the definition of the subject matter disclosed herein. Accordingly, the following examples are intended to illustrate but not limit the present disclosure. 5.5 Pharmaceutical Compositions [00340] The present disclosure further provides a composition, such as a pharmaceutical composition, comprising at least one of the following: a binding agent provided herein (e.g., one antibody or antigen-binding fragment thereof of the present disclosure), a nucleic acid provided herein, a vector provided herein, or a cell provided herein. In certain embodiments, a pharmaceutical composition comprises a therapeutically effective amount of a LAIR1 binding agent (see Section 5.3) provided herein (e.g., an antibody or antigen-binding fragment thereof provided herein) and a pharmaceutically acceptable excipient. In certain embodiments, a pharmaceutical composition comprises a therapeutically effective amount of a nucleic acid provided herein (such as a nucleic acid encoding an antibody or antigen- binding fragment thereof provided herein) and a pharmaceutically acceptable excipient. In certain embodiments, a pharmaceutical composition comprises a therapeutically effective amount of a vector provided herein (such as a vector comprising a nucleic acid as disclosed herein and expressing a LAIR1 binding agent as disclosed herein) and a pharmaceutically acceptable excipient. In certain embodiments, a pharmaceutical composition comprises a therapeutically effective amount of a cell provided herein (such as a cell comprising a nucleic acid encoding an antibody or antigen-binding fragment thereof provided herein and/or expressing an antibody or antigen-binding fragment thereof provided herein) and a pharmaceutically acceptable excipient. [00341] In certain embodiments, the pharmaceutical composition disclosed herein is used in combination a second pharmaceutical composition comprising a PD-1 antagonist (e.g., PD-1 NAI-1539756353v1 120 antagonists disclosed in Section 5.6). In certain embodiments, the LAIR1-binding agent and the PD-1 antagonist are not provided in the same composition (e.g., different pharmaceutical compositions), such as when the LAIR1-binding agent and the PD-1 antagonist are to be separately administered (e.g., separately administered at different time or through different administering routes). In certain embodiments, the pharmaceutical composition disclosed herein further comprises a PD-1 antagonist (e.g., PD-1 antagonists disclosed in Section 5.6) such that the LAIR1 binding agent and the PD-1 antagonist are included in the same pharmaceutical composition. [00342] In certain embodiments, pharmaceutical compositions provided herein are prepared for storage by mixing the binding agents, nucleic acids, vectors, or cells provided herein having the desired degree of purity with optional pharmaceutically acceptable excipients (see, e.g., Remington, Remington’s Pharmaceutical Sciences (18th ed.1980)) in the form of aqueous solutions or lyophilized or other dried forms. [00343] The binding agents, nucleic acids, vectors, or cells of the present disclosure may be formulated in any suitable form for delivery to a target cell/tissue as described in Remington, Remington’s Pharmaceutical Sciences (18th ed.1980). 5.6 Methods of Treating Osteosarcoma [00344] Osteosarcoma is one type of bone cancer that usually occurs in the osteoblast cells that form bone. It develops most often in children, adolescents, and young adults. Sites for osteosarcoma include long bones around the knee, upper leg, or thighbone, the lower leg, upper arm bone, or any bone in the body, including those in the pelvis, shoulder, and skull. Osteosarcoma may grow into nearby tissues, such as tendons or muscles, and may spread, or metastasize, through the bloodstream to other organs or bones in the body. [00345] The present disclosure provides methods for treating osteosarcoma using a combination of a LAIR1-binding agent (e.g., LAIR1 binding agents disclosed in Section 5.3 herein, and LAIR1 binding agents described in International Patent Publication No. WO 2021/262597, which is incorporated herein by reference) and a PD-1 antagonist (e.g., PD-1 antagonists disclosed in Section 5.6 herein). The present disclosure further provides methods for activating, promoting, increasing, and/or enhancing an immune response to osteosarcoma cells using a combination of a LAIR1-binding agent (e.g., LAIR1 binding agents disclosed in Section 5.3 herein, and LAIR1 binding agents described in International Patent Publication No. WO 2021/262597) and a PD-1 antagonist (e.g., PD-1 antagonists disclosed in Section 5.6 herein). Methods disclosed herein can be in vitro, ex vivo, or in vivo methods. NAI-1539756353v1 121 [00346] In certain embodiments, the present disclosure provides a method for disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a cell mixture, wherein the cell mixture comprises osteosarcoma cells. In certain embodiments, the method comprises contacting the cell mixture with a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein. In certain embodiments, the cell mixture comprises intratumoral cells. In certain embodiments, the cell mixture comprises immune cells (e.g., intratumoral immune cells). In certain embodiments, the intratumoral cells (e.g., intratumoral immune cells) are or were present in osteosarcoma or a tumor microenvironment thereof. In certain embodiments, the cell mixture comprises at least one of myeloid cells, NK cells, T-cells, cytotoxic T-cells, monocytes, macrophages, dendritic cells, APCs, MDSCs, and T-regs. In certain embodiments, the method results in disrupting, inhibiting, or blocking collagen- induced LAIR1 activity. In certain embodiments, the method results in disrupting, inhibiting, or blocking LAIR1-induced suppression of myeloid cells. In certain embodiments, the method results in disrupting, inhibiting, or blocking of LAIR1-induced suppression of myeloid cell activity. In certain embodiments, the method results in disrupting, inhibiting, or blocking of LAIR1-induced suppression of NK cells or NK cell activity. In certain embodiments, the method results in disrupting, inhibiting, or blocking of LAIR1-induced suppression of T-cells or T-cell activity. In certain embodiments, the method (i) restores FcR signaling activity in myeloid cells; (ii) restores cytokine and/or chemokine production by myeloid cells; and/or (iii) restores immune cell (e.g., T-cell) proliferation and/or activity. In certain embodiments, the myeloid cell is a monocyte, a macrophage, a dendritic cell, or an APC. [00347] In certain embodiments, the present disclosure provides a method for disrupting, inhibiting, or blocking the binding of LAIR1 to MARCO in a cell mixture, wherein the cell mixture comprises osteosarcoma cells. In certain embodiments, the method comprises contacting the cell mixture with a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein. In certain embodiments, the cell mixture comprises intratumoral cells. In certain embodiments, the cell mixture comprises immune cells (e.g., intratumoral immune cells). In certain embodiments, the intratumoral cells (e.g., intratumoral immune cells) are or were present in osteosarcoma or a tumor microenvironment thereof. In certain embodiments, the cell mixture comprises at least one of myeloid cells, NK cells, T cells, cytotoxic T-cells, monocytes, macrophages, dendritic cells, APCs, MDSCs, and T-regs. In certain embodiments, the method results in disrupting, inhibiting, or blocking MARCO- induced LAIR1 activity. In certain embodiments, the method results in disrupting, inhibiting, NAI-1539756353v1 122 or blocking LAIR1-induced suppression of myeloid cells. In certain embodiments, the method results in disrupting, inhibiting, or blocking of LAIR1-induced suppression of myeloid cell activity. In certain embodiments, the method results in disrupting, inhibiting, or blocking of LAIR1-induced suppression of NK cells or NK cell activity. In certain embodiments, the method results in disrupting, inhibiting, or blocking of LAIR1-induced suppression of T-cells or T-cell activity. In certain embodiments, the method (i) restores FcR signaling activity in myeloid cells; (ii) restores cytokine and/or chemokine production by myeloid cells; and/or (iii) restores immune cell (e.g., T-cell) proliferation and/or activity. In certain embodiments, the myeloid cell is a monocyte, a macrophage, a dendritic cell, or an APC. [00348] In certain embodiments, the present disclosure provides a method for disrupting, inhibiting, or blocking the binding of LAIR1 to COLEC12 in a cell mixture, wherein the cell mixture comprises osteosarcoma cells. In certain embodiments, the method comprises contacting the cell mixture with a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein. In certain embodiments, the cell mixture comprises intratumoral cells. In certain embodiments, the cell mixture comprises immune cells (e.g., intratumoral immune cells). In certain embodiments, the intratumoral cells (e.g., intratumoral immune cells) are or were present in osteosarcoma or a tumor microenvironment thereof. In certain embodiments, the cell mixture comprises at least one of myeloid cells, NK cells, T-cells, cytotoxic T-cells, monocytes, macrophages, dendritic cells, APCs, MDSCs, and T-regs. [00349] In certain embodiments, the method for treating osteosarcoma or for activating, promoting, increasing, and/or enhancing an immune response to osteosarcoma cells disclosed herein disrupts, inhibits, or blocks collagen-induced LAIR1 activity in a cell, wherein the method comprises contacting the cell with a LAIR1-binding agent disclosed herein and a PD- 1 antagonist disclosed herein. In certain embodiments, the method for treating osteosarcoma or for activating, promoting, increasing, and/or enhancing an immune response to osteosarcoma cells disclosed herein disrupts and/or inhibits LAIR1 signaling in a cell, wherein the method comprises contacting the cell with a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein. In certain embodiments, the cell is an intratumoral cell, and is or was present in osteosarcoma or a tumor microenvironment thereof. In certain embodiments, the cell is an immune cell. In certain embodiments, the immune cell is a myeloid cell, a NK cell, a T-cell, a cytotoxic T-cell, a monocyte, a macrophage, a dendritic cell, an APC, a MDSC, or a T-reg. NAI-1539756353v1 123 [00350] In certain embodiments, the method for treating osteosarcoma or for activating, promoting, increasing, and/or enhancing an immune response to osteosarcoma cells disclosed herein disrupts, inhibits, or blocks LAIR1-induced suppression of a myeloid cell, wherein the method comprises contacting the myeloid cell with a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein. In certain embodiments, the myeloid cell is a monocyte, a macrophage, a dendritic cell, or an APC. In certain embodiments, the myeloid cell is an intratumoral cell, and is or was present in osteosarcoma or a tumor microenvironment thereof. [00351] In certain embodiments, the method for treating osteosarcoma or for activating, promoting, increasing, and/or enhancing an immune response to osteosarcoma cells disclosed herein disrupts, inhibits, or blocks LAIR1-induced suppression of a NK cell or NK cell activity, wherein the method comprises contacting the NK cell with a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein. In certain embodiments, the method for treating osteosarcoma or for activating, promoting, increasing, and/or enhancing an immune response to osteosarcoma cells disclosed herein disrupts, inhibits, or blocks LAIR1- induced suppression of a T-cell or T-cell activity, wherein the method comprises contacting the T-cell with a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein. In certain embodiments, the T-cell is a cytotoxic T-cell (CTL). In certain embodiments, the method for treating osteosarcoma or for activating, promoting, increasing, and/or enhancing an immune response to osteosarcoma cells disclosed herein disrupts, inhibits, or blocks the activity of a MDSC, wherein the method comprises contacting the MDSC with a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein. In certain embodiments, the method for treating osteosarcoma or for activating, promoting, increasing, and/or enhancing an immune response to osteosarcoma cells disclosed herein disrupts, inhibits, or blocks the activity of a Treg, wherein the method comprises contacting the T-reg with a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein. In certain embodiments, the NK cell, the T-cell, the MDSC, or the Treg is an intratumoral cell, and is or was present in osteosarcoma or a tumor microenvironment thereof. [00352] In certain embodiments, the present disclosure provides methods of disrupting, inhibiting, or blocking the binding of LAIR1 to collagen, MARCO, and/or COLEC12 in a subject having osteosarcoma, comprising administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein. NAI-1539756353v1 124 [00353] In certain embodiments, the present disclosure provides methods for disrupting, inhibiting, or blocking collagen-induced LAIR1 activity in a subject having osteosarcoma comprising administering to the subject a therapeutically effective amount of a LAIR1- binding agent disclosed herein and a PD-1 antagonist disclosed herein. In certain embodiments, the present disclosure provides methods for disrupting, inhibiting, or blocking LAIR1-induced suppression of a myeloid cell or myeloid cell activity in a subject having osteosarcoma comprising administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein. In certain embodiments, the method (i) restores FcR activity in myeloid cells; (ii) restores cytokine and/or chemokine production by myeloid cells; and/or (iii) restores immune cell (e.g., T-cell) proliferation and/or activity. In certain embodiments, the myeloid cell is a monocyte, a macrophage, a dendritic cell, or an APC. [00354] In certain embodiments, the present disclosure provides methods for disrupting, inhibiting, or blocking LAIR1-induced suppression of a NK cell or NK cell activity in a subject having osteosarcoma comprising administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein. In certain embodiments, the present disclosure provides methods for disrupting, inhibiting, or blocking LAIR1-induced suppression of a T-cell or T-cell activity in a subject having osteosarcoma comprising administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein. In certain embodiments, the T-cell is a cytotoxic T-cell (CTL). In certain embodiments, the T-cell is a tumor-associated T-cell. [00355] In certain embodiments, the present disclosure provides methods for disrupting, inhibiting, or blocking the activity of a MDSC in a subject having osteosarcoma comprising administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein. In certain embodiments, the present disclosure provides methods for disrupting, inhibiting, or blocking the activity of a Treg in a subject having osteosarcoma comprising administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein. [00356] In certain embodiments, the present disclosure provides methods for activating, promoting, increasing, and/or enhancing an immune response in a subject having osteosarcoma using a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein. In certain embodiments, the activating, promoting, increasing, and/or enhancing of an NAI-1539756353v1 125 immune response comprises stimulating myeloid cells, monocytes, macrophages, dendritic cells, and/or APCs. In certain embodiments, the activating, promoting, increasing, and/or enhancing of an immune response comprises increasing cell-mediated immunity. In certain embodiments, the activating, promoting, increasing, and/or enhancing of an immune response comprises increasing effector T-cell activity, and/or increasing CTL activity. In certain embodiments, the activating, promoting, increasing, and/or enhancing of an immune response comprises inhibiting or decreasing the suppressive activity of Tregs, and/or the suppressive activity of MDSCs. In certain embodiments, the immune response is a result of antigenic stimulation from an osteosarcoma cell or osteosarcoma. [00357] In certain embodiments, the present disclosure provides methods for inhibiting growth of osteosarcoma or osteosarcoma cells comprising contacting a cell mixture with a LAIR1-binding agent and a PD-1 antagonist in vitro., wherein the cell mixture comprises osteosarcoma cells. For example, an osteosarcoma cell line mixed with immune cells (e.g., T-cells or myeloid cells) is cultured in medium to which is added a test agent that binds LAIR1. In certain embodiments, the osteosarcoma cells are from a patient sample such as, for example, a tissue biopsy, pleural effusion, or blood sample, mixed with immune cells (e.g., T-cells or myeloid cells), and cultured in medium to which is added a test agent that binds LAIR1. In certain embodiments, the present disclosure provides the use of a LAIR1- binding agent disclosed herein in combination with a PD-1 antagonist disclosed herein in the manufacture or preparation of a medicament for inhibiting growth of osteosarcoma or osteosarcoma cells. In certain embodiments, the combination of the LAIR1-binding agent and the PD-1 antagonist increases, promotes, and/or enhances the activity of effector immune cells. In certain embodiments, the combination of the LAIR1-binding agent and the PD-1 antagonist inhibits osteosarcoma cell growth. [00358] In certain embodiments, the present disclosure provides a method of inhibiting osteosarcoma growth comprises contacting the osteosarcoma and/or osteosarcoma microenvironment with a combination of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein in vivo. In certain embodiments, contacting an osteosarcoma and/or osteosarcoma microenvironment with a combination of a LAIR1-binding agent and a PD-1 antagonist is undertaken in an animal model (e.g., a mouse model). In certain embodiments, a test agent may be administered to mice that have osteosarcoma. In certain embodiments, the test agent is a LAIR1 binding agent that binds mouse LAIR1. In certain embodiments, the test agent is a surrogate antibody that binds mouse LAIR1. In certain embodiments, the test agent is an anti-mouse LAIR1 antibody disclosed herein. In certain NAI-1539756353v1 126 embodiments, the test agent is anti-mouse LAIR1 antibody 43H2 (see Table 7 disclosed herein). In certain embodiments, the combination of the LAIR1-binding agent and the PD-1 antagonist increases, promotes, and/or enhances the activity of immune cells in the mice. In certain embodiments, the combination of the LAIR1-binding agent and the PD-1 antagonist inhibits tumor growth. In certain embodiments, the combination of the LAIR1-binding agent and the PD-1 antagonist causes the osteosarcoma to regress. In certain embodiments, the LAIR1-binding agent and the PD-1 antagonist are administered at the same time or shortly after introduction of osteosarcoma cells into the animal to prevent tumor growth (“preventative model”). In certain embodiments, the LAIR1-binding agent and the PD-1 antagonist are administered after osteosarcoma has grown to a specified size or have become “established” for treatment (“therapeutic model”). In certain embodiments, the LAIR1- binding agent and the PD-1 antagonist are administered to a transgenic animal (e.g., a transgenic mouse) that expresses human LAIR1, wherein the transgenic animal has osteosarcoma derived from human cells. In certain embodiments, the LAIR1-binding agent is an anti-mouse LAIR1 antibody disclosed herein. In certain embodiments, the LAIR1- binding agent is anti-mouse LAIR1 antibody 43H2. In certain embodiments, the LAIR1- binding agent is an anti-human LAIR1 antibody disclosed herein and a PD-1 antagonist disclosed herein. [00359] In certain embodiments, a method of inhibiting osteosarcoma growth in a subject comprises administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein. In certain embodiments, a method of increasing or enhancing an immune response to osteosarcoma or osteosarcoma cells in a subject comprises administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein. In certain embodiments, a method of activating or enhancing a persistent or long-term immune response to osteosarcoma or osteosarcoma cells in a subject comprises administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein. In certain embodiments, a method of inhibiting osteosarcoma relapse or osteosarcoma regrowth in a subject comprises administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein. In certain embodiments, a method of inducing a persistent or long-term immunity that inhibits osteosarcoma relapse or osteosarcoma regrowth in a subject comprises administering to the subject a therapeutically effective amount of a LAIR1- binding agent disclosed herein and a PD-1 antagonist disclosed herein. NAI-1539756353v1 127 [00360] In certain embodiments, the present disclosure provides use of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein in the manufacture or preparation of a medicament for inhibiting growth of osteosarcoma or osteosarcoma cells. [00361] In certain embodiments, the subject has osteosarcoma or the subject had osteosarcoma that was at least partially removed. [00362] In certain embodiments, the present disclosure provides methods of treating osteosarcoma comprising administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein. In certain embodiments, the LAIR1-binding agent binds LAIR1 and inhibits or reduces growth of osteosarcoma. In certain embodiments, the LAIR1-binding agent binds LAIR1-expressing cells, enhances an immune response to osteosarcoma, and inhibits or reduces growth of the osteosarcoma. In certain embodiments, the LAIR1-binding agent binds LAIR1-expressing cells, activates myeloid cells, enhances an immune response to osteosarcoma, and inhibits or reduces growth of the osteosarcoma. In certain embodiments, the subject has osteosarcoma. In certain embodiments, the subject has had osteosarcoma, which is at least partially removed. [00363] In certain embodiments, the present disclosure provides use of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein in the manufacture or preparation of a medicament for the treatment of osteosarcoma. [00364] In certain embodiments, the present disclosure provides methods of activating myeloid cells in the tumor microenvironment in a subject having osteosarcoma, comprising administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein. In certain embodiments, the myeloid cells comprise at least one dendritic cells, monocytes, macrophages, and APCs. [00365] In certain embodiments, the present disclosure provides methods of activating T- cells in the tumor microenvironment in a subject having osteosarcoma, comprising administering to the subject a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist disclosed herein. In certain embodiments, the T-cells are CTLs, and/or tumor-associated T-cells. [00366] In certain embodiments, the method disclosed herein is an in vitro method comprising contacting an osteosarcoma cell with a LAIR-binding agent disclosed herein and a PD-1 antagonist. In certain embodiments, the method disclosed herein is an in vivo method comprising administering a therapeutically effective amount of a LAIR1-binding agent disclosed herein and a PD-1 antagonist to a subject having osteosarcoma. NAI-1539756353v1 128 [00367] The appropriate dosages of the LAIR1-binding agent and the PD-1 antagonist used with the presently disclosed methods depend on severity and course of the osteosarcoma, the responsiveness of the osteosarcoma, whether the LAIR1-binding agent and the PD-1 antagonist are administered for therapeutic or preventative purposes, previous therapy, the patient’s clinical history, and so on. The LAIR1-binding agent and the PD-1 antagonist can be administered one time or over a series of treatments lasting from several days to several months, or until a cure is effected or a diminution of the osteosarcoma is achieved. [00368] Any suitable PD-1 antagonists can be used with the presently disclosed subject matter. In certain embodiments, the PD-1 antagonist is an antagonistic anti-PD-1 antibody. In certain embodiments, the antagonistic anti-PD-1 antibody is selected from the group consisting of pembrolizumab (MK-3475; KEYTRUDA), pidilizumab (CT-011), nivolumab (OPDIVO), durvalumab (MEDI0680), budigalimab (ABBV-181), cemiplimab (REGN2810), tislelizumab (BGB-A317), spartalizumab (PDR-001), STI-A1110, and combinations thereof. Exemplary antagonistic anti-PD-1 antibodies are described in in US Patent Nos.10316089, 9580504, 9856320, 8609089, and 8952136; the contents of each which are incorporated by reference herein in their entireties. In certain embodiments, the antagonistic anti-PD-1 antibodies are described in International Patent Publication No. WO 2014/179664, for example, an antibody identified as APE2058, APE1922, APE1923, APE1924, APE 1950, or APE1963, or an antibody containing the CDR regions of any of these antibodies, the content of WO 2014/179664 is incorporated herein by reference. In certain embodiments, the PD-1 antagonist is a fusion protein that comprises PD-L2, for example, AMP-224. In certain embodiments, the PD-1 antagonist is a peptide inhibitor, for example, AU P-12. [00369] In certain embodiments, the method disclosed herein comprises administering the LAIR-1 binding agent disclosed herein in combination with an antagonistic anti-PD-1 antibody, wherein the antagonistic anti-PD-1 antibody is administered once or sequentially. [00370] In certain embodiments, administration of the LAIR1-binding agent can occur prior to, concurrently with, or subsequent to the administration of the PD-1 antagonist. In certain embodiments, combined administration of the LAIR1-binding agent and the PD-1 antagonist includes co-administration, either in a single pharmaceutical formulation or using separate formulations, or consecutive administration in either order but generally within a time period such that all active agents can exert their biological activities. In certain embodiments, preparation of agents and/or dosing schedules for the PD-1 antagonist are according to manufacturers' instructions or as determined empirically by the skilled practitioner. NAI-1539756353v1 129 [00371] In certain embodiments, the method disclosed herein comprises administering the LAIR1 binding agent and the PD-1 antagonist, in combination with at least one additional therapeutic agent or therapy. Combination therapy using agents with different mechanisms of action may result in additive or synergetic effects. Combination therapy may allow for a lower dose of each agent than is used in monotherapy, thereby reducing toxic side effects and/or increasing the therapeutic index of the agent(s). Combination therapy may decrease the likelihood that resistance to an agent will develop. [00372] In certain embodiments, the combination therapy disclosed herein results in additive or synergistic results. In certain embodiments, the combination therapy disclosed herein results in an increase in the therapeutic index of the LAIR1-binding agent and/or the PD-1 antagonist. In certain embodiments, the combination therapy disclosed herein results in an increase in the therapeutic index of the at least one additional therapeutic agent or therapy. In certain embodiments, the combination therapy disclosed herein results in a decrease in the toxicity and/or side effects of the LAIR1-binding agent and/or the PD-1 antagonist. In certain embodiments, the combination therapy disclosed herein results in a decrease in the toxicity and/or side effects of the at least one additional therapeutic agent or therapy. In certain embodiments, the at least one additional therapeutic agent or therapy comprises a therapeutic agent or therapy that affects the immune response (e.g., enhances or activates the response) and a therapeutic agent that affects (e.g., inhibits or kills) the tumor/cancer cells. [00373] In certain embodiments, the at least one additional therapeutic agent or therapy comprises one additional therapeutic agent or therapy. In certain embodiments, the at least one additional therapeutic agent or therapy comprises two or more additional therapeutic agent or therapy. [00374] In certain embodiments, the at least one additional therapeutic agent is a modulator of PD-L1 activity, a modulator of PD-L2 activity, a modulator of CTLA-4 activity, a modulator of CD28 activity, a modulator of CD80 activity, a modulator of CD86 activity, a modulator of 4-1BB activity, an modulator of OX40 activity, a modulator of KIR activity, a modulator of Tim-3 activity, a modulator of LAG3 activity, a modulator of CD27 activity, a modulator of CD40 activity, a modulator of GITR activity, a modulator of TIGIT activity, a modulator of CD20 activity, a modulator of CD96 activity, or a modulator of IDO1 activity. In certain embodiments, the at least one additional therapeutic agent is selected from the group consisting of PD-L1 antagonists, PD-L2 antagonists, CTLA-4 antagonists, CD80 antagonists, CD86 antagonists, KIR antagonists, Tim-3 antagonists, LAG3 antagonists, NAI-1539756353v1 130 TIGIT antagonists, CD20 antagonists, CD96 antagonists, IDO1 antagonists, and any combinations thereof. [00375] In certain embodiments, the at least one additional therapeutic agent is selected from the group consisting of anti-PD-L1 antibodies, anti-PD-L2 antibodies, anti-CTLA-4 antibodies, anti-TIGIT antibodies, anti-CD28 antibodies, anti-CD80 antibodies, anti-CD86 antibodies, anti-4-1BB antibodies, anti-OX40 antibodies, anti-KIR antibodies, anti-Tim-3 antibodies, anti-LAG3 antibodies, anti-CD27 antibodies, anti-CD40 antibodies, anti-GITR antibodies, anti-TIGIT antibodies, anti-CD20 antibodies, anti-CD96 antibodies, an anti-IDO1 antibodies, and any combinations thereof. [00376] Any suitable PD-L1 antagonists can be used with the presently disclosed subject matter. PD-L1 antagonists disclosed herein can block, inhibit, or neutralize the function or activity of PD-L1 (e.g., the binding of PD-L1 to PD-1). In certain embodiments, the PD-L1 antagonist is an anti-PD-L1 antibody. In certain embodiments, the PD-L1 antagonist is a small molecule antagonist. Exemplary anti-PD-L1 antibodies that can be used with the present disclosure include but not limited to BMS-936559 (MDX-1105), MEDI4736, MPDL3280A (RG7446), MSB0010718C, atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi). Exemplary small molecule PD-L1 antagonists that can be used with the present disclosure include but not limited to CA-170, INCB-086550, MX-10181, GS-4224, and IMMH-010, and the PD-L1 antagonists disclosed in Sasikumar and Ramachandra, Front Immunol.2022;13:752065; Liu et al., Cancer Cell International. 2021;21: Article number: 239, the content of each of which is incorporated herein by reference. [00377] In certain embodiments, the CTLA-4 antagonist is an antibody that specifically binds CTLA-4. In certain embodiments, the antibody that binds CTLA-4 is ipilimumab (YERVOY) or tremelimumab (CP-675,206). In certain embodiments, the CTLA-4 antagonist a CTLA-4 fusion protein, for example, KAHR-102. [00378] In certain embodiments, the LAG3 antagonist is an antibody that specifically binds LAG3. In certain embodiments, the antibody that binds LAG3 is IΜΡ701, IMP731, BMS- 986016, LAG525, and GSK2831781. In certain embodiments, the LAG3 antagonist includes a soluble LAG3 receptor, for example, IMP321. [00379] In certain embodiments, the KIR antagonist is an antibody that specifically binds KIR. In certain embodiments, the antibody that binds KIR is lirilumab. NAI-1539756353v1 131 [00380] In certain embodiments, the at least one additional therapeutic agent is selected from the group consisting of: a CD28 agonist, a 4-1BB agonist, an OX40 agonist, a CD27 agonist, a CD80 agonist, a CD86 agonist, a CD40 agonist, and a GITR agonist. [00381] In certain embodiments, the OX40 agonist includes OX40 ligand, or an OX40- binding portion thereof. For example, the OX40 agonist may be MEDI6383. In certain embodiments, the OX40 agonist is an antibody that specifically binds OX40. In certain embodiments, the antibody that binds OX40 is MEDI6469, MEDI0562, or MOXR0916 (RG7888). In certain embodiments, the OX40 agonist is a vector (e.g., an expression vector or virus, such as an adenovirus) capable of expressing OX40 ligand. In certain embodiments the OX40-expressing vector is tasadenoturev (DNX-2401). [00382] In certain embodiments, the 4-1BB (CD137) agonist is a binding molecule, such as an anticalin. In certain embodiments, the anticalin is PRS-343. In certain embodiments, the 4-1BB agonist is an antibody that specifically binds 4-1BB. In certain embodiments, antibody that binds 4-1BB is PF-2566 (PF-05082566) or urelumab (BMS-663513). [00383] In certain embodiments, the CD27 agonist is an antibody that specifically binds CD27. In certain embodiments, the antibody that binds CD27 is varlilumab (CDX-1127). [00384] In certain embodiments, the GITR agonist comprises a GITR ligand or a GITR- binding portion thereof. In certain embodiments, the GITR agonist is an antibody that specifically binds GITR. In certain embodiments, the antibody that binds GITR is TRX518, MK-4166, or INBRX-110. [00385] In certain embodiments, the at least one additional therapeutic agent used herein include, but are not limited to, cytokines such as chemokines, interferons, interleukins, lymphokines, and members of the tumor necrosis factor (TNF) family. In certain embodiments, the at least one additional therapeutic agent is an immunostimulatory oligonucleotides, such as CpG dinucleotides. [00386] In certain embodiments, the at least one additional therapeutic agent is selected from the group consisting of granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage colony stimulating factor (M-CSF), granulocyte colony stimulating factor (G- CSF), interleukin 3 (IL- 3), interleukin 12 (IL-12), interleukin 1 (IL-1), interleukin 2 (IL-2), B7-1 (CD80), B7-2 (CD86), 4-1BB ligand, and anti-CD3 antibody. [00387] In certain embodiments, the at least one additional therapeutic agent is selected from the group consisting of anti-tubulin agents, auristatins, DNA minor groove binders, DNA replication inhibitors, alkylating agents (e.g., platinum complexes such as cisplatin, mono(platinum), bis(platinum) and tri-nuclear platinum complexes and carboplatin), NAI-1539756353v1 132 anthracyclines, antibiotics, anti-folates, anti-metabolites, chemotherapy sensitizers, duocarmycins, etoposides, fluorinated pyrimidines, ionophores, lexitropsins, nitrosoureas, platinols, purine antimetabolites, puromycins, radiation sensitizers, steroids, taxanes, topoisomerase inhibitors, vinca alkaloids, alkylating agents, antimetabolites, antimitotics, topoisomerase inhibitors, and angiogenesis inhibitors. [00388] In certain embodiments, the at least one additional therapeutic agent comprises a chemotherapeutic agent or a cocktail of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents that can be used with the present disclosure include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamime; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti- metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6- mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytosine arabinoside, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenishers such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK; razoxane; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"- NAI-1539756353v1 133 trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); taxoids, e.g. paclitaxel (TAXOL) and docetaxel (TAXOTERE); chlorambucil; gemcitabine; 6- thioguanine; mercaptopurine; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; ibandronate; CPT 11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine (XELODA); and pharmaceutically acceptable salts, acids or derivatives of any of the above. [00389] In certain embodiments, the chemotherapeutic agent is an anti-hormonal agent that acts to regulate or inhibit hormone action on tumors, such as anti-estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (FARESTON); and anti- androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above. [00390] In certain embodiments, the chemotherapeutic agent is a topoisomerase inhibitor. Topoisomerase inhibitors include, but are not limited to, doxorubicin HC1, daunorubicin citrate, mitoxantrone HC1, actinomycin D, etoposide, topotecan HC1, teniposide (VM-26), and irinotecan, as well as pharmaceutically acceptable salts, acids, or derivatives of any of these. [00391] In certain embodiments, the chemotherapeutic agent is an anti-metabolite. Anti- metabolites include, but are not limited to, gemcitabine, fluorouracil, capecitabine, methotrexate sodium, ralitrexed, pemetrexed, tegafur, cytosine arabinoside, thioguanine, 5- azacytidine, 6-mercaptopurine, azathioprine, 6-thioguanine, pentostatin, fludarabine phosphate, and cladribine, as well as pharmaceutically acceptable salts, acids, or derivatives of any of these. [00392] In certain embodiments, the chemotherapeutic agent is an antimitotic agent, including, but not limited to, agents that bind tubulin. In certain embodiments, the agent is a taxane. In certain embodiments, the agent is paclitaxel or docetaxel, or a pharmaceutically acceptable salt, acid, or derivative of paclitaxel or docetaxel. In certain embodiments, the agent is paclitaxel (TAXOL), docetaxel (TAXOTERE), albumin-bound paclitaxel (nab- paclitaxel; ABRAXANE), DHA-paclitaxel, or PG-paclitaxel. In certain embodiments, the antimitotic agent comprises a vinca alkaloid, such as vincristine, vinblastine, vinorelbine, or vindesine, or pharmaceutically acceptable salts, acids, or derivatives thereof. In certain NAI-1539756353v1 134 embodiments, the antimitotic agent is an inhibitor of kinesin Eg5 or an inhibitor of a mitotic kinase such as Aurora A or Plkl. [00393] In certain embodiments, the at least one additional therapeutic agent comprises a small molecule acting as an inhibitor against tumor-associated antigens including, but not limited to, EGFR, HER2 (ErbB2), and/or VEGF. In certain embodiments, the at least one additional therapeutic agent comprises a protein kinase inhibitor selected from the group consisting of: gefitinib (IRESSA), erlotinib (TARCEVA), sunitinib (SUTENT), lapatanib, vandetanib (ZACTIMA), AEE788, CI-1033, cediranib (RECENTIN), sorafenib (NEXAVAR), and pazopanib (GW786034B). In certain embodiments, the at least one additional therapeutic agent comprises comprises an mTOR inhibitor. [00394] In certain embodiments, the at least one additional therapeutic agent comprises a biological molecule, such as an antibody. For example, treatment can involve the combined administration of a LAIR1-binding agent of the present disclosure with antibodies against tumor-associated antigens including, but not limited to, antibodies that bind EGFR, HER2/ErbB2, and/or VEGF. [00395] In certain embodiments, the at least one additional therapeutic agent comprises an antibody that is an angiogenesis inhibitor (e.g., an anti-VEGF or VEGF receptor antibody). In certain embodiments, the additional therapeutic agent is bevacizumab (AVASTIN), ramucirumab, trastuzumab (HERCEPTIN), pertuzumab (OMNITARG), panitumumab (VECTIBIX), nimotuzumab, zalutumumab, or cetuximab (ERBITUX). [00396] In certain embodiments, the at least one additional therapeutic agent comprises an ILT3 antibody. U.S. Provisional Application No.63/265,824, which is hereby incorporated by reference in its entirety, provides various descriptions and uses of the ILT3 antibodies provided herein. In certain embodiments, any of the ILT-3 antibodies disclosed in U.S. Provisional Application No.63/265,824 can be used in any of the methods disclosed herein. [00397] In certain embodiments, the anti-ILT3 antibody and the anti-LAIR1 antibody are formulated into two separate pharmaceutical compositions for use. In certain embodiments, the anti-ILT3 antibody and the anti-LAIR1 antibody are formulated into the same pharmaceutical composition for use. [00398] In certain embodiments, an anti-ILT3 antibody includes a VH including a VH CDR1, a VH CDR2, a VH CDR3, and a VL including a VL CDR1, a VL CDR2, and a VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 are from any one of the VH and VL sequences of the antibodies described in U.S. Provisional Application No.63/265,824 (e.g., 3A3, 5A7, 12A12, 16C5, 45G10, 48A6, 53F10, or NAI-1539756353v1 135 Hz5A7.v5). In certain embodiments, the anti-ILT3 antibody is a humanized version of an antibody disclosed herein, (e.g., 3A3, 5A7, 12A12, 16C5, 45G10, 48A6, 53F10). Furthermore, treatment with a LAIR1-binding agent disclosed herein can include combination treatment with other biologic molecules, such as one or more cytokines (e.g., lymphokines, interleukins, tumor necrosis factors, and/or growth factors) or can be accompanied by surgical removal of tumors, removal of cancer cells, or any other therapy deemed necessary by a treating physician. [00399] In certain embodiments, the at least one additional therapeutic agent comprises a growth factor selected from the group consisting of: adrenomedullin (AM), angiopoietin (Ang), BMPs, BDNF, EGF, erythropoietin (EPO), FGF, GDNF, G-CSF, GM-CSF, GDF9, HGF, HDGF, IGF, migration-stimulating factor, myostatin (GDF-8), NGF, neurotrophins, PDGF, thrombopoietin, TGF-a, TGF-β, TNF-a, VEGF, PIGF, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-12, IL-15, and IL-18. [00400] In certain embodiments, treatment with the LAIR1 binding agent and the PD-1 antagonist disclosed herein can occur prior to, concurrently with, or subsequent to the administration of the at least one additional therapeutic agent. In certain embodiments, combined administration includes co-administration, either in a single pharmaceutical formulation or using separate formulations, or consecutive administration in either order but generally within a time period such that all active agents can exert their biological activities. In certain embodiments, preparation of agents and/or dosing schedules for additional therapeutic agents are according to manufacturers' instructions or as determined empirically by the skilled practitioner. [00401] In certain embodiments, the LAIR1 binding agent and/or the PD-1 antagonist is administered to the subject that have previously undergone treatment with the at least one additional therapeutic agent. In certain embodiments, the LAIR1 binding agent and/or the PD-1 antagonist is administered substantially simultaneously or concurrently with the at least one additional therapeutic agent. In certain embodiments, the LAIR1 binding agent and/or the PD-1 antagonist is administered within 1 year of the treatment with the at least one additional therapeutic agent. In certain embodiments, the LAIR1 binding agent and/or the PD-1 antagonist is administered within 10, 8, 6, 4, or 2 months of any treatment with the at least one additional therapeutic agent. In certain embodiments, the LAIR1 binding agent and/or the PD-1 antagonist is administered within 4, 3, 2, or 1 weeks of any treatment with the at least one additional therapeutic agent. In certain embodiments, the LAIR1 binding agent and/or the PD-1 antagonist is administered within 5, 4, 3, 2, or 1 days of any treatment NAI-1539756353v1 136 with the at least one additional therapeutic agent. It will further be appreciated that the two (or more) agents or treatments can be administered to the subject within a matter of hours or minutes (i.e., substantially simultaneously). 5.7 Kits [00402] Also provided herein are kits comprising an LAIR1 binding agent (e.g., an anti- LAIR1 antibody) provided herein or a composition (e.g., a pharmaceutical composition) comprising thereof and a PD-1 antagonist or a composition (e.g., a pharmaceutical composition) comprising thereof, packaged into suitable packaging material. A kit optionally includes a label or packaging insert including a description of the components or instructions for use in vitro, in vivo, or ex vivo, of the components therein. [00403] The term “packaging material” refers to a physical structure housing the components of the kit. The packaging material can maintain the components sterilely, and can be made of material commonly used for such purposes (e.g., paper, corrugated fiber, glass, plastic, foil, ampoules, vials, tubes, etc.). [00404] Kits provided herein can include labels or inserts. Labels or inserts include “printed matter,” e.g., paper or cardboard, separate or affixed to a component, a kit or packing material (e.g., a box), or attached to, for example, an ampoule, tube, or vial containing a kit component. Labels or inserts can additionally include a computer readable medium, such as a disk (e.g., hard disk, card, memory disk), optical disk such as CD- or DVD-ROM/RAM, DVD, MP3, magnetic tape, or an electrical storage media such as RAM and ROM or hybrids of these such as magnetic/optical storage media, FLASH media, or memory type cards. Labels or inserts can include information identifying manufacturer information, lot numbers, manufacturer location, and date. [00405] Kits provided herein can additionally include other components. Each component of the kit can be enclosed within an individual container, and all of the various containers can be within a single package. Kits can also be designed for cold storage. A kit can further be designed to contain antibodies provided herein, or cells that contain nucleic acids encoding the antibodies provided herein. The cells in the kit can be maintained under appropriate storage conditions until ready to use. [00406] Also provided herein are panels of antibodies that immunospecifically bind to an LAIR1 antigen. In specific embodiments, provided herein are panels of antibodies having different association rate constants, different dissociation rate constants, different affinities for LAIR1 antigen, and/or different specificities for an LAIR1 antigen. In certain embodiments, provided herein are panels of about 10, preferably about 25, about 50, about NAI-1539756353v1 137 75, about 100, about 125, about 150, about 175, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, or about 1000 antibodies or more. Panels of antibodies can be used, for example, in 96 well or 384 well plates, such as for assays such as ELISAs. [00407] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those disclosed herein can be used in the practice or testing of the invention, suitable methods and materials are disclosed herein. [00408] As used herein, numerical values are often presented in a range format throughout this document. The use of a range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention unless the context clearly indicates otherwise. Accordingly, the use of a range expressly includes all possible subranges, all individual numerical values within that range, and all numerical values or numerical ranges including integers within such ranges and fractions of the values or the integers within ranges unless the context clearly indicates otherwise. This construction applies regardless of the breadth of the range and in all contexts throughout this patent document. Thus, for example, reference to a range of 90-100% includes 91-99%, 92-98%, 93-95%, 91-98%, 91-97%, 91-96%, 91-95%, 91-94%, 91-93%, and so forth. Reference to a range of 90-100% also includes 91%, 92%, 93%, 94%, 95%, 95%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth. [00409] In addition, reference to a range of 1-3, 3-5, 5-10, 10-20, 20-30, 30-40, 40-50, 50- 60, 60-70, 70-80, 80-90, 90-100, 100-110, 110-120, 120-130, 130-140, 140-150, 150-160, 160-170, 170-180, 180-190, 190-200, 200-225, 225-250 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc. In a further example, reference to a range of 25- 250, 250-500, 500-1,000, 1,000-2,500, 2,500-5,000, 5,000-25,000, 25,000-50,000 includes any numerical value or range within or encompassing such values, e.g., 25, 26, 27, 28, 29…250, 251, 252, 253, 254…500, 501, 502, 503, 504…, etc. [00410] As also used herein a series of ranges are disclosed throughout this document. The use of a series of ranges includes combinations of the upper and lower ranges to provide another range. This construction applies regardless of the breadth of the range and in all contexts throughout this patent document. Thus, for example, reference to a series of ranges NAI-1539756353v1 138 such as 5-10, 10-20, 20-30, 30-40, 40-50, 50-75, 75-100, 100-150, includes ranges such as 5- 20, 5-30, 5-40, 5-50, 5-75, 5-100, 5-150, and 10-30, 10-40, 10-50, 10-75, 10-100, 10-150, and 20-40, 20-50, 20-75, 20-100, 20-150, and so forth. [00411] It is understood that modifications which do not substantially affect the activity of the various embodiments disclosed herein are also provided within the definition of the subject matter disclosed herein. Accordingly, the following examples are intended to illustrate but not limit the present disclosure 6. EMBODIMENTS [00412] The present disclosure provides the following non-limiting embodiments: 1. A method of disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a subject having osteosarcoma, comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M; and (b) a PD-1 antagonist. 2. A method of disrupting, inhibiting, or blocking collagen-induced LAIR1 activity in a subject having osteosarcoma, comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M; and (b) a PD-1 antagonist. 3. A method of disrupting, inhibiting, or blocking LAIR1-induced suppression of an immune cell or immune cell activity in a subject having osteosarcoma, comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; NAI-1539756353v1 139 (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M; and (b) a PD-1 antagonist, wherein the immune cell or immune cell activity is a myeloid cell or myeloid cell activity, a natural killer (NK) cell or NK cell activity, a T-cell or T-cell activity, a myeloid- derived suppressor cell (MDSC) or MDSC activity, a regulatory T-cell (Treg) or Treg activity. 4. The method of embodiment 3, wherein (i) the myeloid cell is a monocyte, a macrophage, a dendritic cell, or an APC; and/or (ii) the T-cell is a cytotoxic T-cell (CTL). 5. A method of treating osteosarcoma in a subject, comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M; and (b) a PD-1 antagonist. 6. A method of (a) inhibiting tumor growth, (b) increasing or enhancing an immune response to a tumor or tumor cells, (c) activating or enhancing a persistent or long-term immune response to a tumor or tumor cells, (d) inhibiting tumor relapse or tumor regrowth, and/or (e) inducing a persistent or long-term immunity that inhibits tumor relapse or tumor regrowth, in a subject having osteosarcoma, the method comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M; and (b) a PD-1 antagonist. NAI-1539756353v1 140 7. A method of activating immune cells in the tumor microenvironment in a subject having osteosarcoma, comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M; and (b) a PD-1 antagonist, wherein the immune cells are myeloid cells, NK cells, and/or T-cells. 8. The method of embodiment 7, wherein (i) the myeloid cells are monocytes, macrophages, dendritic cells, or APCs; and/or (ii) the T-cells are cytotoxic T-cells (CTLs). 9. Use of (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof and (b) a PD-1 antagonist for (a) treatment of osteosarcoma; (b) disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a subject having osteosarcoma; (c) disrupting, inhibiting, or blocking collagen-induced LAIR1 activity in a subject having osteosarcoma; (d) disrupting, inhibiting, or blocking LAIR1-induced suppression of an immune cell or immune cell activity in a subject having osteosarcoma; (e) inhibiting tumor growth, increasing or enhancing an immune response to a tumor or tumor cells, activating or enhancing a persistent or long-term immune response to a tumor or tumor cells, inhibiting tumor relapse or tumor regrowth, and/or inducing a persistent or long-term immunity that inhibits tumor relapse or tumor regrowth, in a subject having osteosarcoma; and/or (f) activating immune cells in the tumor microenvironment in a subject having osteosarcoma, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M. NAI-1539756353v1 141 10. Use of (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof and (b) a PD-1 antagonist in the manufacture of a medicament for (a) treatment of osteosarcoma; (b) disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a subject having osteosarcoma; (c) disrupting, inhibiting, or blocking collagen-induced LAIR1 activity in a subject having osteosarcoma; (d) disrupting, inhibiting, or blocking LAIR1-induced suppression of an immune cell or immune cell activity in a subject having osteosarcoma; (e) inhibiting tumor growth, increasing or enhancing an immune response to a tumor or tumor cells, activating or enhancing a persistent or long-term immune response to a tumor or tumor cells, inhibiting tumor relapse or tumor regrowth, and/or inducing a persistent or long-term immunity that inhibits tumor relapse or tumor regrowth, in a subject having osteosarcoma; and/or (f) activating immune cells in the tumor microenvironment in a subject having osteosarcoma, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M. 11. A method of disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a cell mixture comprising osteosarcoma cells to enhance the immune response to the osteosarcoma cells, the method comprising contacting the cell mixture with (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M; and (b) a PD-1 antagonist. 12. The method of embodiment 11, wherein the cell mixture comprises at least one of myeloid cells, NK cells, T-cells, cytotoxic T-cells, MDSCs, and T-regs. NAI-1539756353v1 142 13. The method of embodiment 12, wherein the myeloid cells comprise at least one of monocytes, macrophages, dendritic cells, and APCs. 14. A method of disrupting, inhibiting, or blocking LAIR1-induced suppression of an immune cell or immune cell activity to enhance the immune response to osteosarcoma cells, comprising contacting a cell mixture comprising the osteosarcoma cells and the immune cell with (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M; and (b) a PD-1 antagonist, wherein the immune cell or immune cell activity is a myeloid cell or myeloid cell activity, a NK cell or NK cell activity, a T-cell or T-cell activity, a MDSC or MDSC activity, a Treg or Treg activity, and wherein the immune cell is an intratumoral cell, and is or was present in osteosarcoma or a tumor microenvironment thereof. 15. The method of embodiment 14, wherein (i) the myeloid cell is a monocyte, a macrophage, a dendritic cell, or an APC; and/or (ii) the T-cell is a cytotoxic T-cell (CTL). 16. The method or use of any one of embodiments 1-15, wherein the PD-1 antagonist is an antagonistic anti-PD-1 antibody. 17. The method or use of embodiment 16, wherein the anti-PD-1 antibody is selected from the group consisting of pembrolizumab, pidilizumab, nivolumab, durvalumab, budigalima, cemiplimab, tislelizumab, spartalizumab, and STI-A1110. 18. The method or use of any one of embodiments 1-10, 16, and 17, wherein the antagonistic PD-1 antagonist is administered to the subject prior to, concurrently, or subsequent to the administration of the antibody that binds to LAIR1. 19. The method or use of any one of embodiments 1-18, wherein the antibody comprises: (i) a heavy chain variable region complementarity determining region 1 (VH CDR1), a heavy chain variable region complementarity determining region 2 (VH CDR2) and a heavy chain variable region complementarity determining region 3 (VH CDR3) as set forth in a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:119; and a light chain variable region complementarity determining region 1 (VL CDR1), a light NAI-1539756353v1 143 chain variable region complementarity determining region 2 (VL CDR2), and a light chain variable region complementarity determining region 3 (VL CDR3) as set forth in a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:120, (ii) a VH CDR1, a VH CDR2 and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:117; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:118, (iii) a VH CDR1, a VH CDR2 and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:115; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:116, (iv) a VH CDR1, a VH CDR2 and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:121; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:122, (v) a VH CDR1, a VH CDR2 and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:123; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:124, (vi) a VH CDR1, a VH CDR2 and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:125; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:126, (vii) a VH CDR1, a VH CDR2 and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:127; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:128, (viii) a VH CDR1, a VH CDR2 and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:129; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:130, or (ix) a VH CDR1, a VH CDR2 and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:131; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:132. 20. The method or use of embodiment 19, wherein the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:25, SEQ ID NO:31, SEQ ID NO:34, or SEQ ID NO:35; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:44, or SEQ ID NO:45; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:27, or NAI-1539756353v1 144 SEQ ID NO:37, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:28 or SEQ ID NO:38; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:42 or SEQ ID NO:39; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:30 or SEQ ID NO:40. 21. The method or use of embodiment 20, wherein the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:41, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27, the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:42, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:31, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:43, the VH CDR3 comprises the amino acid of SEQ ID NO:27; the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:42, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; (iii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:44, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:42, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; (iv) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:34, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:41, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:42, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; and (v) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:35, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:45, the VH CDR3 comprises the NAI-1539756353v1 145 amino acid sequence of SEQ ID NO:37; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:38, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:39, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:40. 22. The method or use of embodiment 20 or 21, wherein the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:119, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:120. 23. The method or use of any one of embodiments 20-22, wherein the VH comprises the amino acid sequence of SEQ ID NO:119, and/or the VL comprises the amino acid sequence of SEQ ID NO:120. 24. The method or use of any one of embodiments 20-23, wherein the antibody comprises a heavy chain having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:134 and a light chain having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:136. 25. The method or use of embodiment 24, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:134 and a light chain comprising the amino acid sequence of SEQ ID NO:136. 26. The method or use of embodiment 19, wherein the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:25, SEQ ID NO:31, SEQ ID NO:34, or SEQ ID NO:35; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:26, SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:36; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:27 or SEQ ID NO:37 , and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:28 or SEQ ID NO:38; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:29 or SEQ ID NO:39; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:30 or SEQ ID NO:40. NAI-1539756353v1 146 27. The method or use of embodiment 26, wherein the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:26, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:31, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:32, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; (iii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:33, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; (iv) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:34, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:26, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; and (v) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:35, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:36, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:37; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:38, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:39, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:40. NAI-1539756353v1 147 28. The method or use of embodiment 26 or 27, wherein the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:117, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:118. 29. The method or use of any one of embodiments 26-28, wherein the VH comprises the amino acid sequence of SEQ ID NO:117, and/or the VL comprises the amino acid sequence of SEQ ID NO:118. 30. The method or use of embodiment 19, wherein the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:9, SEQ ID NO:15, SEQ ID NO:18, or SEQ ID NO:19; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:10, SEQ ID NO:16, SEQ ID NO:17, or SEQ ID NO:20; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:11 or SEQ ID NO:21, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:12 or SEQ ID NO:22; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:13 or SEQ ID NO:23; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:14 or SEQ ID NO:24. 31. The method or use of embodiment 30, wherein the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:9, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:10, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:11; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:12, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:13, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:14; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:15, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:16, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:11; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:12, the VL CDR2 comprises the amino acid sequence NAI-1539756353v1 148 of SEQ ID NO:13, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:14; (iii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:9, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:17, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:11; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:12, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:13, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:14; (iv) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:18, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:10, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:11; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:12, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:13, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:14; and (v) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:19, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:20, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:21; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:22, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:23, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:24. 32. The method or use of embodiment 30 or 31, wherein the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:115, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:116. 33. The method or use of any one of embodiments 30-32, wherein the VH comprises the amino acid sequence of SEQ ID NO:115, and/or the VL comprises the amino acid sequence of SEQ ID NO:116. 34. The method or use of embodiment 19, wherein the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:46, SEQ ID NO:52, SEQ ID NO:55, or SEQ ID NO:56; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:47, SEQ ID NO:53, SEQ ID NO:54 or SEQ ID NO:57; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:48 or SEQ ID NO:58 , NAI-1539756353v1 149 and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:49 or SEQ ID NO:59; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:50 or SEQ ID NO:60; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:51 or SEQ ID NO:61. 35. The method or use of embodiment 34, wherein the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:46, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:47, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:48; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:49, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:50, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:51; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:52, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:53, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:48; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:49, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:50, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:51; (iii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:46, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:54, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:48; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:49, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:50, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:51; (iv) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:55, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:47, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:48; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:49, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:50, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:51; and NAI-1539756353v1 150 (v) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:56, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:57, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:58; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:59, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:60, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:61. 36. The method or use of embodiment 34 or 35, wherein the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:121, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:122. 37. The method or use of any one of embodiments 34-36, wherein the VH comprises the amino acid sequence of SEQ ID NO:121, and/or the VL comprises the amino acid sequence of SEQ ID NO:122. 38. The method or use of embodiment 19, wherein the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:62, SEQ ID NO:68, SEQ ID NO:71, or SEQ ID NO:72; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:63, SEQ ID NO:69, SEQ ID NO:70, or SEQ ID NO:73; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:64 or SEQ ID NO:74, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:65 or SEQ ID NO:75; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:66 or SEQ ID NO:76; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:67 or SEQ ID NO:77. 39. The method or use of embodiment 38, wherein the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:62, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:63, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:64; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:65, the VL CDR2 comprises the amino acid sequence NAI-1539756353v1 151 of SEQ ID NO:66, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:67; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:68, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:69, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:64; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:65, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:66, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:67; (iii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:62, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:70, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:64; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:65, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:66, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:67; (iv) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:71, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:63, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:64; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:65, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:66, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:67; and (v) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:72, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:73, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:74; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:75, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:76, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:77. 40. The method or use of embodiment 38 or 39, wherein the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:123, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:124. 41. The method or use of any one of embodiments 38-40, wherein the VH comprises the amino acid sequence of SEQ ID NO:123, and/or the VL comprises the amino acid sequence of SEQ ID NO:124. 42. The method or use of embodiment 19, wherein the antibody comprises (a) a VH comprising: NAI-1539756353v1 152 (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:25, SEQ ID NO:31, SEQ ID NO:34, or SEQ ID NO:35; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:78, SEQ ID NO:82, SEQ ID NO:83, or SEQ ID NO:84; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:79 or SEQ ID NO:85, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:80 or SEQ ID NO:86; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:29 or SEQ ID NO:39; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:81 or SEQ ID NO:87. 43. The method or use of embodiment 42, wherein the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:78, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:79; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:80, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:81; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:31, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:82, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:79; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:80, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:81; (iii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:83, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:79; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:80, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:81; NAI-1539756353v1 153 (iv) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:34, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:78, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:79; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:80, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:81; and (v) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:35, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:84, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:85; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:86, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:39, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:87. 44. The method or use of embodiment 42 or 43, wherein the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:125, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:126. 45. The method or use of any one of embodiments 42-44, wherein the VH comprises the amino acid sequence of SEQ ID NO:125, and/or the VL comprises the amino acid sequence of SEQ ID NO:126. 46. The method or use of embodiment 42 or 43, wherein the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:127, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:128. 47. The method or use of any one of embodiments 42, 43, and 46, wherein the VH comprises the amino acid sequence of SEQ ID NO:127, and/or the VL comprises the amino acid sequence of SEQ ID NO:128. 48. The method or use of any one of embodiments 42, 43, 46, and 47, wherein the antibody comprises a heavy chain having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:138 and a light chain having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:140. 49. The method or use of embodiment 48, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:138 and a light chain comprising the amino acid sequence of SEQ ID NO:140. 50. The method or use of embodiment 19, wherein the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:25, NAI-1539756353v1 154 SEQ ID NO:31, SEQ ID NO:34, or SEQ ID NO:35; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:88, SEQ ID NO:32, SEQ ID NO:93, or SEQ ID NO:94; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:89 or SEQ ID NO:95, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:90 or SEQ ID NO:96; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:91 or SEQ ID NO:97; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:92 or SEQ ID NO:98. 51. The method or use of embodiment 50, wherein the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:88, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:89; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:90, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:91, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:92; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:31, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:32, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:89; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:90, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:91, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:92; (iii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:93, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:89; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:90, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:91, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:92; (iv) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:34, the VH NAI-1539756353v1 155 CDR2 comprises the amino acid sequence of SEQ ID NO:88, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:89; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:90, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:91, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:92; and (v) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:35, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:94, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:95; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:96, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:97, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:98. 52. The method or use of embodiment 50 or 51, wherein the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:129, and/or the light chain variable region has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:130. 53. The method or use of any one of embodiments 50-52, wherein the VH comprises the amino acid sequence of SEQ ID NO:129, and/or the VL comprises the amino acid sequence of SEQ ID NO:130. 54. The method or use of embodiment 19, wherein the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:99, SEQ ID NO:105, SEQ ID NO:108, or SEQ ID NO:109; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:100, SEQ ID NO:106, SEQ ID NO:107 or SEQ ID NO:110; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:101 or SEQ ID NO:111, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:102 or SEQ ID NO:112; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:103 or SEQ ID NO:113; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:104 or SEQ ID NO:114. NAI-1539756353v1 156 55. The method or use of embodiment 54, wherein the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:99, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:100, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:101; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:102, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:103, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:104; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:105, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:106, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:101; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:102, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:103, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:104; (iii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:99, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:107, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:101; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:102, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:103, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:104; (iv) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:108, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:100, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:101; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:102, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:103, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:104; and (v) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:109, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:110, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:111; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:112, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:113, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:114. 56. The method or use of embodiment 54 or 55, wherein the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:131, and/or the light chain NAI-1539756353v1 157 variable region has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:132. 57. The method or use of any one of embodiments 54-56, wherein the VH comprises the amino acid sequence of SEQ ID NO:131, and/or the VL comprises the amino acid sequence of SEQ ID NO:132. 58. The method or use of any one of embodiments 1-57, wherein the antibody is a recombinant antibody, a monoclonal antibody, a chimeric antibody, a humanized antibody, a bispecific antibody, or a multispecific antibody. 59. The method or use of any one of embodiments 1-58, wherein the antibody is an IgG1 antibody, an IgG2 antibody, or an IgG4 antibody; optionally wherein the antibody is a human IgG1 antibody, a human IgG2 antibody, or a human IgG4 antibody. 60. The method or use of any one of embodiments 1-59, wherein the antibody comprises a kappa light chain or a lambda light chain, optionally wherein the antibody comprises a human kappa light chain or a human lambda light chain. 61. The method or use of any one of embodiments 1-60, wherein the antibody is attached to a half-life extending moiety. 62. The method or use of any one of embodiments 1-61, wherein the antibody is an antibody fragment, optionally wherein the antibody fragment comprises at least one antigen binding site that binds to LAIR1. 63. The method or use of embodiment 62, wherein the antibody fragment is a Fab, a Fab’, a F(ab’)2, a Fv, a scFv, a (scFv)2, a single chain antibody, a dual variable region antibody, a diabody, or a nanobody. 64. The method or use of any one of embodiments 1-63, wherein the antibody inhibits binding of LAIR-1 to one or more LAIR ligands and optionally has at least one of the following properties: (i) binding human LAIR1; (ii) binding cyno LAIR1; (iii) not binding mouse LAIR1; (iv) not binding human LAIR-2; (v) being a LAIR1 antagonist; (vi) inhibiting LAIR1 activity; (vii) inhibiting LAIR1 signaling in cells that express LAIR1; (viii) inhibiting binding of LAIR1 to collagen; (ix) inhibiting binding of LAIR1 to MARCO; NAI-1539756353v1 158 (x) inhibiting binding of LAIR1 to COLEC12; (xi) inhibiting LAIR1-induced suppression of myeloid cells; (xii) inhibiting LAIR1-induced suppression of myeloid cell activity; (xiii) restoring FcR activation in myeloid cells; (xiv) restoring cytokine and/or chemokine production in myeloid cells; (xv) inhibiting LAIR1-induced suppression of NK cells; (xvi) inhibiting LAIR1-induced suppression of NK activity; (xvii) inhibiting LAIR1-induced suppression of T-cell activity; and (xviii) inhibiting MDSC activity, optionally wherein the one or more LAIR ligands is selected from the group consisting of collagen, MARCO, COLEC12, MBL, SPD, and C1 complex. 65. The method or use of any one of embodiments 1-64, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. 66. The method or use of any one of embodiments 1-65, wherein the antibody or the pharmaceutical composition is administered at a therapeutically effective amount. 7. EXAMPLES [00413] The following is a description of various methods and materials used in the studies. They are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that the experiments below were performed and are all of the experiments that may be performed. It is to be understood that exemplary descriptions written in the present tense were not necessarily performed, but rather that the descriptions can be performed to generate the data and the like associated with the teachings of the present invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, percentages, etc.), but some experimental errors and deviations should be accounted for. 7.1 Example 1: Expression of LAIR1 in Osteosarcoma [00414] Expression of LAIR1, CD163, OSCAR, and IBA1 were assessed in human osteosarcoma biopsies using in situ hybridization and immunohistochemistry. [00415] For immunohistochemistry, ten biopsied human osteosarcoma samples were stained with anti-LAIR1 antibody (NKTA255, GeneTex, Irvine, CA), anti-IBA1 antibody (Clone E404W, Cell Signaling Technology, Danvers, MA), or anti-CD163 antibody (Clone D6U1J, Cell Signaling Technology). The staining was performed on a Leica Bond platform (Leica NAI-1539756353v1 159 Biosystems, Buffalo Grove, IL) and scanned on an AT2 slide scanner (Leica Biosystems). The tumor samples were evaluated for the abundance of the proteins of interest and their spatial distribution. As shown in representative images in Figures 1A and 1B, human osteosarcoma is enriched with cells expressing LAIR1 protein. LAIR1 expression essentially overlapped with IBA1 and CD163 expression in non-cancerous cells, indicating that the cells expressing LAIR1 are of myeloid origin (Figures 1A and 1B). [00416] Since OSCAR mediates an anti-LAIR1 antibody induced inflammatory activation in myeloid cells (data not shown), OSCAR expression was assessed in ten biopsied human osteosarcoma samples. In situ hybridization was performed and the samples were hybridized with OSCAR probes (Cat No.553178; Advanced Cell Diagnostics). Probes for PPIB (Cat No.313908; Advanced Cell Diagnostics) were used as the house-keeping mRNA control on the Leica Bond platform. The slides were evaluated for the spatial distribution of OSCAR mRNA. As shown in Figure 2, OSCAR was widely expressed in non-cancerous cells surrounding cancer cells, which was consistent with the LAIR1 expression patten in intratumoral myeloid cells in human osteosarcoma samples. This result supports that LAIR1 plays an important role in suppression of myeloid cells in osteosarcoma. [00417] LAIR1 mediates suppression of immune cells through interaction with collagen. See International Publication No. WO 2021/262597. Thus, collagen abundance was assessed in osteosarcoma resection specimens using immunohistochemistry. As shown in Figure 3A, collagen deposition was highly expressed in osteosarcoma. The abundance of both LAIR1 and its ligand collagen in tumor-infiltrating myeloid cells supporting that the collagen/LAIR1 signaling drives immune cell suppression in osteosarcoma. 7.2 Example 2: Stromal Content in Osteosarcoma [00418] LAIR1-mediated suppression of immune cells is through its interaction with collagen, and collagen is the most abundant protein found within tumor stroma. As such, collagen and stromal abundance in osteosarcoma was compared with other solid tumors. [00419] The collagen expression level was compared across different cancer types, including osteosarcoma (OS), liposarcoma, pleomorphic sarcoma (PISarc), angiosarcoma, mesothelioma (MESO), pancreatic ductal adenocarcinoma (PDAC), gastric cancer, ovarian cancer, colorectal cancer (CRC), hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), lung squamous cell carcinoma (LuSCC), head and neck squamous cell carcinoma (HNSCC), lung adenocarcinoma (LUAD), glioblastoma (GBM), small cell lung cancer (SCLC). Osteosarcoma showed the highest level of collagen expression (Figure 3B). NAI-1539756353v1 160 [00420] A set of 58 genes was previously identified to be associated with cancer stroma and worse prognosis (Chakravarthy et al., Nature Communications 2018). This gene set was scored in the TCGA and TARGET OS datasets based on FPKM values using the ssGSEA method in the GSVA R package, and osteosarcoma was found to be one of the most stroma- rich cancers among the 33 indications compared including pancreatic adenocarcinoma (PAAD), sarcoma (SARC), mesothelioma (MESO), breast invasive carcinoma (BRCA), lung squamous cell carcinoma (LUSC), uterine carcinoma (UCS), lung adenocarcinoma (LUAD), head and neck squamous cell carcinoma (HNSC), stomach adenocarcinoma (STAD), esophageal carcinoma (ESCA), rectum adenocarcinoma (READ), testicular germ cell tumors (TGCT), colon adenocarcinoma (COAD), urothelial bladder carcinoma (BLCA), cholangiocarcinoma (CHOL), skin cutaneous melanoma (SKCM), kidney renal clear cell carcinoma (KIRC), ovarian serous cystadenocarcinoma (OV), glioblastoma multiforme (GBM), uterine corpus endometrial carcinoma (UCEC), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), prostate adenocarcinoma (PRAD), thyroid carcinoma (THCA), adrenocortical carcinoma (ACC), pheochromocytoma and paraganglioma (PCPG), liver hepatocellular carcinoma (LIHC), kidney renal papillary cell carcinoma (KIRP), thymoma (THYM), uveal melanoma (UVM), brain low grade glioma (LGG), and kidney chromophobe (KICH) (Figure 4). High stromal content in osteosarcoma supports LAIR1-mediated immune cell suppression in this cancer, and the use of anti-LAIR1 antibody in treating osteosarcoma. 7.3 Example 3: LAIR1 Inhibition Blocks Osteosarcoma Progression in A Mouse Model [00421] The effect of blocking collagen/LAIR1 interaction is assessed in a murine osteosarcoma model. Balb/c mice are inoculated with 106 syngeneic K7M3 osteosarcoma cells by lateral tail vein injection. One week following the inoculation, the tumor-bearing mice are randomized into 4 treatment groups receiving the following interventions: 1) Group 1- isotype control (anti-KLH antibody) a. 10 mg/kg intraperitoneal (IP) administration on days 7, 14, and 21 2) Group 2- anti-LAIR1 antibody (murine anti-LAIR1 antibody clone 43H2, see WO 2021/262597) a. 10 mg/kg IP administration on days 7, 14, and 21 3) Group 3- anti-PD-1 antibody (Clone RMP1-14) a. 10 mg/kg IP administration on days 7, 11, 15, and 19 NAI-1539756353v1 161 4) Group 4- anti-LAIR1 antibody + anti-mouse PD-1 antibody (RMP1-14 clone, Bio X cell) a. Anti-LAIR1: 10 mg/kg IP on days 7, 14, and 21 b. Anti-PD-1: 10 mg/kg IP on days 7, 11, 15, and 19 [00422] All treatment groups are sacrificed 25-28 days post the inoculation. Various tissues including the lung tissue are collected and evaluated for tumor volume (burden) and tumor- infiltrating lymphocytes. It is observed that the anti-LAIR1 antibody administration reduces tumor growth and tumor metastasis in the mice. In addition, the anti-LAIR1 antibody increases the number of infiltrating lymphocytes in the tumors. Co-administration of the anti- LAIR1 antibody and anti-PD-1 antibody further enhances the effect of the anti-LAIR1 antibody on reduction of tumor growth and tumor metastasis, indicating a synergistic effect resulting from myeloid reprogramming imposed by the anti-LAIR1 antibody and immune cell activation imposed by the anti-PD-1 antibody. SEQUENCES [00423] Following are sequences disclosed in the application. CDR sequences are listed in Tables 1-7 as SEQ ID NOs:9-114. Human LAIR1 amino acid sequence with predicted signal sequence underlined (SEQ ID NO:1) MSPHPTALLGLVLCLAQTIHTQEEDLPRPSISAEPGTVIPLGSHVTFVCRGPVGVQTFRLER ESRSTYNDTEDVSQASPSESEARFRIDSVSEGNAGPYRCIYYKPPKWSEQSDYLELLVKETS GGPDSPDTEPGSSAGPTQRPSDNSHNEHAPASQGLKAEHLYILIGVSVVFLFCLLLLVLFCL HRQNQIKQGPPRSKDEEQKPQQRPDLAVDVLERTADKATVNGLPEKDRETDTSALAAGSSQE VTYAQLDHWALTQRTARAVSPQSTKPMAESITYAAVARH Human LAIR1 amino acid sequence without predicted signal sequence (SEQ ID NO:2) QEEDLPRPSISAEPGTVIPLGSHVTFVCRGPVGVQTFRLERESRSTYNDTEDVSQASPSESE ARFRIDSVSEGNAGPYRCIYYKPPKWSEQSDYLELLVKETSGGPDSPDTEPGSSAGPTQRPS DNSHNEHAPASQGLKAEHLYILIGVSVVFLFCLLLLVLFCLHRQNQIKQGPPRSKDEEQKPQ QRPDLAVDVLERTADKATVNGLPEKDRETDTSALAAGSSQEVTYAQLDHWALTQRTARAVSP QSTKPMAESITYAAVARH Human LAIR1 extracellular domain (aa 22-165) (SEQ ID NO:3) QEEDLPRPSISAEPGTVIPLGSHVTFVCRGPVGVQTFRLERESRSTYNDTEDVSQASPSESE ARFRIDSVSEGNAGPYRCIYYKPPKWSEQSDYLELLVKETSGGPDSPDTEPGSSAGPTQRPS DNSHNEHAPASQGLKAEHLY Human LAIR1 Ig-like C2-type domain amino acid sequence (aa 29-117) (SEQ ID NO:4) PSISAEPGTVIPLGSHVTFVCRGPVGVQTFRLERESRSTYNDTEDVSQASPSESEARFRIDS VSEGNAGPYRCIYYKPPKWSEQSDYLE Cyno LAIR1 amino acid sequence with predicted signal sequence underlined (SEQ ID NO:5) NAI-1539756353v1 162 MSPHPTALLGLVLCLAQTIHAQEGPLPRPSISAEPGTVIPPGRPVTIVCRGPVGVDQFRLER EDRSKFNDTKDVSQASPSESEARFRIDSVSEGNAGHYRCLYVKSTRWSEHSDYLDLVVKETS GDTDSPVTEPDSSAGPTQRPSDNSHNEHAPASQGLSAEHLYILIGVSVVFLFCLLLLVLFFL HRQNQMKQGPPRSKDEEQKLQQRPDLAVDVLERTADKATVNGLPEKDRETDTSAPAAGSSQE VTYAQLDHWALTWRTAQAVSPQSTEPMAESSTYAAVARH Cyno LAIR1 amino acid sequence without predicted signal sequence (SEQ ID NO:6) QEGPLPRPSISAEPGTVIPPGRPVTIVCRGPVGVDQFRLEREDRSKFNDTKDVSQASPSESE ARFRIDSVSEGNAGHYRCLYVKSTRWSEHSDYLDLVVKETSGDTDSPVTEPDSSAGPTQRPS DNSHNEHAPASQGLSAEHLYILIGVSVVFLFCLLLLVLFFLHRQNQMKQGPPRSKDEEQKLQ QRPDLAVDVLERTADKATVNGLPEKDRETDTSAPAAGSSQEVTYAQLDHWALTWRTAQAVSP QSTEPMAESSTYAAVARH Cyno LAIR1 extracellular domain (aa 22-165) (SEQ ID NO:7) QEGPLPRPSISAEPGTVIPPGRPVTIVCRGPVGVDQFRLEREDRSKFNDTKDVSQASPSESE ARFRIDSVSEGNAGHYRCLYVKSTRWSEHSDYLDLVVKETSGDTDSPVTEPDSSAGPTQRPS DNSHNEHAPASQGLSAEH Cyno LAIR1 Ig-like C2-type domain amino acid sequence (aa 29-117) (SEQ ID NO:8) EPGTVIPPGRPVTIVCRGPVGVDQFRLEREDRSKFNDTKDVSQASPSESEARFRIDSVSEGN AGHYRCLYVKSTRWSEHSDYLDLVVK 47A1 Heavy chain variable region amino acid sequence (SEQ ID NO:115) EVQLVESGGGLVQPKGSLKLSCAASGFTFNTYAIHWVRQAPGKGLEWVARIRSKSTNYATYY ADSVKDRFTISRDDSQSMVFLQMNNLKTEDTAMYYCVRENWYYYALDYWGQGTSVTVSS 47A1 Light chain variable region amino acid sequence (SEQ ID NO:116) DIQMTQSPASLSASVGETVTITCRASGNIHNYLTWYQQKQGKSPQVLVYNAKTLEDGVPSRF SGSESGTQYSLKINSLQPEDFGSYYCQHFWSTPFTFGSGTKLEIK 47H1 Heavy chain variable region amino acid sequence (SEQ ID NO:117) EVQLVETGGGLVQPKGSLKLSCAASGFTFNINAMNWVRQAPGKGLEWVARIRTKNNNYATFY ADSVKDRFTISRDDSQSMLYLQMNNLKTDDTAMYYCVRDRAGFFAYWGQGTPVTVSA 47H1 Light chain variable region amino acid sequence (SEQ ID NO:118) DIQMTQSPASQSASLGESVTITCLASQTIGTWLGWYRQKPGKSPQLLIYAATSLADGVPSRF SGSGSGTKFSFKISSLQAEDFVIYYCQQLYSTPLTFGSGTKLEIK Hz47H1.v4 Heavy chain variable region amino acid sequence (SEQ ID NO:119) EVQLVESGGGLVQPGGSLRLSCAASGFTFNINAMNWVRQAPGKGLEWVARIRTKNYNYATFY ADSVKDRFTISRDDSKNSLYLQMNSLKTEDTAVYYCVRDRAGFFAYWGQGTTVTVSS Hz47H1.v4 Light chain variable region amino acid sequence (SEQ ID NO:120) DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLGWYQQKPGKAPKLLIYAATSLAEGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQLYSTPLTFGGGTKVEIK 57D12 Heavy chain variable region amino acid sequence (SEQ ID NO:121) QVQLQQSGAELARPGASVNLSCRASGYSFTSFGISWVKQRTGQGLEWIGEIYPRSDNTFYNE KFKGKATLTADKSSSTAYMELRSLTSEDSAVYFCARHFGSSSFDYWGQGTTLTVSS 57D12 Light chain variable region amino acid sequence (SEQ ID NO:122) NAI-1539756353v1 163 ENVLTQSPPIMAASLGQKVTMTCSASSSVSSIYFHWYQQKSGTSPKPLIHRASNLASGVPAR FSGSGSGTSYSLTISSVEAEDDATYYCQQWSGYPLTFGGGTKLEIK 61H4 Heavy chain variable region amino acid sequence (SEQ ID NO:123) EVQLQQSGPEVLKPGASVKISCKASGYTFTDYYYMNWVKQSHGKSLEWIGYIYPNNGATSYN QKFKGKATLTVDKSSSTAYMELRSLTSEDSAVYYCARDGYSSNYYTMDYWGQGTSVTVSS 61H4 Light chain variable region amino acid sequence (SEQ ID NO:124) DVQMIQSPSSLSASLGDIVTMTCQASQGTSINLNWFQQKPGKAPKLLIYGASNLEDGVPSRF SGSRYGTDFTLTISSLEDEDMATYFCLQHTYLPYTFGGGTKLEIK 62G10 Heavy chain variable region amino acid sequence (SEQ ID NO:125) EVQLVETGGGLVQPKGSLKLSCATSGFTFNINAMNWVRQAPGKGLEWVARIRTKNNNFATYY ADSVKDRFTISRDDSQSMLYLQMNNLKTEDTAMYYCVRGPYFDYWGQGTTLTVSS 62G10 Light chain variable region amino acid sequence (SEQ ID NO:126) DIQMTQSPASQSASLGESVTITCLASQTIGTWLAWYQQKPGKSPQLLIYAATSLADGVPSRF SGSGSGTKFSFKISNLQAEDFVTYYCQQLYSTPYTFGGGTKLEIK Hz62G10.v1 Heavy chain variable region amino acid sequence (SEQ ID NO:127) EVQLVESGGGLVKPGGSLRLSCAASGFTFNINAMNWVRQAPGKGLEWVARIRTKNNNFATYY ADSVKDRFTISRDDSKNTLYLQMNSLKTEDTAVYYCVRGPYFDYWGQGTLVTVSS Hz62G10.v1 Light chain variable region amino acid sequence (SEQ ID NO:128) DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLAWYQQKPGKAPKLLIYAATSLADGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQLYSTPYTFGGGTKVEIK 108D10 Heavy chain variable region amino acid sequence (SEQ ID NO:129) EVQLVETGGGLVQPKGSLKLSCAASGFTFNINAMNWVRQAPGKGLEWVARIRTKNNNYATYY ADSVKDRFTISRDDSESMLYLQMNNLKTEDTAMYYCVRDRYGGAMAYWGQGTSVTVSS 108D10 Light chain variable region amino acid sequence (SEQ ID NO:130) DIQMTQSSSSFSVSLGDRVTITCKASEDIYNRLAWYQQKPGNVPRLLISSATSLETGVPSRF SGSGSGKDYTLSLTSLQSEDVATYYCQQYWTIPYTFGGGTKLEIK 43H2 Heavy chain variable region amino acid sequence (SEQ ID NO:131) EVQLVESGGGLVQPGRSLKVSCAASGFTFSNYGIHWIRQAPTKGLEWVASISPSGRSTYFRD SVKGRFTISRDNAKNTLYLQLDSLRSEDTATYYCATGINYSSFDYWGQGVMVTVSS 43H2 Light chain variable region amino acid sequence (SEQ ID NO:132) DIVMTQSPTSMSISVGDRVTMNCKASQNVGSHVDWYQQKTGQSPKLLISTASNRYTGVPDRF TGSGSGTDFTFTINNMQTEDLAVYYCMQSNSYPPTFGGGTKLELK Hz47H1.v4 Heavy chain amino acid sequence with signal sequence underlined (SEQ ID NO:133) MDMRVPAQLLGLLLLWLRGARCEVQLVESGGGLVQPGGSLRLSCAASGFTFNINAMNWVRQA PGKGLEWVARIRTKNYNYATFYADSVKDRFTISRDDSKNSLYLQMNSLKTEDTAVYYCVRDR AGFFAYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV NAI-1539756353v1 164 YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Hz47H1.v4 Heavy chain amino acid sequence without signal sequence (SEQ ID NO:134) EVQLVESGGGLVQPGGSLRLSCAASGFTFNINAMNWVRQAPGKGLEWVARIRTKNYNYATFY ADSVKDRFTISRDDSKNSLYLQMNSLKTEDTAVYYCVRDRAGFFAYWGQGTTVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPK PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTV LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGK Hz47H1.v4 Light chain amino acid sequence with signal sequence underlined (SEQ ID NO:135) MDMRVPAQLLGLLLLWLRGARCDIQMTQSPSSLSASVGDRVTITCLASQTIGTWLGWYQQKP GKAPKLLIYAATSLAEGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQLYSTPLTFGGGT KVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Hz47H1.v4 Light chain amino acid sequence without signal sequence (SEQ ID NO:136) DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLGWYQQKPGKAPKLLIYAATSLAEGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQLYSTPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPVTKSFNRGEC Hz62G10.v1 Heavy chain amino acid sequence with signal sequence underlined (SEQ ID NO:137) MDMRVPAQLLGLLLLWLRGARCEVQLVESGGGLVKPGGSLRLSCAASGFTFNINAMNWVRQA PGKGLEWVARIRTKNNNFATYYADSVKDRFTISRDDSKNTLYLQMNSLKTEDTAVYYCVRGP YFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Hz62G10.v1 Heavy chain amino acid sequence without signal sequence (SEQ ID NO:138) EVQLVESGGGLVKPGGSLRLSCAASGFTFNINAMNWVRQAPGKGLEWVARIRTKNNNFATYY ADSVKDRFTISRDDSKNTLYLQMNSLKTEDTAVYYCVRGPYFDYWGQGTLVTVSSASTKGPS VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV TVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLH QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK Hz62G10.v1 Light chain amino acid sequence with signal sequence underlined (SEQ ID NO:139) MDMRVPAQLLGLLLLWLRGARCDIQMTQSPSSLSASVGDRVTITCLASQTIGTWLAWYQQKP GKAPKLLIYAATSLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQLYSTPYTFGGGT NAI-1539756353v1 165 KVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Hz62G10.v1 Light chain amino acid sequence without signal sequence (SEQ ID NO:140) DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLAWYQQKPGKAPKLLIYAATSLADGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQLYSTPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPVTKSFNRGEC Human IgG1 constant region - CH1, hinge, CH2, and CH3 (SEQ ID NO:141) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK Human IgG1 constant region E233A/L235A (SEQ ID NO:142) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPALAGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK Human IgG1 constant region L234A/L235A (SEQ ID NO:143) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK Human IgG1 constant region L234A/L235A/P329G (SEQ ID NO:144) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK Human IgG1 constant region N297G (SEQ ID NO:145) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK Human IgG1 constant region N297G/H310A (SEQ ID NO:146) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF NAI-1539756353v1 166 LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVV SVLTVLAQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK Human Kappa light chain constant region (SEQ ID NO:147) RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Human Lambda light chain constant region (SEQ ID NO:148) GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQS NNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Mouse LAIR1 amino acid sequence with predicted signal sequence underlined (SEQ ID NO:149) MSLHPVILLVLVLCLGWKINTQEGSLPDITIFPNSSLMISQGTFVTVVCSYSDKHDLYNMVR LEKDGSTFMEKSTEPYKTEDEFEIGPVNETITGHYSCIYSKGITWSERSKTLELKVIKENVI QTPAPGPTSDTSWLKTYSIYIFTVVSVIFLLCLSALLFCFLRHRQKKQGLPNNKRQQQRPEE RLNLATNGLEMTPDIVADDRLPEDRWTETWTPVAGDLQEVTYIQLDHHSLTQRAVGAVTSQS TDMAESSTYAAIIRH Mouse LAIR1 amino acid sequence without predicted signal sequence (SEQ ID NO:150) QEGSLPDITIFPNSSLMISQGTFVTVVCSYSDKHDLYNMVRLEKDGSTFMEKSTEPYKTEDE FEIGPVNETITGHYSCIYSKGITWSERSKTLELKVIKENVIQTPAPGPTSDTSWLKTYSIYI FTVVSVIFLLCLSALLFCFLRHRQKKQGLPNNKRQQQRPEERLNLATNGLEMTPDIVADDRL PEDRWTETWTPVAGDLQEVTYIQLDHHSLTQRAVGAVTSQSTDMAESSTYAAIIRH Mouse LAIR1 extracellular domain (aa 22-144) (SEQ ID NO:151) QEGSLPDITIFPNSSLMISQGTFVTVVCSYSDKHDLYNMVRLEKDGSTFMEKSTEPYKTEDE FEIGPVNETITGHYSCIYSKGITWSERSKTLELKVIKENVIQTPAPGPTSDTSWLKTYSIY Mouse LAIR1 Ig-like C2-type domain amino acid sequence (aa 27-114) (SEQ ID NO:152) PDITIFPNSSLMISQGTFVTVVCSYSDKHDLYNMVRLEKDGSTFMEKSTEPYKTEDEFEIGP VNETITGHYSCIYSKGITWSERSKTL Hexahistidine peptide tag (SEQ ID NO:153) HHHHHH Human MARCO (SEQ ID NO:154) MRNKKILKEDELLSETQQAAFHQIAMEPFEINVPKPKRRNGVNFSLAVVVIYLILLTAGAGL LVVQVLNLQARLRVLEMYFLNDTLAAEDSPSFSLLQSAHPGEHLAQGASRLQVLQAQLTWVR VSHEHLLQRVDNFTQNPGMFRIKGEQGAPGLQGHKGAMGMPGAPGPPGPPAEKGAKGAMGRD GATGPSGPQGPPGVKGEAGLQGPQGAPGKQGATGTPGPQGEKGSKGDGGLIGPKGETGTKGE KGDLGLPGSKGDRGMKGDAGVMGPPGAQGSKGDFGRPGPPGLAGFPGAKGDQGQPGLQGVPG PPGAVGHPGAKGEPGSAGSPGRAGLPGSPGSPGATGLKGSKGDTGLQGQQGRKGESGVPGPA GVKGEQGSPGLAGPKGAPGQAGQKGDQGVKGSSGEQGVKGEKGERGENSVSVRIVGSSNRGR AEVYYSGTWGTICDDEWQNSDAIVFCRMLGYSKGRALYKVGAGTGQIWLDNVQCRGTESTLW SCTKNSWGHHDCSHEEDAGVECSV Human MARCO extracellular domain (aa 65-520) (SEQ ID NO:155) VQVLNLQARLRVLEMYFLNDTLAAEDSPSFSLLQSAHPGEHLAQGASRLQVLQAQLTWVRVS HEHLLQRVDNFTQNPGMFRIKGEQGAPGLQGHKGAMGMPGAPGPPGPPAEKGAKGAMGRDGA NAI-1539756353v1 167 TGPSGPQGPPGVKGEAGLQGPQGAPGKQGATGTPGPQGEKGSKGDGGLIGPKGETGTKGEKG DLGLPGSKGDRGMKGDAGVMGPPGAQGSKGDFGRPGPPGLAGFPGAKGDQGQPGLQGVPGPP GAVGHPGAKGEPGSAGSPGRAGLPGSPGSPGATGLKGSKGDTGLQGQQGRKGESGVPGPAGV KGEQGSPGLAGPKGAPGQAGQKGDQGVKGSSGEQGVKGEKGERGENSVSVRIVGSSNRGRAE VYYSGTWGTICDDEWQNSDAIVFCRMLGYSKGRALYKVGAGTGQIWLDNVQCRGTESTLWSC TKNSWGHHDCSHEEDAGVECSV Human MARCO collagen-like domain (aa 147-419) (SEQ ID NO:156) KGEQGAPGLQGHKGAMGMPGAPGPPGPPAEKGAKGAMGRDGATGPSGPQGPPGVKGEAGLQG PQGAPGKQGATGTPGPQGEKGSKGDGGLIGPKGETGTKGEKGDLGLPGSKGDRGMKGDAGVM GPPGAQGSKGDFGRPGPPGLAGFPGAKGDQGQPGLQGVPGPPGAVGHPGAKGEPGSAGSPGR AGLPGSPGSPGATGLKGSKGDTGLQGQQGRKGESGVPGPAGVKGEQGSPGLAGPKGAPGQAG QKGDQGVKGSSGEQGVKGEKGERGE Human MARCO SRCR domain (aa 424-519) (SEQ ID NO:157) VRIVGSSNRGRAEVYYSGTWGTICDDEWQNSDAIVFCRMLGYSKGRALYKVGAGTGQIWLDN VQCRGTESTLWSCTKNSWGHHDCSHEEDAGVECS Human IgG1 constant region L234F/L235E/P331G (SEQ ID NO:158) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAGIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK Human IgG1 constant region L234A/L235A/P331G (SEQ ID NO:159) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAGIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK * * * * * [00424] Throughout this application various publications, patents, patent applications and other documents have been referenced. The disclosures of these publications, patents, patent applications and other documents in their entireties are hereby incorporated by reference in this application for all purposes, including in order to more fully describe the state of the art to which this the subject matter disclosed herein pertains. Although the disclosed subject matter has been described with reference to the examples provided above, it should be understood that various modifications can be made without departing from the spirit of the disclosed subject matter. Many variations will become apparent to those skilled in the art upon review of this specification. NAI-1539756353v1 168

Claims

WHAT IS CLAIMED IS: 1. A method of disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a subject having osteosarcoma, comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M; and (b) a PD-1 antagonist.
2. A method of disrupting, inhibiting, or blocking collagen-induced LAIR1 activity in a subject having osteosarcoma, comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M; and (b) a PD-1 antagonist.
3. A method of disrupting, inhibiting, or blocking LAIR1-induced suppression of an immune cell or immune cell activity in a subject having osteosarcoma, comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M; and (b) a PD-1 antagonist, wherein the immune cell or immune cell activity is a myeloid cell or myeloid cell activity, a natural killer (NK) cell or NK cell activity, a T-cell or T-cell activity, a myeloid- NAI-1539756353v1 169 derived suppressor cell (MDSC) or MDSC activity, a regulatory T-cell (Treg) or Treg activity.
4. The method of claim 3, wherein (i) the myeloid cell is a monocyte, a macrophage, a dendritic cell, or an APC; and/or (ii) the T-cell is a cytotoxic T-cell (CTL).
5. A method of treating osteosarcoma in a subject, comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M; and (b) a PD-1 antagonist.
6. A method of (a) inhibiting tumor growth, (b) increasing or enhancing an immune response to a tumor or tumor cells, (c) activating or enhancing a persistent or long-term immune response to a tumor or tumor cells, (d) inhibiting tumor relapse or tumor regrowth, and/or (e) inducing a persistent or long-term immunity that inhibits tumor relapse or tumor regrowth, in a subject having osteosarcoma, the method comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M; and (b) a PD-1 antagonist.
7. A method of activating immune cells in the tumor microenvironment in a subject having osteosarcoma, comprising administering to the subject (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: NAI-1539756353v1 170 (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M; and (b) a PD-1 antagonist, wherein the immune cells are myeloid cells, NK cells, and/or T-cells.
8. The method of claim 7, wherein (i) the myeloid cells are monocytes, macrophages, dendritic cells, or APCs; and/or (ii) the T-cells are cytotoxic T-cells (CTLs).
9. Use of (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof and (b) a PD-1 antagonist for (a) treatment of osteosarcoma; (b) disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a subject having osteosarcoma; (c) disrupting, inhibiting, or blocking collagen-induced LAIR1 activity in a subject having osteosarcoma; (d) disrupting, inhibiting, or blocking LAIR1-induced suppression of an immune cell or immune cell activity in a subject having osteosarcoma; (e) inhibiting tumor growth, increasing or enhancing an immune response to a tumor or tumor cells, activating or enhancing a persistent or long-term immune response to a tumor or tumor cells, inhibiting tumor relapse or tumor regrowth, and/or inducing a persistent or long-term immunity that inhibits tumor relapse or tumor regrowth, in a subject having osteosarcoma; and/or (f) activating immune cells in the tumor microenvironment in a subject having osteosarcoma, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M.
10. Use of (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof and (b) a PD-1 antagonist in the manufacture of a medicament for NAI-1539756353v1 171 (a) treatment of osteosarcoma; (b) disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a subject having osteosarcoma; (c) disrupting, inhibiting, or blocking collagen-induced LAIR1 activity in a subject having osteosarcoma; (d) disrupting, inhibiting, or blocking LAIR1-induced suppression of an immune cell or immune cell activity in a subject having osteosarcoma; (e) inhibiting tumor growth, increasing or enhancing an immune response to a tumor or tumor cells, activating or enhancing a persistent or long-term immune response to a tumor or tumor cells, inhibiting tumor relapse or tumor regrowth, and/or inducing a persistent or long-term immunity that inhibits tumor relapse or tumor regrowth, in a subject having osteosarcoma; and/or (f) activating immune cells in the tumor microenvironment in a subject having osteosarcoma, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M.
11. A method of disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a cell mixture comprising osteosarcoma cells to enhance the immune response to the osteosarcoma cells, the method comprising contacting the cell mixture with (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M; and (b) a PD-1 antagonist.
12. The method of claim 11, wherein the cell mixture comprises at least one of myeloid cells, NK cells, T-cells, cytotoxic T-cells, MDSCs, and T-regs. NAI-1539756353v1 172
13. The method of claim 12, wherein the myeloid cells comprise at least one of monocytes, macrophages, dendritic cells, and APCs.
14. A method of disrupting, inhibiting, or blocking LAIR1-induced suppression of an immune cell or immune cell activity to enhance the immune response to osteosarcoma cells, comprising contacting a cell mixture comprising the osteosarcoma cells and the immune cell with (a) an antibody that binds to LAIR1 or a pharmaceutical composition comprising thereof, wherein the antibody: (i) binds to human LAIR1 and cynomolgus LAIR1; (ii) binds to human LAIR1 with a dissociation constant (KD) of less than 1 × 10-9 M; and/or (iii) binds to cynomolgus LAIR1 with a KD of less than 1 × 10-8 M; and (b) a PD-1 antagonist, wherein the immune cell or immune cell activity is a myeloid cell or myeloid cell activity, a NK cell or NK cell activity, a T-cell or T-cell activity, a MDSC or MDSC activity, a Treg or Treg activity, and wherein the immune cell is an intratumoral cell, and is or was present in osteosarcoma or a tumor microenvironment thereof.
15. The method of claim 14, wherein (i) the myeloid cell is a monocyte, a macrophage, a dendritic cell, or an APC; and/or (ii) the T-cell is a cytotoxic T-cell (CTL).
16. The method or use of any one of claims 1-15, wherein the PD-1 antagonist is an antagonistic anti-PD-1 antibody.
17. The method or use of claim 16, wherein the anti-PD-1 antibody is selected from the group consisting of pembrolizumab, pidilizumab, nivolumab, durvalumab, budigalima, cemiplimab, tislelizumab, spartalizumab, and STI-A1110.
18. The method or use of any one of claims 1-10, 16, and 17, wherein the antagonistic PD-1 antagonist is administered to the subject prior to, concurrently, or subsequent to the administration of the antibody that binds to LAIR1.
19. The method or use of any one of claims 1-18, wherein the antibody comprises: (i) a heavy chain variable region complementarity determining region 1 (VH CDR1), NAI-1539756353v1 173 a heavy chain variable region complementarity determining region 2 (VH CDR2) and a heavy chain variable region complementarity determining region 3 (VH CDR3) as set forth in a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:119; and a light chain variable region complementarity determining region 1 (VL CDR1), a light chain variable region complementarity determining region 2 (VL CDR2), and a light chain variable region complementarity determining region 3 (VL CDR3) as set forth in a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:120, (ii) a VH CDR1, a VH CDR2 and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:117; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:118, (iii) a VH CDR1, a VH CDR2 and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:115; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:116, (iv) a VH CDR1, a VH CDR2 and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:121; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:122, (v) a VH CDR1, a VH CDR2 and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:123; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:124, (vi) a VH CDR1, a VH CDR2 and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:125; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:126, (vii) a VH CDR1, a VH CDR2 and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:127; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:128, (viii) a VH CDR1, a VH CDR2 and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:129; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:130, or (ix) a VH CDR1, a VH CDR2 and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:131; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:132.
20. The method or use of claim 19, wherein the antibody comprises (a) a VH comprising: NAI-1539756353v1 174 (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:25, SEQ ID NO:31, SEQ ID NO:34, or SEQ ID NO:35; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:44, or SEQ ID NO:45; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:27, or SEQ ID NO:37, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:28 or SEQ ID NO:38; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:42 or SEQ ID NO:39; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:30 or SEQ ID NO:40.
21. The method or use of claim 20, wherein the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:41, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27, the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:42, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:31, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:43, the VH CDR3 comprises the amino acid of SEQ ID NO:27; the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:42, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; (iii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:44, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:42, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; (iv) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:34, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:41, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL CDR1 comprises the NAI-1539756353v1 175 amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:42, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; and (v) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:35, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:45, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:37; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:38, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:39, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:40.
22. The method or use of claim 20 or 21, wherein the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:119, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:120.
23. The method or use of any one of claims 20-22, wherein the VH comprises the amino acid sequence of SEQ ID NO:119, and/or the VL comprises the amino acid sequence of SEQ ID NO:120.
24. The method or use of any one of claims 20-23, wherein the antibody comprises a heavy chain having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:134 and a light chain having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:136.
25. The method or use of claim 24, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:134 and a light chain comprising the amino acid sequence of SEQ ID NO:136.
26. The method or use of claim 19, wherein the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:25, SEQ ID NO:31, SEQ ID NO:34, or SEQ ID NO:35; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:26, SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:36; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:27 or SEQ ID NO:37 , and NAI-1539756353v1 176 (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:28 or SEQ ID NO:38; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:29 or SEQ ID NO:39; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:30 or SEQ ID NO:40.
27. The method or use of claim 26, wherein the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:26, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:31, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:32, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; (iii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:33, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; (iv) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:34, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:26, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:28, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:30; and (v) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:35, the VH NAI-1539756353v1 177 CDR2 comprises the amino acid sequence of SEQ ID NO:36, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:37; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:38, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:39, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:40.
28. The method or use of claim 26 or 27, wherein the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:117, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:118.
29. The method or use of any one of claims 26-28, wherein the VH comprises the amino acid sequence of SEQ ID NO:117, and/or the VL comprises the amino acid sequence of SEQ ID NO:118.
30. The method or use of claim 19, wherein the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:9, SEQ ID NO:15, SEQ ID NO:18, or SEQ ID NO:19; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:10, SEQ ID NO:16, SEQ ID NO:17, or SEQ ID NO:20; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:11 or SEQ ID NO:21, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:12 or SEQ ID NO:22; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:13 or SEQ ID NO:23; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:14 or SEQ ID NO:24.
31. The method or use of claim 30, wherein the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:9, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:10, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:11; and the VL comprises the VL CDR1 comprises the NAI-1539756353v1 178 amino acid sequence of SEQ ID NO:12, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:13, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:14; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:15, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:16, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:11; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:12, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:13, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:14; (iii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:9, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:17, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:11; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:12, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:13, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:14; (iv) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:18, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:10, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:11; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:12, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:13, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:14; and (v) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:19, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:20, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:21; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:22, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:23, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:24.
32. The method or use of claim 30 or 31, wherein the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:115, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:116. NAI-1539756353v1 179
33. The method or use of any one of claims 30-32, wherein the VH comprises the amino acid sequence of SEQ ID NO:115, and/or the VL comprises the amino acid sequence of SEQ ID NO:116.
34. The method or use of claim 19, wherein the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:46, SEQ ID NO:52, SEQ ID NO:55, or SEQ ID NO:56; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:47, SEQ ID NO:53, SEQ ID NO:54 or SEQ ID NO:57; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:48 or SEQ ID NO:58 , and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:49 or SEQ ID NO:59; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:50 or SEQ ID NO:60; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:51 or SEQ ID NO:61.
35. The method or use of claim 34, wherein the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:46, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:47, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:48; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:49, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:50, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:51; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:52, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:53, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:48; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:49, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:50, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:51; NAI-1539756353v1 180 (iii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:46, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:54, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:48; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:49, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:50, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:51; (iv) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:55, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:47, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:48; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:49, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:50, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:51; and (v) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:56, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:57, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:58; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:59, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:60, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:61.
36. The method or use of claim 34 or 35, wherein the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:121, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:122.
37. The method or use of any one of claims 34-36, wherein the VH comprises the amino acid sequence of SEQ ID NO:121, and/or the VL comprises the amino acid sequence of SEQ ID NO:122.
38. The method or use of claim 19, wherein the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:62, SEQ ID NO:68, SEQ ID NO:71, or SEQ ID NO:72; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:63, SEQ ID NO:69, SEQ ID NO:70, or SEQ ID NO:73; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:64 or SEQ ID NO:74, NAI-1539756353v1 181 and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:65 or SEQ ID NO:75; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:66 or SEQ ID NO:76; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:67 or SEQ ID NO:77.
39. The method or use of claim 38, wherein the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:62, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:63, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:64; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:65, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:66, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:67; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:68, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:69, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:64; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:65, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:66, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:67; (iii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:62, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:70, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:64; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:65, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:66, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:67; (iv) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:71, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:63, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:64; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:65, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:66, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:67; and NAI-1539756353v1 182 (v) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:72, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:73, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:74; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:75, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:76, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:77.
40. The method or use of claim 38 or 39, wherein the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:123, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:124.
41. The method or use of any one of claims 38-40, wherein the VH comprises the amino acid sequence of SEQ ID NO:123, and/or the VL comprises the amino acid sequence of SEQ ID NO:124.
42. The method or use of claim 19, wherein the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:25, SEQ ID NO:31, SEQ ID NO:34, or SEQ ID NO:35; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:78, SEQ ID NO:82, SEQ ID NO:83, or SEQ ID NO:84; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:79 or SEQ ID NO:85, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:80 or SEQ ID NO:86; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:29 or SEQ ID NO:39; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:81 or SEQ ID NO:87.
43. The method or use of claim 42, wherein the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:78, the VH CDR3 comprises the NAI-1539756353v1 183 amino acid sequence of SEQ ID NO:79; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:80, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:81; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:31, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:82, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:79; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:80, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:81; (iii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:83, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:79; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:80, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:81; (iv) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:34, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:78, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:79; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:80, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:81; and (v) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:35, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:84, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:85; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:86, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:39, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:87.
44. The method or use of claim 42 or 43, wherein the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:125, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:126. NAI-1539756353v1 184
45. The method or use of any one of claims 42-44, wherein the VH comprises the amino acid sequence of SEQ ID NO:125, and/or the VL comprises the amino acid sequence of SEQ ID NO:126.
46. The method or use of claim 42 or 43, wherein the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:127, and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:128.
47. The method or use of any one of claims 42, 43, and 46, wherein the VH comprises the amino acid sequence of SEQ ID NO:127, and/or the VL comprises the amino acid sequence of SEQ ID NO:128.
48. The method or use of any one of claims 42, 43, 46, and 47, wherein the antibody comprises a heavy chain having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:138 and a light chain having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:140.
49. The method or use of claim 48, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:138 and a light chain comprising the amino acid sequence of SEQ ID NO:140.
50. The method or use of claim 19, wherein the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:25, SEQ ID NO:31, SEQ ID NO:34, or SEQ ID NO:35; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:88, SEQ ID NO:32, SEQ ID NO:93, or SEQ ID NO:94; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:89 or SEQ ID NO:95, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:90 or SEQ ID NO:96; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:91 or SEQ ID NO:97; NAI-1539756353v1 185 (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:92 or SEQ ID NO:98.
51. The method or use of claim 50, wherein the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:88, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:89; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:90, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:91, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:92; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:31, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:32, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:89; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:90, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:91, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:92; (iii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:25, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:93, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:89; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:90, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:91, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:92; (iv) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:34, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:88, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:89; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:90, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:91, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:92; and (v) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:35, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:94, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:95; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:96, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:97, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:98. NAI-1539756353v1 186
52. The method or use of claim 50 or 51, wherein the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:129, and/or the light chain variable region has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:130.
53. The method or use of any one of claims 50-52, wherein the VH comprises the amino acid sequence of SEQ ID NO:129, and/or the VL comprises the amino acid sequence of SEQ ID NO:130.
54. The method or use of claim 19, wherein the antibody comprises (a) a VH comprising: (1) the VH CDR1 comprising the amino acid sequence of SEQ ID NO:99, SEQ ID NO:105, SEQ ID NO:108, or SEQ ID NO:109; (2) the VH CDR2 comprising the amino acid sequence of SEQ ID NO:100, SEQ ID NO:106, SEQ ID NO:107 or SEQ ID NO:110; (3) the VH CDR3 comprising the amino acid sequence of SEQ ID NO:101 or SEQ ID NO:111, and (b) a VL comprising: (1) the VL CDR1 comprising the amino acid sequence of SEQ ID NO:102 or SEQ ID NO:112; (2) the VL CDR2 comprising the amino acid sequence of SEQ ID NO:103 or SEQ ID NO:113; (3) the VL CDR3 comprising the amino acid sequence of SEQ ID NO:104 or SEQ ID NO:114.
55. The method or use of claim 54, wherein the antibody comprises at least one of (i)-(v): (i) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:99, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:100, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:101; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:102, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:103, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:104; (ii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:105, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:106, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:101; and the VL comprises the VL CDR1 comprises the NAI-1539756353v1 187 amino acid sequence of SEQ ID NO:102, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:103, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:104; (iii) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:99, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:107, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:101; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:102, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:103, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:104; (iv) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:108, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:100, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:101; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:102, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:103, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:104; and (v) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:109, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:110, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:111; and the VL comprises the VL CDR1 comprises the amino acid sequence of SEQ ID NO:112, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:113, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:114.
56. The method or use of claim 54 or 55, wherein the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:131, and/or the light chain variable region has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:132.
57. The method or use of any one of claims 54-56, wherein the VH comprises the amino acid sequence of SEQ ID NO:131, and/or the VL comprises the amino acid sequence of SEQ ID NO:132.
58. The method or use of any one of claims 1-57, wherein the antibody is a recombinant antibody, a monoclonal antibody, a chimeric antibody, a humanized antibody, a bispecific antibody, or a multispecific antibody. NAI-1539756353v1 188
59. The method or use of any one of claims 1-58, wherein the antibody is an IgG1 antibody, an IgG2 antibody, or an IgG4 antibody; optionally wherein the antibody is a human IgG1 antibody, a human IgG2 antibody, or a human IgG4 antibody.
60. The method or use of any one of claims 1-59, wherein the antibody comprises a kappa light chain or a lambda light chain, optionally wherein the antibody comprises a human kappa light chain or a human lambda light chain.
61. The method or use of any one of claims 1-60, wherein the antibody is attached to a half-life extending moiety.
62. The method or use of any one of claims 1-61, wherein the antibody is an antibody fragment, optionally wherein the antibody fragment comprises at least one antigen binding site that binds to LAIR1.
63. The method or use of claim 62, wherein the antibody fragment is a Fab, a Fab’, a F(ab’)2, a Fv, a scFv, a (scFv)2, a single chain antibody, a dual variable region antibody, a diabody, or a nanobody.
64. The method or use of any one of claims 1-63, wherein the antibody inhibits binding of LAIR-1 to one or more LAIR ligands and optionally has at least one of the following properties: (i) binding human LAIR1; (ii) binding cyno LAIR1; (iii) not binding mouse LAIR1; (iv) not binding human LAIR-2; (v) being a LAIR1 antagonist; (vi) inhibiting LAIR1 activity; (vii) inhibiting LAIR1 signaling in cells that express LAIR1; (viii) inhibiting binding of LAIR1 to collagen; (ix) inhibiting binding of LAIR1 to MARCO; (x) inhibiting binding of LAIR1 to COLEC12; (xi) inhibiting LAIR1-induced suppression of myeloid cells; (xii) inhibiting LAIR1-induced suppression of myeloid cell activity; (xiii) restoring FcR activation in myeloid cells; (xiv) restoring cytokine and/or chemokine production in myeloid cells; NAI-1539756353v1 189 (xv) inhibiting LAIR1-induced suppression of NK cells; (xvi) inhibiting LAIR1-induced suppression of NK activity; (xvii) inhibiting LAIR1-induced suppression of T-cell activity; and (xviii) inhibiting MDSC activity, optionally wherein the one or more LAIR ligands is selected from the group consisting of collagen, MARCO, COLEC12, MBL, SPD, and C1 complex.
65. The method or use of any one of claims 1-64, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
66. The method or use of any one of claims 1-65, wherein the antibody or the pharmaceutical composition is administered at a therapeutically effective amount. NAI-1539756353v1 190
PCT/US2024/023913 2023-04-11 2024-04-10 Methods of treating osteosarcoma using lair1 binding agents and pd-1 antagonists Pending WO2024215787A1 (en)

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