[go: up one dir, main page]

WO2025054312A1 - Hla-g antibodies in antibody-drug conjugates - Google Patents

Hla-g antibodies in antibody-drug conjugates Download PDF

Info

Publication number
WO2025054312A1
WO2025054312A1 PCT/US2024/045367 US2024045367W WO2025054312A1 WO 2025054312 A1 WO2025054312 A1 WO 2025054312A1 US 2024045367 W US2024045367 W US 2024045367W WO 2025054312 A1 WO2025054312 A1 WO 2025054312A1
Authority
WO
WIPO (PCT)
Prior art keywords
seq
molecule
sequence consisting
sequence
antibody
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/045367
Other languages
French (fr)
Inventor
Courtney BEERS
John Corbin
Tony DESBIEN
Doug HODGES
Jeff Jones
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tizona Therapeutics
Original Assignee
Tizona Therapeutics
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tizona Therapeutics filed Critical Tizona Therapeutics
Publication of WO2025054312A1 publication Critical patent/WO2025054312A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68033—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a maytansine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68037—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a camptothecin [CPT] or derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6853—Carcino-embryonic antigens

Definitions

  • ADC antibody-drug conjugate
  • ADC is a type of targeted cancer therapy that combines the specificity of antibodies with the potency of cytotoxic drugs. This approach aims to selectively deliver a toxic payload to cancer cells while sparing healthy tissues, thereby enhancing the therapeutic index and reducing adverse effects associated with conventional chemotherapy.
  • Antibodies recognize specific antigens present on the surface of cancer cells. They are highly specific and can bind to these antigens with high affinity.
  • Antibodies act as vehicles for delivering the cytotoxic payload to the cancer cells.
  • the cytotoxic payload is a potent drug designed to kill cancer cells. These drugs are highly toxic and can damage the DNA or interfere with cellular processes, leading to cell death. However, the challenge with conventional chemotherapy is that these drugs also affect healthy cells, causing side effects.
  • ADCs overcome this limitation by selectively delivering the cytotoxic payload to cancer cells.
  • the antibody and the cytotoxic payload are connected by a linker molecule. The linker molecule should be mostly stable in circulation but capable of releasing the drug once the ADC is internalized by the cancer cell.
  • linkers such as cleavable and non-cleavable linkers, which determine how and when the payload is released.
  • HLA-G histocompatibility antigen, class I, G also known as human leukocyte antigen G (HLA-G)
  • HLA-G is a protein that in humans is encoded by the HLA-G gene.
  • HLA-G belongs to the HLA nonclassical class I heavy chain paralogues.
  • HLA-G is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). There are membrane bound and soluble forms of HLA-G.
  • HLA-G is normally expressed at the maternal-fetal interface and other immune-privileged sites. HLA-G may play a role in immune tolerance in pregnancy, being expressed in the placenta by extravillous trophoblast cells, while the classical MHC class I genes (HLA-A and HLA-B) are not. As HLA-G was first identified in placenta samples, many studies have evaluated its role in pregnancy disorders, such as preeclampsia and recurrent pregnancy loss.
  • HLA-G has been shown to be immune-suppressive. By binding receptors expressed on various myeloid and lymphoid cells, HLA-G may directly inhibit the functions of NK cells, cytotoxic T-lymphocytes, B cells, neutrophils, monocytes, macrophages, and dendritic cells. HLA-G also inhibits T and NK cell proliferation and cytolytic activities. HLA-G suppresses phagocytosis and induces the generation or expansion of regulatory T cells.
  • HLA-G mediates immune function through at least three ITIM-containing inhibitory receptors, ILT2, ILT4, and KIR2DL4.
  • ILT2, ILT4, and KIR2DL4 On lymphoid and myeloid cells, for example, HLA-G mediates function through ILT2.
  • HLA-G mediates function through ILT4.
  • HLA-G On decidual NK cells, HLA-G mediates immune function through KIR2DL4 and ILT2.
  • HLA-G is an immune checkpoint target.
  • HLA-G can directly inhibit immune cell function through receptor binding and/or trogocytosis and impairment of chemotaxis.
  • HLA-G can lend tumor cells a higher invasive and metastatic potential.
  • HLA-G has also been found to be correlated with clinical parameters in advanced disease, such as tumor metastasis, poor prognosis, immune escape, and tumor invasiveness.
  • HLA-G is an attractive target for diseases especially in the context of an ADC.
  • the present invention is drawn to antibody-drug conjugates with antibodies specifically binding HLA-G and compositions comprising the conjugates, including pharmaceutical compositions.
  • the conjugates provided herein also include payloads such as DGN549C, Monomethyl auristatin E, Deruxtecan, SN-38, vc-SECO-DUBA, Calicheamicin, SPDB-DM4, and Tesirine.
  • a first aspect provides a conjugate comprising, consisting essentially of, or consisting of (i) an antibody that binds specifically to a human HLA-G (hHLA-G) and (ii) a molecule coupled to the antibody.
  • the antibody has 1, 2, 3, 4, 5, 6, or 7 of the following characteristics: a) is a monoclonal antibody; b) is a human antibody, a humanized antibody, or a chimeric antibody; c) is a bispecific antibody, a multi-specific antibody, a diabody, or a multivalent antibody; d) is of the IgA, IgGl, IgG2, IgG3, IgG4, or IgM type; e) is an antigen-binding antibody fragment; f) is a Fab fragment, a Fab' fragment, a F(ab')2 fragment, or an Fv fragment; and/or g) is a single chain antibody, a single domain antibody, or a nanobody.
  • the molecule coupled to the antibody comprises one selected from the group consisting of a detectable label, a drug, a toxin, a cytokine, a radionuclide, an enzyme, and combinations thereof.
  • the molecule coupled to the antibody comprises a DNA- alkylating cytotoxic molecule or an antineoplastic agent.
  • the molecule coupled to the antibody comprises one selected from the group consisting of Formulas I-VIII: Formula I: DGN549-C
  • the antibody binds to a human HLA-G polypeptide or a variant thereof with a K D of less than about 20 nM.
  • the antibody comprises, consists essentailly of, or consists of a human heavy chain constant region or fragment or a variant thereof and/or a light chain constant region or fragment or variant thereof; and the constant region or fragment of variant thereof comprises, consists essentailly of, or consists of up to 20 conservatively modified amino acid substitutions from any sequence set forth SEQ ID NOS: 170-200 and/or SEQ ID NOS: 204-228.
  • the antibody comprises, consists essentially of, or consists of : an isolated antibody molecule capable of binding to human HLA-G (hHLA- G), comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH and/or VL comprising 1, 2, 3, 4, 5, or 6 of: a VHCDR1 having the sequence set forth in SEQ ID NOS: 1 -14 or SEQ ID NOS: 18- 34, a VHCDR2 having the sequence set forth in SEQ ID NOS: 38-50 or SEQ ID NOS: 54-71 , a VHCDR3 having the sequence set forth in SEQ ID NOS: 76-101, a VLCDR1 having the sequence set forth in SEQ ID NOS: 105-124, a VLCDR2 having the sequence set forth in SEQ ID NOS: 128-145, and a VLCDR3 having the sequence set forth in SEQ ID NOS: 149-166.
  • hHLA- G human HLA-G
  • VH heavy
  • the antibody comprises, consists essentially of, or consists of : an isolated antibody molecule capable of binding to human HLA-G (hHLA-G), comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising: a) a VHCDR1 having a sequence set forth in SEQ ID NOS: 1-14 or SEQ ID NOS: 18- 34, b) a VHCDR2 having a sequence set forth in SEQ ID NOS: 38-50 or SEQ ID NOS: 54- 71 , and c) a VHCDR3 having a sequence set forth in SEQ ID NOS: 76-101; and the VL comprising: d) a VLCDR1 having a sequence set forth in SEQ ID NO: 105-124, e) a VLCDR2 having a sequence set forth in SEQ ID NO: 128-145, and f) a VLCDR3 having a sequence set forth in SEQ ID NO
  • the antibody comprises, consists essentially of, or consists of : an isolated antibody molecule capable of binding to human HLA-G (hHLA-G), and comprising a heavy chain variable region (VH) and/or a light chain variable region (VL), the VH comprising at least one sequence set forth in any of SEQ ID NOS: 170-200 and the VL comprising at least one sequence set forth in any of SEQ ID NOS: 204-228.
  • hHLA-G human HLA-G
  • VH heavy chain variable region
  • VL light chain variable region
  • the antibody comprises, consists essentially of, or consists of : an isolated antibody molecule capable of binding to human HLA-G (hHLA-G), the isolated antibody molecule comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising 1, 2, or 3 of: a VHCDR1 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOS: 1-14 or 18-34, a VHCDR2 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOS: 54-71, and a VHCDR3 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOS: 76-101; and the VL comprising 1, 2, or 3 of: a VLCDR1 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOS: 105-124, a VLCDR2 having an amino acid sequence that is at least 90% identical to the sequence
  • the antibody comprises, consists essentially of, or consists of: an isolated antibody molecule capable of binding to human HLA-G (hHLA-G), the isolated antibody molecule comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising 1, 2, or 3 of: a VHCDR1 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 1-14 or SEQ ID NOS: 18-34, a VHCDR2 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 38-50 or SEQ ID NOS: 54-71, and a VHCDR3 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 76-101; and the VL comprising 1, 2, or 3 of: a VLCDR1 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 105-124, a VLCDR2 having an amino acid
  • the antibody comprises, consists essentially of, or consists of : an isolated antibody molecule capable of binding to human HLA-G (hHLA-G), the isolated antibody molecule comprising a heavy chain and a light chain, the heavy chain comprising one or more molecules having a sequence consisting of one of SEQ ID NOS: 232-262 or SEQ ID NOS: 266-296, and the light chain comprising one or more molecules having a sequence consisting of one of SEQ ID NOS: 300-330.
  • hHLA-G human HLA-G
  • the isolated antibody molecule comprising a heavy chain and a light chain
  • the heavy chain comprising one or more molecules having a sequence consisting of one of SEQ ID NOS: 232-262 or SEQ ID NOS: 266-296
  • the light chain comprising one or more molecules having a sequence consisting of one of SEQ ID NOS: 300-330.
  • the antibody comprises, consists essentially of, or consists of : an isolated antibody molecule capable of binding to human HLA-G (HLA-G), the isolated antibody molecule comprising a heavy chain and a light chain and being selected from the group consisting of: the heavy chain comprising one or more molecules each having a sequence consisting of SEQ ID NO: 232 and the light chain comprising one or more molecules each having a sequence consisting of SEQ ID NO: 300; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 233 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 301 ; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 234 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 302; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO:
  • the antibody comprises, consists essentially of, or consists of : an isolated antibody molecule capable of binding to human HLA-G (hHLA-G), the isolated antibody molecule comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH and/or VL comprising 1, 2, 3, 4, 5, or 6 of: a) a VHCDR1 sequence comprising: a Kabat CDR-H1 sequence defined by the consensus sequence S-S- ⁇ 3- ⁇ 4-Y-W- ⁇ 7 (SEQ ID NOS: 18-21, 23, and 34), where ⁇ 3 is D or S; ⁇ 4 is T or Y; and ⁇ 7 is A, G, or S; a Kabat CDR-H1 sequence defined by the consensus sequence S-G- ⁇ 3-Y- W- ⁇ 6 (SEQ ID NOS: 24-29), where ⁇ 3 is F, H, or Y; and ⁇ 6 is F, G, I, L, or T; a Chothia CDR
  • a second aspect provides a pharmaceutical composition
  • a pharmaceutical composition comprising, consisting essentailly of, or consisting of an effective amount of any of the conjugates provided herein; and a pharmaceutically acceptable diluent, carrier or excipient.
  • the pharmaceutical composition provided herein further comprises an effective amount of at least one of the following: a) an anti-ILT2 antibody; b) an anti-ILT3 antibody; c) an anti-ILT4 antibody; d) an anti-KIR2DL4 antibody; e) an anti-HLA-E antibody; f) an anti-NKG2A antibody; g) an anti-HLA-F antibody h) an anti-HLA-J antibody; i) an anti-PD-L1 antibody; j) an anti-PD-1 antibody; k) an anti-CD38 antibody; l) an anti-CD39 antibody; m) an anti-CD73 antibody; n) an anti-A2A receptor antibody; o) an anti-A2B receptor antibody;
  • any of the pharmaceutical compositions provided herein further comprises at least one of a) an antibody to an immune inhibitory receptor or ligand and/or b) an antibody to an immune stimulatory receptor or ligand.
  • a third aspect provides a method for treatment of a subject suffering from cancer, a chronic infection, and/or from an inflammatory disease, the method comprising, consisting essentially of, or consisting of administering to the subject a pharmaceutical composition comprising an effective amount of the conjugate of any aspect and/or any embodiment described herein or the pharmaceutical composition of any aspect and/or any embodiment described herein.
  • the cancer is a solid cancer or a hematological cancer.
  • the subject is a human subject.
  • the inhibitory receptor is one of or is selected from the group consisting of ILT2, ILT3, ILT4, KIR2DL4, CTLA-4, PD-l , CD39, CD73, PD-L1, PD-L2, LAG-3, Tim3, TIGIT, B7-H3, B7-H4, neuritin, BTLA, CECAM-l , CECAM-5, VISTA, LAIR1, CD160, 2B4,TGF-B (including traps and GARP), NKG2A, a Killer-cell immunoglobulin-like receptor (KIR), and combinations thereof.
  • the one or more immunostimulatory agents comprise, consist essentially of, or consist of an agonist of a co-stimulatory receptor of an immune cell.
  • the co-stimulatory receptor is at least one of OX40, CD2, CD27, ICAM-l, LFA-l , ICOS (CD278), 4-1BB (CD 137), GITR, CD28, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp30, NKp46, NKp80, CD160, and/or a CD83 ligand.
  • the one or more immunostimulatory agents comprise, consist essentially of, or consist of an ADCC competent antibody selected from the group consisting of an anti-CD19, anti-CD20, anti-EGFR, anti-Her2, anti-SLAMF7, anti-CD52, anti-BCMA, anti-GD2, anti-CD38, anti-CCR4, anti-CTLA4, antibody, and combinations thereof.
  • the one or more immunostimulatory agents comprise, consist essentially of, or consist of a cytokine.
  • the oncolytic virus is a synthetic oncolytic virus.
  • the one or more immunostimulatory agents comprise, consist essentially of, or consist of a chimeric antigen receptor engineered T cell (CAR T cell).
  • CAR T cell chimeric antigen receptor engineered T cell
  • the antigen-binding domain of the CAR T cell recognizes specific cancer cell surface antigens, allowing the CAR T cell to target cancer cells with precision. This recognition leads to the activation and killing of cancer cells by the CAR T cell.
  • the one or more immunostimulatory agents comprise, consist essentially of, or consist of a natural killer cell.
  • the one or more immunostimulatory agents comprise, consist essentially of, or consist of a myeloid cell.
  • the one or more immunostimulatory agents comprise, consist essentially of, or consist of a bi- or multi-specific T cell directed antibody.
  • the specificity of the bi- or multi-specific T cell directed antibody allows them to target cancer cells while minimizing the impact on healthy cells, potentially reducing side effects.
  • Bi- or multi-specific antibodies can be used in combination with other immunotherapies, chemotherapy, and targeted therapies to enhance the overall anti-cancer effect.
  • a fourth aspect provides a method for modulating immune system function in a subject in need thereof, the method comprising, consisting essentially of, or consisting of contacting a population of immune cells of the subject with any of the pharmaceutical compositions provided herein comprising an effective amount of any of the conjugates provided herein, under conditions such that the immune system is modulated.
  • a fifth aspect provides a method for producing the conjugate of any aspect and/or any embodiment described herein, the method comprising conjugating the molecule to the antibody using an amino or sulfhydryl specific linker attached to the molecule that react with lysines or cysteines on the antibody surface.
  • the method comprises treating the antibody to create a conjugation site on the antibody surface and reacting the conjugation site with the amino or sulfhydryl specific linker attached to the molecule.
  • FIGS.1A-1R show the cytotoxicity of multiple free payloads for HLA-G expressing cells.
  • FIGS.2A-2K provide data showing target mediated killing by anti-HLA-G ADC (“ ⁇ -HLA-G”) compared to isotype conjugated ADC.
  • FIGS.3A-3F show the internalization of HLA-G specific antibodies on cells expressing HLA-G.
  • FIGS.6A-6F show data on tumor growth inhibition with anti-HLA-G antibody (“ ⁇ -HLA-G”) conjugated to DGN549C compared to isotype control antibody (“Iso”) conjugated to DGN549C in admixture JEG3 (FIGS.6A-6C, 6F) and A549 (FIGS. 6D-6E) cells expressing 10-100% HLA-G.
  • FIGS.7A-7D show data on tumor growth inhibition with anti-HLA-G antibody (“ ⁇ -HLA-G”) conjugated to DGN549C compared to isotype control antibody (“Iso”) conjugated to DGN549C in admixture TOV-112D cells expressing 20-100% HLA-G.
  • FIGS.8A and 8B show data on tumor growth inhibition with anti-HLA-G antibody (“ ⁇ -HLA-G”) conjugated to DGN549C compared to isotype control antibody (“Iso”) conjugated to DGN549C in a melanoma PDX CRT00465 and pancreatic PDX CRT00400.
  • ⁇ -HLA-G anti-HLA-G antibody
  • Iso isotype control antibody
  • conjugate refers to an “antibody-drug conjugate (ADC),” formed by chemically linking an antibody, a cytotoxic drug, and a linker molecule. This creates a single molecule that can selectively deliver the drug to target cells.
  • ADC antibody-drug conjugate
  • immunoglobulin refers to a class of structurally related proteins generally comprising two pairs of polypeptide chains: one pair of light (L) chains and one pair of heavy (H) chains. In an “intact immunoglobulin,” all four of these chains are interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, e.g., Paul, Fundamental Immunology 7th ed., Ch.5 (2013) Lippincott Williams & Wilkins, Philadelphia, PA. Briefly, each heavy chain typically comprises a heavy chain variable region (V H ) and a heavy chain constant region (C H ).
  • V H heavy chain variable region
  • C H heavy chain constant region
  • the heavy chain constant region typically comprises three domains, CHI, CH2, and CH3. Each light chain typically comprises a light chain variable region (V L ) and a light chain constant region.
  • the light chain constant region typically comprises one domain, abbreviated CL.
  • the term “antibody” describes a type of immunoglobulin molecule and is used herein in its broadest sense. An antibody specifically includes intact antibodies (e.g., intact immunoglobulins) and antibody fragments and antigen binding proteins. Antibodies comprise at least one antigen-binding domain.
  • an antigen-binding domain is an antigen binding domain formed by a V H –V L dimer.
  • HLA-G antibody “anti-HLA-G antibody,” “HLA-G Ab,” “HLA-G-specific antibody,” or “anti-HLA-G Ab” is an antibody, as described herein, which binds specifically to the antigen HLA-G.
  • the VH and VL regions may be further subdivided into regions of hypervariability (“hypervariable regions (HVRs);” also called “complementarity determining regions” (CDRs)) interspersed with regions that are more conserved. The more conserved regions are called framework regions (FRs).
  • HVRs hypervariable regions
  • CDRs complementarity determining regions
  • Each V H and V L generally comprises three CDRs and four FRs, arranged in the following order (from N-terminus to C-terminus): FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4.
  • the CDRs are involved in antigen binding, and confer antigen specificity and binding affinity to the antibody. See Kabat et al., Sequences of Proteins of Immunological Interest 5th ed. (1991) Public Health Service, National Institutes of Health, Bethesda, MD, incorporated by reference in its entirety. [0078]
  • the light chain from any vertebrate species can be assigned to one of two types, called kappa and lambda, based on the sequence of the constant domain.
  • the heavy chain from any vertebrate species can be assigned to one of five different classes (or isotypes): IgA, IgD, IgE, IgG, and IgM. These classes are also designated ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
  • the IgG and IgA classes are further divided into subclasses on the basis of differences in sequence and function. Humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgAl, and IgA2.
  • amino acid sequence boundaries of a CDR can be determined by one of skill in the art using any of a number of known numbering schemes, including those described by Kabat et al., supra (“Kabat” numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-948 (“Chothia” numbering scheme); MacCallum et al., 1996, J. Mol. Biol.262:732-745 (“Contact” numbering scheme); Lefranc et al., Dev. Comp. Immunol., 2003, 27:55-77 (“IMGT” numbering scheme); and Honegge and Plückthun, J. Mol.
  • Table 1 provides the positions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 as identified by the Kabat and Chothia schemes.
  • residue numbering is provided using both the Kabat and Chothia numbering schemes.
  • the numbering scheme used for identification of a particular CDR herein is the Kabat/Chothia numbering scheme. Where the residues encompassed by these two numbering schemes diverge, the numbering scheme is specified as either Kabat or Chothia.
  • Table 1 provides the positions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 as identified by the Kabat and Chothia schemes.
  • residue numbering is provided using both the Kabat and Chothia numbering schemes.
  • the numbering scheme used for identification of a particular CDR herein is the Kabat/Chothia numbering scheme. Where the residues encompassed by these two numbering schemes diverge, the numbering scheme is specified as
  • the C-terminus of CDR-H1 when numbered using the Kabat numbering convention, varies between H32 and H34, depending on the length of the CDR.
  • an “antibody fragment” comprises a portion of an intact antibody, such as the antigen binding or variable region of an intact antibody.
  • Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab′)2 fragments, Fab′ fragments, scFv (sFv) fragments, and scFv-Fc fragments.
  • Fv fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.
  • Fab fragments comprise, in addition to the heavy and light chain variable domains, the constant domain of the light chain and the first constant domain (C HI ) of the heavy chain. Fab fragments may be generated, for example, by papain digestion of a full- length antibody.
  • F(ab′)2 fragments contain two Fab′ fragments joined, near the hinge region, by disulfide bonds. F(ab′) 2 fragments may be generated, for example, by pepsin digestion of an intact antibody.
  • the F(ab′) fragments can be dissociated, for example, by treatment with ß-mercaptoethanol.
  • Single-chain Fv” or “sFv” or “scFv” antibody fragments comprise a VH domain and a V L domain in a single polypeptide chain. The V H and V L are generally linked by a peptide linker. See Plückthun A. (1994). Antibodies from Escherichia coli. In Rosenberg M. & Moore G.P. (Eds.), The Pharmacology of Monoclonal Antibodies vol.113 (pp.269- 315). Springer-Verlag, New York, incorporated by reference in its entirety.
  • scFv-Fc fragments comprise an scFv attached to an Fc domain.
  • an Fc domain may be attached to the C-terminal of the scFv.
  • the Fc domain may follow the V H or V L , depending on the orientation of the variable domains in the scFv (i.e., VH-VL or VL-VH). Any suitable Fc domain known in the art or described herein may be used.
  • the term “monoclonal antibody” refers to an antibody from a population of substantially homogeneous antibodies.
  • a population of substantially homogeneous antibodies comprises antibodies that are substantially similar and that bind the same epitope(s), except for variants that may normally arise during production of the monoclonal antibody.
  • a monoclonal antibody is typically obtained by a process that includes the selection of a single antibody from a plurality of antibodies.
  • the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones.
  • the selected antibody can be further altered, for example, to improve affinity for the target (“affinity maturation”), to humanize the antibody, to improve its production in cell culture, and/or to reduce its immunogenicity in a subject.
  • chimeric antibody refers to an antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species.
  • “Humanized” forms of non-human antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody.
  • a humanized antibody is generally a human immunoglobulin (recipient antibody) in which residues from one or more CDRs are replaced by residues from one or more CDRs of a non-human antibody (donor antibody).
  • the donor antibody can be any suitable non-human antibody, such as a mouse, rat, rabbit, chicken, or non-human primate antibody having a desired specificity, affinity, or biological effect.
  • selected framework region residues of the recipient antibody are replaced by the corresponding framework region residues from the donor antibody.
  • Humanized antibodies may also comprise residues that are not found in either the recipient antibody or the donor antibody. Such modifications may be made to further refine antibody function. For further details, see Jones et al., Nature, 1986, 321:522-525; Riechmann et al., Nature, 1988, 332:323-329; and Presta, Curr. Op. Struct. Biol., 1992, 2:593-596, each of which is incorporated by reference in its entirety.
  • a “human antibody” is one which possesses an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody-encoding sequences (e.g., obtained from human sources or designed de novo). Human antibodies specifically exclude humanized antibodies.
  • An “isolated antibody” is one that has been separated and/or recovered from a component of its natural environment. Components of the natural environment may include enzymes, hormones, and other proteinaceous or nonproteinaceous materials. In some embodiments, an isolated antibody is purified to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence, for example by use of a spinning cup sequenator.
  • an isolated antibody is purified to homogeneity by gel electrophoresis (e.g., SDS-PAGE) under reducing or nonreducing conditions, with detection by Coomassie blue or silver stain.
  • An isolated antibody includes an antibody in situ within recombinant cells, since at least one component of the antibody’s natural environment is not present.
  • an isolated antibody is prepared by at least one purification step. [0095] In some embodiments, an isolated antibody is purified to at least 80%, 85%, 90%, 95%, or 99% by weight.
  • an isolated antibody is provided as a solution comprising at least 85%, 90%, 95%, 98%, 99% to 100% by weight of an antibody, the remainder of the weight comprising the weight of other solutes dissolved in the solvent.
  • a “bispecific antibody” simultaneously target two different antigens or molecules.
  • a bispecific antibody typically consists of two different antigen-binding regions, each with specificity for a distinct target. These regions can be derived from two different mAbs, and they are engineered to bind to specific molecules, such as antigens on the surface of cancer cells or immune cells.
  • a “multi-specific antibody” has the ability to simultaneously bind to and interact with multiple antigens or molecules.
  • a “diabody” is a type of engineered antibody fragment that consists of two antibody variable domains (one heavy chain and one light chain) connected by a short linker. It has a compact structure and retains the ability to bind to a specific antigen, but it lacks the constant domains present in full-length antibodies.
  • a diabody is composed of two single- chain variable fragments (scFv), each containing the variable regions of both heavy and light antibody chains. These scFvs are connected by a short peptide linker that allows the two variable domains to associate and form the diabody structure.
  • Diabodies are much smaller than full-length antibodies and lack the Fc region responsible for effector functions like antibody-dependent cellular cytotoxicity (ADCC) and complement activation. Despite their size, diabodies are bivalent, meaning they can bind to two identical or different antigen molecules simultaneously due to the presence of two binding sites. They can be designed to target specific antigens on cancer cells or other disease-related molecules.
  • a “multivalent antibody” is an antibody that possesses multiple antigen- binding sites or paratopes. These antibodies are capable of simultaneously binding to multiple copies of the same antigen or to different antigens. The “valency” of an antibody refers to the number of antigen-binding sites it has.
  • Standard, full-length antibodies found in the immune system typically have two antigen-binding sites, one on each of the two arms of the Y-shaped molecule.
  • Multivalent antibodies can be engineered to have three or four antigen-binding sites, respectively, by fusing multiple antibody fragments or domains together.
  • a “single domain antibody (sdAb),” also known as a “nanobody” or “VHH antibody,” is a small antibody fragment consisting of a single, independently folded domain that retains antigen-binding properties. This variable domain contains complementarity- determining regions (CDRs) responsible for antigen binding. Their smaller size and simpler structure make sdAbs more stable and less prone to aggregation than traditional antibodies.
  • CDRs complementarity- determining regions
  • Single domain antibodies are derived from heavy-chain-only antibodies found in camelids (llamas, camels, and alpacas) and cartilaginous fish. sdAbs are around one-tenth the size of traditional antibodies, making them suitable for accessing and binding to unique epitopes, including those that might be challenging for larger antibodies.
  • “Affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen).
  • 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 molecule X for its partner Y can generally be represented by the dissociation constant (KD).
  • KD dissociation constant
  • Affinity can be measured by common methods known in the art, including those described herein. Affinity can be determined, for example, using surface plasmon resonance (SPR) technology, such as a Biacore ® instrument, or using bio-layer interferometry technology, such as an Octet ® instrument.
  • SPR surface plasmon resonance
  • Biacore ® instrument such as a Biacore ® instrument
  • bio-layer interferometry technology such as an Octet ® instrument.
  • the terms “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction.
  • Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule.
  • Specific binding can also be determined by competition with a control molecule that is similar to the target, such as an excess of non-labeled target.
  • k d (sec -1 ), as used herein, refers to the dissociation rate constant of a particular antibody-antigen interaction. This value is also referred to as the koff value.
  • ka (M -1 x sec -1 ), as used herein, refers to the association rate constant of a particular antibody-antigen interaction. This value is also referred to as the k on value.
  • K D (M), as used herein, refers to the dissociation equilibrium constant of a particular antibody-antigen interaction.
  • KD kd/ka.
  • K A M -1
  • KA ka/kd.
  • epitope means a portion of an antigen capable of specific binding to an antibody. Epitopes frequently consist of surface-accessible amino acid residues and/or sugar side chains and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents.
  • An epitope may comprise amino acid residues that are directly involved in the binding, and other amino acid residues, which are not directly involved in the binding.
  • the epitope to which an antibody binds can be determined using known techniques for epitope determination such as, for example, testing for antibody binding to HLA-G variants with different point-mutations.
  • Percent “identity” between a polypeptide sequence and a reference sequence is defined as the percentage of amino acid residues in the polypeptide sequence that are identical to the amino acid residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity.
  • Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, or CLUSTAL OMEGA software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
  • a “conservative substitution” or a “conservative amino acid substitution,” refers to the substitution of one or more amino acids with one or more chemically or functionally similar amino acids. Conservative substitution tables providing similar amino acids are well known in the art.
  • Polypeptide sequences having such substitutions are known as “conservatively modified variants.”
  • the following groups of amino acids are considered conservative substitutions for one another.
  • Acidic Residues D and E Basic Residues K, R, and H Hydrophilic Uncharged Residues S, T, N, and Q Aliphatic Uncharged Residues G, A, V, L, and I Non polar Uncharged Residues C, M, and P Aromatic Residues F, Y, and W Alcohol Group-Containing Residues S and T Aliphatic Residues I, L, V, and M Cycloalkenyl-associated Residues F, H, W, and Y Hydrophobic Residues A, C, F, G, H, I, L, M, V, W, and Y Negatively Charged Residues D and E Polar Residues C, D, E, H, K, N, Q, R, S
  • amino acid refers to the twenty common naturally occurring amino acids.
  • Naturally occurring amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C); glutamic acid (Glu; E), glutamine (Gln; Q), Glycine (Gly; G); histidine (His; H), isoleucine (Ile; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V).
  • a "warhead” refers to the active component of the ADCs or conjugates provided herein that produces the desired outcome, such as killing cancer cells, inhibiting a disease pathway, or blocking the activity of a specific protein.
  • the toxic drug payload linked to the antibody is the warhead.
  • a “detectable label” refers to a molecule or substance that is attached to a target molecule (such as a biomolecule or cell) to enable its easy visualization, quantification, or detection. Detectable labels are used to tag or mark a target molecule, especially molecules that are not directly visible or detectable, such as proteins, nucleic acids, and cells, enabling its detection in assays, experiments, or clinical settings.
  • a “cytokine” is a small protein or signaling molecule that plays a crucial role in cell communication and immune responses. They are produced by various cells, especially immune cells, and are involved in coordinating the body's defense mechanisms, inflammation, and cellular interactions. Cytokines act as messengers, transmitting signals between cells to regulate various physiological and immune processes. They regulate immune responses, inflammation, cell growth, differentiation, and tissue repair.
  • a “radionuclide,” also known as a radioactive nuclide or radioisotope is an atom that has an unstable nucleus and undergoes radioactive decay, emitting radiation in the process.
  • Enzymes are biological molecules, typically proteins, which act as catalysts to facilitate and accelerate chemical reactions in living organisms. Enzymes lower the activation energy required for reactions to occur, thereby increasing the rate of these reactions. Enzymes are essential for metabolism, growth, and various cellular functions and play a critical role in various biochemical processes, including digestion, energy production, DNA replication, and cellular signaling.
  • a “DNA-alkylating cytotoxic molecule” is a type of chemical compound that attaches alkyl groups to the DNA molecules in cells, disrupting the normal functioning of DNA and leading to cell death.
  • DNA bases form covalent bonds with DNA bases by attaching alkyl groups to the nitrogen or oxygen atoms of DNA bases, primarily guanine. This alters the DNA's structure and prevents the strands from pairing correctly during replication and transcription, causing structural damage and interfering with DNA replication and transcription.
  • An “antineoplastic agent,” also known as an anticancer or chemotherapy drug, is a type of medication used to treat cancer by inhibiting the growth and spread of cancerous cells. Some inhibit DNA replication and cell division, while others target signaling pathways essential for cancer cell survival.
  • pharmaceutically acceptable describes substances, formulations, or components that meet the necessary criteria for safety, quality, and suitability for use in pharmaceutical products.
  • compositions are deemed suitable for inclusion in drug products intended for human consumption and have a minimal risk of causing harm or adverse effects, based on established standards and guidelines set by regulatory authorities. They are also free from impurities, contaminants, and substances that might compromise the quality and safety of the final pharmaceutical product.
  • Pharmaceutically acceptable substances including active pharmaceutical ingredients (APIs), excipients, solvents, and other components, must meet established quality standards, such as those outlined in pharmacopeias (e.g., United States Pharmacopeia, European Pharmacopoeia).
  • APIs active pharmaceutical ingredients
  • Components that are pharmaceutically acceptable are compatible with each other and maintain stability over the intended shelf life of the pharmaceutical product. They do not interact in ways that would compromise the safety or efficacy of the product.
  • a pharmaceutically acceptable diluent is a substance used to dilute or reduce the concentration of an active pharmaceutical ingredient (API) or other components in a pharmaceutical formulation, making it suitable for administration to patients. Diluents are added to drug formulations for various reasons, including achieving the desired dosage strength, improving stability, aiding in drug delivery, and enhancing patient acceptance. IDiluents should be compatible with the active ingredient and other excipients in the formulation. They should not adversely affect the stability, solubility, or bioavailability of the drug product.
  • Diluents like other excipients used in pharmaceutical formulations, must meet established regulatory standards for safety, quality, and purity.
  • the choice of a pharmaceutically acceptable diluent can depend on the intended route of administration. Different routes (oral, injectable, topical, etc.) may have specific requirements for diluents.
  • the choice of diluent may vary depending on the intended dosage form, such as tablets, capsules, solutions, suspensions, or injectable formulations.
  • diluents can impact the taste, texture, and ease of swallowing, which can influence patient compliance and acceptance.
  • a pharmaceutically acceptable carrier also referred to as an excipient or vehicle, is a substance used in pharmaceutical formulations to provide a suitable medium or matrix for delivering active pharmaceutical ingredients (APIs) to patients.
  • Carriers are inert substances that help achieve the desired physical characteristics, stability, and ease of administration of the final drug product. Carriers are used to formulate APIs into various dosage forms, such as tablets, capsules, creams, solutions, and injections. They provide a stable matrix for the API, aiding in its dispersion, dissolution, and overall effectiveness.
  • a pharmaceutically acceptable excipient is a substance added to a pharmaceutical formulation alongside the active pharmaceutical ingredient (API) to facilitate the preparation of the final dosage form, enhance stability, improve patient acceptance, or aid in the delivery of the medication.
  • Excipients are inert substances that serve various functional roles in pharmaceutical products. Excipients are used for various purposes, such as binding, dilution, disintegration, dissolution, coloration, flavoring, preservation, and enhancing patient acceptability. They help achieve the desired physical and chemical properties of the final dosage form.
  • a “small molecule inhibitor” is a type of chemical compound that binds to a specific target molecule in cells and interferes with its activity, often by blocking or reducing its function.
  • An “effector competent antibody,” also known as a functional antibody or effector-active antibody is an antibody that is capable of engaging with the immune system's effector mechanisms to elicit specific immune responses against its target.
  • Effector mechanisms are processes by which antibodies activate immune responses to eliminate target cells or pathogens. These mechanisms involve interactions with immune cells or proteins that enhance the immune response's effectiveness. Effector mechanisms include processes like antibody-dependent cellular cytotoxicity (ADCC), complement activation, and immune cell recruitment.
  • ADCC antibody-dependent cellular cytotoxicity
  • NK natural killer
  • NK natural killer
  • NK natural killer
  • NK natural killer
  • immune cell recruitment antibodies facilitate the recruitment of immune cells, such as macrophages and neutrophils, to the site of infection or inflammation.
  • Treating” or “treatment” of any disease or disorder refers, in certain embodiments, to ameliorating a disease or disorder that exists in a subject. In another embodiment, “treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible by the subject. In yet another embodiment, “treating” or “treatment” includes modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both.
  • “treating” or “treatment” includes delaying or preventing the onset of the disease or disorder.
  • the term “therapeutically effective amount” or “effective amount” refers to an amount of an antibody or composition that when administered to a subject is effective to treat a disease or disorder.
  • the term “subject” means a mammalian subject. Exemplary subjects include, but are not limited to humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, avians, goats and sheep. In certain embodiments, the subject is a human. In some embodiments, the subject has cancer, an autoimmune disease or condition, and/or an infection that can be treated with an antibody provided herein.
  • the subject is a human that is suspected to have cancer, an autoimmune disease or condition, and/or an acute infection and chronic infection.
  • a “solid cancer,” also known as solid tumor, is a type of cancer that form in the body's tissues and organs, resulting in the development of masses or lumps of abnormal cells. Solid cancers can occur in virtually any organ or tissue in the body. Common examples include but are not limted to breast cancer, lung cancer, colorectal cancer, prostate cancer, and ovarian cancer.
  • a “hematological cancer,” also known as hematologic cancer or blood cancer refers to cancers that originate in the cells of the blood, bone marrow, or lymphatic system.
  • Myeloma is a cancer that affects plasma cells, a type of white blood cell responsible for producing antibodies. In myeloma, abnormal plasma cells accumulate in the bone marrow and interfere with normal cell production.
  • An “immunostimulatory agent,” also known as an immune modulator or immunomodulatory agent, is a substance that influences the immune system's response, either by enhancing or suppressing its activity.
  • An “antagonist” is a type of molecule or substance that binds to a receptor or target in the body, blocking or inhibiting its activity.
  • Antagonists work by preventing the natural or intended interactions between the receptor and its ligands, which are molecules that normally bind to the receptor to produce a response, leading to a reduction or inhibition of the receptor's signaling pathway.
  • An “agonist” is a type of molecule or substance that binds to a receptor or target in the body and activates its function. When an agonist binds to its specific receptor, it triggers a biological response or signal within the cell or tissue. This activation leads to downstream cellular responses, which can include changes in gene expression, enzyme activity, ion channel opening, or the release of signaling molecules. Agonists exhibit specificity for certain receptors, as their chemical structure allows them to interact with complementary binding sites on those receptors.
  • Endogenous agonists are naturally produced molecules in the body that bind to receptors and regulate physiological functions. Synthetic agonists are artificially designed molecules that mimic the effects of endogenous agonists. Partial agonists bind to receptors but only activate them to a limited extent compared to full agonists.
  • An “oncolytic virus” is a type of virus that has been genetically modified or naturally evolved to selectively infect and destroy cancer cells while sparing normal healthy cells.
  • a chimeric antigen receptor (CAR) engineered T cell often referred to as CAR T cell therapy, is an immunotherapy approach that involves genetically modifying a patient's own T cells to enhance their ability to recognize and attack cancer cells.
  • a CAR is a synthetic receptor that combines an antigen-binding domain derived from an antibody with T cell signaling components.
  • Bi- or multi-specific T cell-directed antibodies are antibodies that simultaneously engage T cells and cancer cells, bringing T cells in close proximity to cancer cells, facilitating the immune system's ability to recognize and destroy cancer cells with high specificity. By bringing T cells into direct contact with cancer cells, these antibodies help activate T cells and trigger their cytotoxic response against the cancer cells.
  • Bi-specific antibodies can be designed as T cell engagers (TCEs) or bispecific T cell engagers (BiTEs). BiTEs are a type of bi-specific antibody that binds to both a tumor-specific antigen and a T cell receptor. 2.
  • conjugates that include antibodies selectively bind human HLA-G and molecules coupled to the antibodies.
  • One aspect herein provides a conjugate comprising, consisting essentially of, or consisting of (i) an antibody that binds specifically to a human HLA-G (hHLA-G) and (ii) a molecule coupled to the antibody.
  • the antibody has any of the following characteristics: a) is a monoclonal antibody; b) is a human antibody, a humanized antibody, or a chimeric antibody; c) is a bispecific antibody, a multi-specific antibody, a diabody, or a multivalent antibody; d) is of the IgA, IgGl, IgG2, IgG3, IgG4, or IgM type; e) is an antigen-binding antibody fragment; f) is a Fab fragment, a Fab' fragment, a F(ab')2 fragment, or an Fv fragment; and/or g) is a single chain antibody, a single domain antibody, or a nanobody.
  • the antibody has one of these characteristics. In some embodiments, the antibody has two of these characteristics. In some embodiments, the antibody has three of these characteristics. In some embodiments, the antibody has four of these characteristics. In some embodiments, the antibody has five of these characteristics. In some embodiments, the antibody has six of these characteristics. In some embodiments, the antibody has seven of these characteristics. [0139] In some embodiments, the antibody is a bispecific antibody. By simultaneously binding to two different targets, bispecific antibodies can create connections between cells or molecules that might not naturally interact. This can be used to direct immune cells toward cancer cells, enhance immune responses, or modify signaling pathways. In cancer immunotherapy, bispecific antibodies can be designed to engage both cancer cells and immune cells.
  • Multi-specific antibodies can be designed to bind to various molecules involved in autoimmune responses, with the goal of regulating the immune system and reducing inflammation.
  • Multi-specific antibodies can come in various formats, such as "tri-specific" (binding to three targets) or more complex designs. These formats are designed based on the therapeutic goal and the molecular interactions being targeted.
  • the antibody is a multivalent antibody.
  • Multivalent antibodies can offer enhanced binding affinity and avidity. They can potentially bind more strongly to antigens due to multiple interactions between binding sites and antigens. Multivalent antibodies can neutralize pathogens more effectively by binding to multiple epitopes on the pathogen's surface. Multivalent antibodies are used in cancer immunotherapy to enhance the immune response against cancer cells.
  • the antibody is a single domain antibody. sdAbs often exhibit excellent thermal and chemical stability, making them suitable for various applications, including harsh conditions. sdAbs have therapeutic potential, especially in scenarios where small size, stability, and novel epitope targeting are advantageous. They can be used for cancer therapy, autoimmune diseases, and more. [0143] In some embodiments, the antibody binds to a human HLA-G polypeptide or a variant thereof with a KD of less than about 20 nM.
  • the antibody comprises, consists essentailly of, or consists of a human heavy chain constant region or fragment or a variant thereof and/or a light chain constant region or fragment or variant thereof; and the constant region or fragment of variant thereof comprises, consists essentailly of, or consists of up to 20 conservatively modified amino acid substitutions from any sequence set forth in SEQ ID NOS: 170-200 and/or SEQ ID NOS: 204-228.
  • the antibody comprises, consists essentilly of or consists of: an isolated antibody molecule capable of binding to human HLA-G (hHLA- G), comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH and/or VL comprising 1, 2, 3, 4, 5, or 6 of: a VHCDR1 having the sequence set forth in SEQ ID NOS: 1 -14 or SEQ ID NOS: 18-34, a VHCDR2 having the sequence set forth in SEQ ID NOS: 38-50 or SEQ ID NOS: 54-71 , a VHCDR3 having the sequence set forth in SEQ ID NOS: 76-101, a VLCDR1 having the sequence set forth in SEQ ID NOS: 105-124, a VLCDR2 having the sequence set forth in SEQ ID NOS: 128-145, and a VLCDR3 having the sequence set forth in SEQ ID NOS: 149-166.
  • hHLA- G human HLA-G
  • VH
  • the antibody comprises, consists essentilly of or consists of: an isolated antibody molecule capable of binding to human HLA-G (hHLA-G), comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising: a VHCDR1 having a sequence set forth in SEQ ID NOS: 1-14 or SEQ ID NOS: 18-34, a VHCDR2 having a sequence set forth in SEQ ID NOS: 38-50 or SEQ ID NOS: 54-71 , and c) a VHCDR3 having a sequence set forth in SEQ ID NOS: 76-101; and the VL comprising: a VLCDR1 having a sequence set forth in SEQ ID NO: 105-124, a VLCDR2 having a sequence set forth in SEQ ID NO: 128-145, and a VLCDR3 having a sequence set forth in SEQ ID NO: 149-166.
  • hHLA-G human HLA-G
  • VH
  • the antibody comprises, consists essentilly of or consists of: an isolated antibody molecule capable of binding to human HLA-G (hHLA-G), and comprising a heavy chain variable region (VH) and/or a light chain variable region (VL), the VH comprising at least one sequence set forth in any of SEQ ID NOS: 170-200 and the VL comprising at least one sequence set forth in any of SEQ ID NOS: 204-228;.
  • hHLA-G human HLA-G
  • VH heavy chain variable region
  • VL light chain variable region
  • the antibody comprises, consists essentilly of or consists of: an isolated antibody molecule capable of binding to human HLA-G (hHLA-G), the isolated antibody molecule comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising 1, 2, or 3 of: a VHCDR1 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOS: 1-14 or 18-34, a VHCDR2 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOS: 54-71, and a VHCDR3 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOS: 76-101; and the VL comprising 1, 2, or 3 of: a VLCDR1 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOS: 105-124, a VLCDR2 having an amino acid sequence that is at least 90% identical to the
  • the antibody comprises, consists essentilly of or consists of: an isolated antibody molecule capable of binding to human HLA-G (hHLA-G), the isolated antibody molecule comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising 1, 2, or 3 of: a VHCDR1 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 1-14 or SEQ ID NOS: 18-34, a VHCDR2 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 38-50 or SEQ ID NOS: 54-71, and a VHCDR3 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 76-101; and the VL comprising 1, 2, or 3 of: a VLCDR1 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 105-124, a VLCDR2 having an
  • the antibody comprises, consists essentilly of or consists of: an isolated antibody molecule capable of binding to human HLA-G (hHLA-G), the isolated antibody molecule comprising a heavy chain and a light chain, the heavy chain comprising one or more molecules having a sequence consisting of one of SEQ ID NOS: 232-262 or SEQ ID NOS: 266-296, and the light chain comprising one or more molecules having a sequence consisting of one of SEQ ID NOS: 300-330.
  • hHLA-G human HLA-G
  • the isolated antibody molecule comprising a heavy chain and a light chain
  • the heavy chain comprising one or more molecules having a sequence consisting of one of SEQ ID NOS: 232-262 or SEQ ID NOS: 266-296
  • the light chain comprising one or more molecules having a sequence consisting of one of SEQ ID NOS: 300-330.
  • the antibody comprises, consists essentilly of or consists of: an isolated antibody molecule capable of binding to human HLA-G (HLA-G), the isolated antibody molecule comprising a heavy chain and a light chain and being selected from the group consisting of: the heavy chain comprising one or more molecules each having a sequence consisting of SEQ ID NO: 232 and the light chain comprising one or more molecules each having a sequence consisting of SEQ ID NO: 300; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 233 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 301 ; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 234 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 302; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO:
  • the molecule coupled to the antibody comprises a cytotoxic payload or warhead. In some embodiments, the conjugate provided herein further comprises a linker molecule, and the cytotoxic payload or warhead is coupled to the antibody by the linker molecule. [0154] In some embodiments, in any conjugate provided herein, the molecule coupled to the antibody comprises a cytotoxic payload or warhead and further comprises a linker molecule. The cytotoxic payload or warhead is coupled to the antibody by the linker molecule. [0155] In some embodiments, the linker molecule is cleavable. In some other embodiments, the linker molecule is non-cleavable.
  • the molecule coupled to the antibody comprises one selected from the group consisting of a detectable label, a drug, a toxin, a cytokine, a radionuclide, an enzyme, and combinations thereof.
  • the molecule coupled to the antibody comprises a cytokine. Cytokines are categorized into different groups based on their functions: Interleukins (ILs) mainly act on immune cells and are involved in inflammation, cell proliferation, and differentiation. Tumor Necrosis Factors (TNFs) are involved in inflammation and cell death. Interferons (IFNs) play a role in antiviral responses and regulating immune cell activities.
  • ILs Interleukins
  • TNFs Tumor Necrosis Factors
  • IFNs Interferons
  • Chemokines attract immune cells to specific sites of infection or inflammation. Growth Factors stimulate cell growth, proliferation, and tissue repair. Cytokines help regulate the intensity and duration of immune responses. They can stimulate or inhibit immune cell activities based on the context. They are vital for maintaining a balanced immune response, preventing excessive inflammation, and avoiding immune-related diseases. Dysregulation of cytokines can contribute to various diseases, including autoimmune disorders, allergies, and chronic inflammatory conditions.
  • the molecule coupled to the antibody comprises a DNA-alkylating cytotoxic molecule or an antineoplastic agent.
  • the molecule coupled to the antibody comprises an antineoplastic agent.
  • the antineoplastic agent targets rapidly dividing cells, which includes cancer cells, to disrupt their growth, division, and survival.
  • Antineoplastic agents can be used alone or in combination with other therapies. Cytotoxic antineoplastic agents directly kill rapidly dividing cells; and examples include alkylating agents, antimetabolites, and microtubule inhibitors. Targeted antineoplastic agents specifically target proteins or pathways involved in cancer growth; and examples include tyrosine kinase inhibitors and monoclonal antibodies.
  • Immunotherapeutic antineoplastic agents stimulate the immune system to recognize and attack cancer cells; and examples include immune checkpoint inhibitors and CAR-T cell therapy.
  • the molecule coupled to the antibody comprises a warhead selected from the group consisting of DGN549C, Monomethyl auristatin E (MMAE), Deruxtecan, SN-38, vc-SECO-DUBA (duocarmycin), Calicheamicin, SPDB-DM4, and Tesirine.
  • the molecule coupled to the antibody comprises one selected from the group consisting of Formulas I-VIII: Formula I: DGN549-C
  • compositions comprising, consisting essentailly of, or consisting of any of the conjugates provided herein.
  • One aspect herein provides a pharmaceutical composition comprising, consisting essentailly of, or consisting of an effective amount of any of the conjugates provided herein.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable diluent, carrier, or excipient.
  • the pharmaceutical composition further comprises an effective amount of at least one of the following: a) an anti-ILT2 antibody; b) an anti-ILT3 antibody; c) an anti-ILT4 antibody; d) an anti-KIR2DL4 antibody; e) an anti-HLA-E antibody; f) an anti-NKG2A antibody; g) an anti-HLA-F antibody; h) an anti-HLA-J antibody; i) an anti-PD-L1 antibody; j) an anti-PD-1 antibody; k) an anti-CD38 antibody; l) an anti-CD39 antibody; m) an anti-CD73 antibody; n) an anti-A2A receptor antibody; o) an anti-A2B receptor antibody; p) an anti-A2A/A2B dual receptor antibody or a combination thereof; q) an anti-CD47 antibody; r) a small molecule inhibitor; s) a bi-specific T cell engager and/or CAR-
  • the pharmaceutical composition further comprises an effective amount of a small molecule inhibitor.
  • the small molecule inhibitor binds to a specific target molecule, such as an enzyme, receptor, or signaling protein, and altering its structure or function. By binding to the target, the inhibitor can disrupt the target's activity, signaling pathways, or interactions with other molecules.
  • the small molecule inhibitor preferably target specific signaling pathways that are overactive in cancer cells leading to growth inhibition or cell death. Examples include tyrosine kinase inhibitors, such as imatinib for chronic myeloid leukemia, and proteasome inhibitors, such as bortezomib for multiple myeloma.
  • the pharmaceutical composition further comprises an effective amount of an oncolytic virus.
  • Oncolytic viruses exploit the unique characteristics of cancer cells, such as their altered signaling pathways, weakened antiviral defenses, and impaired ability to respond to viral infections. The viruses replicate preferentially within cancer cells, leading to their lysis (destruction) and release of new viral particles that can infect nearby cancer cells. Oncolytic viruses can kill cancer cells through multiple mechanisms, including direct cell lysis, induction of apoptosis (programmed cell death), stimulation of anti-tumor immune responses, and disruption of tumor vasculature (blood vessels).
  • oncolytic viruses there are various types of oncolytic viruses, including adenoviruses, herpes simplex viruses, reoviruses, vaccinia viruses, and vesicular stomatitis viruses. Some viruses are naturally selective for cancer cells, while others are engineered to enhance their tumor- targeting capabilities. Oncolytic virotherapy can be combined with other treatment modalities, such as chemotherapy, radiation therapy, and immunotherapy, to enhance the overall anti-cancer effect. Oncolytic viruses can stimulate the immune system to recognize and attack cancer cells by releasing tumor antigens and promoting the activation of immune cells.
  • the pharmaceutical composition further comprises at least one of a) an antibody to an immune inhibitory receptor or ligand and/or b) an antibody to an immune stimulatory receptor or ligand.
  • the pharmaceutical composition may comprise one or more pharmaceutical excipients or pharmaceutically acceptable excipients. Any suitable pharmaceutical excipient may be used, and one of ordinary skill in the art is capable of selecting suitable pharmaceutical excipients. Accordingly, the pharmaceutical excipients provided below are intended to be illustrative, and not limiting. Additional pharmaceutical excipients include, for example, those described in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), incorporated by reference in its entirety.
  • the pharmaceutical composition may comprise an anti-foaming agent. Any suitable anti-foaming agent may be used.
  • the anti-foaming agent may be one of an alcohol, an ether, an oil, a wax, a silicone, a surfactant, or combinations thereof.
  • the anti-foaming agent may be one of a mineral oil, a vegetable oil, ethylene bis stearamide, a paraffin wax, an ester wax, a fatty alcohol wax, a long chain fatty alcohol, a fatty acid soap, a fatty acid ester, a silicon glycol, a fluorosilicone, a polyethylene glycol-polypropylene glycol copolymer, polydimethylsiloxane-silicon dioxide, ether, octyl alcohol, capryl alcohol, sorbitan trioleate, ethyl alcohol, 2-ethyl-hexanol, dimethicone, oleyl alcohol, simethicone, or combinations thereof.
  • the pharmaceutical composition may comprise a cosolvent.
  • cosolvents include ethanol, poly(ethylene) glycol, butylene glycol, dimethylacetamide, glycerin, and propylene glycol.
  • the pharmaceutical composition may comprise a buffer.
  • buffers include acetate, borate, carbonate, lactate, malate, phosphate, citrate, hydroxide, diethanolamine, monoethanolamine, glycine, methionine, guar gum, and monosodium glutamate.
  • the pharmaceutical composition may comprise a carrier or filler.
  • compositions include lactose, maltodextrin, mannitol, sorbitol, chitosan, stearic acid, xanthan gum, and guar gum.
  • the pharmaceutical composition may comprise a surfactant.
  • surfactants include d-alpha tocopherol, benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride, docusate sodium, glyceryl behenate, glyceryl monooleate, lauric acid, macrogol 15 hydroxystearate, myristyl alcohol, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxylglycerides, sodium lauryl sulfate, sorbitan esters, and vitamin E polyethylene(glycol) succinate.
  • the pharmaceutical composition may comprise an anti-caking agent.
  • anti-caking agents include calcium phosphate (tribasic), hydroxymethyl cellulose, hydroxypropyl cellulose, and magnesium oxide.
  • Other excipients that may be used with the pharmaceutical compositions include, for example, albumin, antioxidants, antibacterial agents, antifungal agents, bioabsorbable polymers, chelating agents, controlled release agents, diluents, dispersing agents, dissolution enhancers, emulsifying agents, gelling agents, ointment bases, penetration enhancers, preservatives, solubilizing agents, solvents, stabilizing agents, and sugars. Specific examples of each of these agents are described, for example, in the Handbook of Pharmaceutical Excipients, Rowe et al.
  • the pharmaceutical composition may comprise a solvent.
  • the solvent may be saline solution, such as a sterile isotonic saline solution or dextrose solution.
  • the solvent may be water for injection.
  • the pharmaceutical composition provided herein may be in a single unit dosage form. 3.1. Parenteral Dosage Forms [0179]
  • the pharmaceutical compositions provided herein may be in parenteral dosage forms administered to subjects via intravenous injection. Because their administration typically bypasses subjects’ natural defenses against contaminants, parenteral dosage forms are typically, sterile or capable of being sterilized prior to administration to a subject.
  • parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
  • Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art.
  • Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection; water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection
  • water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polyprop
  • Excipients that increase the solubility of one or more of the conjugates disclosed herein can also be incorporated into the parenteral dosage forms.
  • 3.2. Dosage and Unit Dosage Forms [0182] In human therapeutics, the doctor will determine the dosology which they consider most appropriate according to the treatment and according to the age, weight, condition and other factors specific to the subject to be treated. [0183] The amount of the conjugate or pharmaceutical composition provided herein which will be effective in the treatment of a disorder or one or more symptoms thereof will vary with the nature and severity of the disease or condition.
  • exemplary doses of the pharmaceutical composition provided herein include milligram or microgram amounts of the conjugate per kilogram of subject or sample weight (e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 microgram per kilogram to about 10 milligrams per kilogram).
  • the dosage of the pharmaceutical composition provided herein, based on weight of the conjugate is about 0.1 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 10 mg/kg, or about 15 mg/kg or more of a subject’s body weight. In some embodiments, the dosage of the pharmaceutical composition provided herein, based on weight of the conjugate, is 0.1 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 10 mg/kg, or 15 mg/kg or more of a subject’s body weight.
  • the dosage of the pharmaceutical composition is about 0.1 mg to about 200 mg, about 0.1 mg to about 100 mg, about 0.1 mg to about 50 mg, about 0.1 mg to about 25 mg, about 0.1 mg to about 20 mg, about 0.1 mg to about 15 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 7.5 mg, about 0.1 mg to about 5 mg, about 0.1 to about 2.5 mg, about 0.25 mg to about 20 mg, about 0.25 to about 15 mg, about 0.25 to about 12 mg, about 0.25 to about 10 mg, about 0.25 mg to about 7.5 mg, about 0.25 mg to about 5 mg, about 0.25 mg to about 2.5 mg, about 0.5 mg to about 20 mg, about 0.5 to 15 mg, about 0.5 to 12 mg, about 0.5 to about 10 mg, about 0.5 mg to about 7.5 mg, about 0.5 mg to about 5 mg, about 0.5 mg to about 2.5 mg, about 1 mg to about 20 mg, about 1 mg to about 15 mg, about 1 mg to about 12 mg, about 1 mg to about 10 mg, about 0.5 mg to
  • the dosage of the pharmaceutical composition is 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.25 mg to 2.5 mg, 0.5 mg to 20 mg, 0.5 to 15 mg, 0.5 to 12 mg, 0.5 to 10 mg, 0.5 mg to 7.5 mg, 0.5 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.
  • the dose can be administered according to a suitable schedule, for example, once, two times, three times, or four times weekly. It may be necessary to use dosages of the conjugate or pharmaceutical composition outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with subject response. [0188] Different therapeutically effective amounts may be applicable for different diseases and conditions, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to manage, treat, or ameliorate such disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the conjugate provided herein are also encompassed by the herein described dosage amounts and dose frequency schedules.
  • the dosage administered to the subject may be increased to improve the effect of the conjugate or pharmaceutical composition, or it may be decreased to reduce one or more side effects that a particular subject is experiencing.
  • treatment can be initiated with one or more loading doses of a pharmaceutical composition or conjugate provided herein followed by one or more maintenance doses.
  • administration of the same conjugate or pharmaceutical composition may be repeated, and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. 4.
  • One aspect herein provides a method for treatment of a subject suffering from cancer, a chronic infection, and/or from an inflammatory disease, the method comprising, consisting essentially of, or consisting of administering to the subject a pharmaceutical composition comprising, consisting essentially of, or consisting of an effective amount of a conjugate provided herein or a pharmaceutical composition provided herein.
  • the conjugates or pharmaceutical compositions provided herein may be useful for the treatment of any disease or condition involving HLA-G, such as cancer, autoimmune disease, and infection.
  • Any suitable cancer may be treated with the conjugates or pharmaceutical compositions provided herein.
  • Illustrative suitable cancers include, for example, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, basal cell carcinoma, brain tumor, bile duct cancer, bladder cancer, bone cancer, breast cancer, bronchial tumor, Burkitt Lymphoma, carcinoma of unknown primary origin, cardiac tumor, cervical cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasm, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, fibrous histiocytoma, Ewing sarcoma, eye cancer, germ cell tumor, gallbla
  • the cancer is selected from breast, lung, CRC, gastric, esophageal, neuroblastoma, cervical, and hematological cancers.
  • Any suitable autoimmune disease may be treated with the conjugates or pharmaceutical compositions provided herein.
  • interstitial cystitis juvenile arthritis, juvenile diabetes (Type 1 diabetes), juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, capitaous conjunctivitis, linear IgA disease (LAD), lupus (SLE), Lyme disease (chronic), Meniere’s disease, microscopic polyangiitis, mixed connective tissue disease (MCTD), Mooren’s ulcer, Mucha-Habermann disease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica (Devic’s), neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglob
  • any suitable infection may be treated with the conjugates or pharmaceutical compositions provided herein.
  • suitable infections include, for example, hepatitis A virus, hepatitis B virus, hepatitis C virus (HCV), human immunodeficiency virus (HIV), and other viral infections.
  • the cancer is a solid cancer or a hematological cancer.
  • the subject is a human subject.
  • the method of treatment provided herein further comprises one or more of the following: a) administering chemotherapy; b) administering radiation therapy; and/or c) administering one or more additional therapeutic agents.
  • the method of treatment provided herein comprises administering one or more additional therapeutic agents.
  • the one or more additional therapeutic agents comprise, consist essentially of, or consist of one or more immunostimulatory agents.
  • Immunostimulatory agents enhance the immune system's response against pathogens, cancer cells, or other antigens. They can boost immune cell activation, proliferation, and the production of cytokines and antibodies. Immunostimulatory agents can also suppress the immune system, often used to manage autoimmune diseases or prevent transplant rejection. Immunostimulatory agents are a key component of cancer immunotherapy, which aims to harness the immune system to target and eliminate cancer cells.
  • Immune checkpoint inhibitors, cancer vaccines, and adoptive T cell therapies are examples of immunostimulatory approaches used in cancer treatment.
  • immunostimulatory agents can be used to suppress immune responses and reduce inflammation.
  • the one or more immunostimulatory agents comprise, consist essentially of, or consist of an antagonist to an inhibitory receptor of an immune cell.
  • the inhibitory receptor is one of or is selected from the group consisting of ILT2, ILT3, ILT4, KIR2DL4, CTLA-4, PD-l, CD39, CD73, PD-L1, PD- L2, LAG-3, Tim3, TIGIT, B7-H3, B7-H4, neuritin, BTLA, CECAM-l , CECAM-5, VISTA, LAIR1, CD160, 2B4,TGF-B (including traps and GARP), NKG2A, a Killer-cell immunoglobulin-like receptor (KIR), and combinations thereof.
  • the one or more immunostimulatory agents comprise, consist essentially of, or consist of an agonist of a co-stimulatory receptor of an immune cell.
  • the co-stimulatory receptor is at least one of OX40, CD2, CD27, ICAM-l, LFA-l, ICOS (CD278), 4-1BB (CD 137), GITR, CD28, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp30, NKp46, NKp80, CD160, and/or a CD83 ligand.
  • the one or more immunostimulatory agents comprise, consist essentially of, or consist of an ADCC competent antibody selected from the group consisting of an anti-CD19, anti-CD20, anti-EGFR, anti-Her2, anti-SLAMF7, anti-CD52, anti-BCMA, anti-GD2, anti-CD38, anti-CCR4, anti-CTLA-4 antibody, and combinations thereof.
  • the one or more immunostimulatory agents comprise, consist essentially of, or consist of a cytokine.
  • the cytokine is one of or is selected from the group consisting of IL-l, IL-2, IL-5, IL-7, IL-10, IL-12, IL-15, IL-21, IL-27, and combinations thereof.
  • the one or more immunostimulatory agents comprise, consist essentially of, or consist of an oncolytic virus.
  • the oncolytic virus is one of or is selected from the group consisting of a Herpes simplex virus, a Vesicular stomatitis virus, an adenovirus, a Newcastle disease virus, a vaccinia virus, and a maraba virus.
  • the one or more immunostimulatory agents comprise, consist essentially of, or consist of a chimeric antigen engineered T cell.
  • the one or more immunostimulatory agents comprise, consist essentially of, or consist of a bi- or multi-specific T cell directed antibody.
  • Another aspect herein provides a method for modulating immune system function in a subject in need thereof, the method comprising, consisting essentially of, or consisting of contacting a population of immune cells of the subject with a pharmaceutical composition comprising an effective amount of any of the conjugates provided herein, under conditions such that the immune system is modulated.
  • Modulating the immune system function involves intentionally influencing the activity and responses of the immune system to achieve specific outcomes.
  • the subject is a human subject.
  • the method for modulating immune system function in a subject in need thereof provided herein further comprises administering chemotherapy, administering radiation therapy, and/or administering one or more additional therapeutic agents.
  • the one or more additional therapeutic agents comprise one or more immunostimulatory agents.
  • the one or more immunostimulatory agents comprise an antagonist to an inhibitory receptor of an immune cell.
  • the inhibitory receptor is at least one of ILT2, ILT3, ILT4, KIR2DL4, CTLA- 4, PD-1, CD39, CD73, PD-L1, PD-L2, LAG-3, TIGIT, B7-H3, B7-H4, Tim3, neuritin, BTLA, CECAM-1, CECAM-5, VISTA, LAIR1, CD160, 2B4, TGF-B (including traps and GARP), NKG2A, and/or a Killer-cell immunoglobulin-like receptor (KIR).
  • the one or more immunostimulatory agents comprise an agonist of a co-stimulatory receptor of an immune cell.
  • the co- stimulatory receptor comprises one or more of OX40, CD2, CD27, ICAM-1, LFA-1, ICOS (CD278), 4-1BB (CD137), GITR, CD28, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp30, NKp46, NKp80, CD160, and/or a CD83 ligand.
  • the one or more immunostimulatory agents comprise a cytokine.
  • the cytokine is at least one of IL-1, IL-2, IL-5, IL-7, IL-10, IL-12, IL-15, IL-21, and/or IL-27.
  • the one or more immunostimulatory agents comprise an oncolytic virus.
  • the oncolytic virus comprises one or more of the oncolytic virus is a Herpes simplex virus, a Vesicular stomatitis virus, an adenovirus, a Newcastle disease virus, a vaccinia virus, or a maraba virus.
  • the one or more immunostimulatory agents comprise a chimeric antigen engineered T cell.
  • the immunostimulatory agents comprise a bi- or multi-specific T cell directed antibody.
  • the one or more immunostimulatory agents comprises or consists of an ADCC competent antibody that may target CD19, CD20, EGFR, Her2, SLAMF7, CD52, BCMA, GD2, CD38, CCR4, or CTLA- 4.
  • the ADCC competent antibody is effector enhanced through afucosylation, point mutations, or otherwise.
  • the one or more immunostimulatory agents comprise a bi-specific T cell engager and/or CAR-T therapy, CAR-NK therapy, CAR-macrophage therapy, adoptive T cell therapy. 5.
  • kits [0220]
  • a conjugate or pharmaceutical composition provided herein is provided in the form of a kit, i.e., a packaged combination of reagents in predetermined amounts with instructions for performing a procedure.
  • the procedure is a therapeutic procedure. 6.
  • Production of the conjugates [0221] Provided herein are also methods of production of the conjugates described herein. [0222] The development of an ADC can be challenging due to considerations such as antibody selection, linker stability, drug potency, and overall safety. Creating an ADC involves a series of complex steps that combine the antibody, the cytotoxic drug, and a linker molecule to form a single molecule capable of targeting and killing specific cells, such as cancer cells.
  • the linker molecule can be designed to connect the antibody and the cytotoxic drug.
  • the linker molecule should be stable in circulation but may be cleavable within the target cell to release the drug.
  • the drug may usually be modified with a functional group that can be conjugated to the linker molecule.
  • the modified drug may be attached to the linker molecule, forming a drug-linker complex.
  • the drug-linker complex may then be conjugated to the antibody using specific conjugation chemistry, which may involve chemical reactions like thiol-maleimide or click chemistry.
  • the ADC then may be purified to remove unreacted components and byproducts.
  • the ADC can then be analyzed using various analytical techniques to ensure that the conjugation was successful and that the desired drug-to-antibody ratio is achieved.
  • the stability of the ADC can be assessed under various conditions, including temperature, pH, and storage time, and the appropriate formulation to maintain ADC stability can be determined.
  • the ADC can be tested in cell culture to confirm its ability to selectively bind to target cells and induce cell death. Preclinical studies can be conducted in animal models to evaluate the ADC's efficacy, safety, and pharmacokinetics. If preclinical studies are successful, clinical trials can then be conducted to evaluate the safety and effectiveness of the ADC in humans.
  • Thiol-maleimide and click chemistry are two distinct chemical reactions frequently used in the context of creating ADCs or other bioconjugates. These reactions enable the specific and efficient attachment of molecules while maintaining the stability and activity of the final product.
  • Thiol-maleimide chemistry is a reaction between a thiol (-SH) group and a maleimide functional group. The reaction is highly selective and occurs efficiently under mild conditions, making it suitable for bioconjugation applications. In ADC development, maleimide groups are often introduced to the cytotoxic drug or linker, while thiol groups are introduced to the antibody.
  • the choice between these chemistries may depend on factors such as the specific functional groups available for modification, the stability of the conjugate under physiological conditions, and the overall design of the ADC.
  • selecting the appropriate conjugation chemistry is a critical decision that can influence the stability, activity, and therapeutic potential of the final product. Factors to be considered include the characteristics of the components being conjugated, the desired drug-to-antibody ratio, and the potential impact of the chemistry on the antibody's binding affinity and biological function.
  • the cytotoxic payload of the ADC may be conjugated to an HLA-G antibody via a covalent linker.
  • the conjugate may be produced by conjugating the cytotoxic payload to the antibody using an amino or sulfhydryl specific linker that reacts with lysines or cysteines on the antibody surface.
  • the conjugation reaction happens in a closed system. In the closed system, no reactants or products can escape, only heat can be exchanged freely.
  • the method comprises treating the antibody to create a conjugation site on the antibody surface and reacting the conjugation site with the amino or sulfhydryl specific linker attached to the molecule.
  • kits for ADC conjugation There are commercially available kits for ADC conjugation. Some ADC kits apply to general payloads with certain functional groups. Some ADC kits supply the selected, standard linkage molecules conjugated to a selected payload, ready with the appropriate reactive modifications to directly attach the payload and linker to the specific antibody of interest. The kits may be complete with all reagents and procedures for attaching the selected payload directly to the antibody of interest and purifying the final ADC.
  • the cytotoxic payloads used herein, such as DGN549C, Monomethyl auristatin E (MMAE), Deruxtecan, SN-38, vc-SECO-DUBA (duocarmycin), Calicheamicin, SPDB-DM4, or Tesirine, may be commercially available.
  • the cytotoxic payloads used herein may include a linker moiety that can react with the lysines or cysteines of the antibody provided herein to creat a covalent linkage between the cytotoxic payload and the antibody to thereby produce the conjugates provided here.
  • FBS fetal bovine serum
  • Pen Strep penicillin streptomycin
  • FIGS.1A-1R show killing curves of CL2A-SN38, Deruxtecan, PABC- MMAE, calcheamicin, SPDB-DM4, teserine, seco-DUBA, and DGN549-C on multiple HLA-G endogenous (BICR6, HUP-T3, RERF, JEG3, HT1376) and over-expressing (AU565, OV90, TOV-112D, HEC-1-B, SK-MES-1, 22RV1, 721.221, A549, SKOV3) cells.
  • IC50 half-maximal inhibitory concentration
  • Table 1 provides IC50 values (in nM) of different payloads on HLA-G expressing cell lines.
  • Example 2 Anti-HLA-G Antibody Conjugated to Different Payloads Demonstrates Increased Cytotoxicity in Multiple Tumor Cell Lines [0236] To determine the in vitro cytotoxic potential of combining anti-HLA-G antibody with different cytotoxic payloads, HLA-G expressing cells were plated at 4000 cells per well in 50 ⁇ l of RPMI and 10% FBS and allowed to adhere overnight at 37° C, 5% CO2.
  • FIGS.2A-2K show that an anti-HLA-G antibody conjugated to a cytotoxic payload can significantly increase the target mediated cytotoxicity of multiple HLA-G expressing tumor cell lines compared to an isotype control conjugated molecule.
  • Table 2 provides IC50 values (in nM) of anti-HLA-G ADCs on multiple HLA- G expressing cell lines.
  • Example 3 Anti-HLA-G Antibodies Demonstrate Target Specific Internalization [0239] To determine whether anti-HLA-G antibodies can efficiently deliver payloads to the lysosome, cells over-expressing HLA-G or wildtype cells were cultured in 50 ⁇ l RPMI, 10% FBS, 1% Pen Strep and incubated overnight at 37° C, 5% CO 2 .
  • FIGS.3A-3F show internalization of anti-HLA-G antibodies on HLA-G expressing cells. Cells expressing HLA-G internalize Fabfluor-conjugated anti-HLA-G antibodies in the lysosome.
  • Example 4 Anti-HLA-G Antibody Drug Conjugates Show In Vivo Efficacy in Multiple Tumor Models [0241] To evaluate the tumor growth inhibition capacity of anti-HLA-G ADC molecules, nude mice were implanted with 1-5 ⁇ 106 HLA-G expressing tumor cell lines. Treatment of mice started between days 9 and 15 when mice had palpable tumors.
  • FIGS.4A-4E show anti-tumor activity of anti-HLA-G ADCs. Mice treated with either isotype (hIgG1 AAA) or anti-HLA-G conjugated to VcMMAE (3 mg/kg), Deruxtecan (6 mg/kg), DGN549C (1 mg/kg or 0.3 mg/kg) or SN38 (30 mg/kg), and tumors were measured biweekly.
  • FIGS.6A-6F show anti-tumor activity of the anti-HLA-G-DGN549C conjugate (0.3 mg/kg) in admixture tumor models with 10-100% HLA-G expression.
  • Cells for an admixture implantation were prepared by normalizing HLA-G positive and HLA-G negative (parental or HLA-G KO) cell lines to the same concentration of cells/ml, and then mixing the cell lines at the desired ratio of HLA-G positive and negative cells.
  • mice were treated with three doses of anti-HLA-G-DGN549C weekly.
  • Tumor growth curves show reduced tumor growth in mice treated with anti-HLA-G-DGN549C compared to isotype treated mice in JEG3 (FIGS.6A-6C) and A549 (FIGS.6D-6E) tumor model.
  • FIG.6F shows increased survival in mice treated with anti-HLA-G-DGN549C compared to isotype treated mice in JEG3 admixture tumor model.
  • FIGS.7A-7D show anti-tumor activity of the anti-HLA-G-DGN549C conjugate (0.3 mg/kg or 0.1 mg/kg) in TOV-112D admixture tumor models with 100% or 20% HLA-G expression.
  • Mice were treated with one dose of anti-HLA-G-DGN549C at 0.3 mg/kg or two doses of anti-HLA-G-DGN549C at 0.1 mg/kg.
  • Tumor growth curves show reduced tumor growth in mice treated with anti-HLA-G-DGN549C compared to isotype treated mice (FIGS.7A-7B).
  • FIGS.7C-7D show increased survival in mice treated with anti-HLA-G-DGN549C compared to isotype treated mice in TOV-112D admixture tumor model.
  • the in vivo cytotoxicity of the conjugates provided herein is measured by the tumor volume changing with the days after tumor implantation, compared with the respective isotypes. The results show that when the isotypes were used, the tumor volume continued to grow with time. In contrast, all the conjugates provided herein were able to effectively suppress the growth of the tumor, especially after a short period, such as after the first 13, 16, 20, or 24 days after the tumor implantation, depending on the conjugate used.
  • the anti-HLA-G-DGN549C conjugate at 1mg/kg, or at 0.3mg/kg on a single dose, was able to effectively reduce the tumor volume as soon as 6 days after treatment in established tumors.
  • the anti-HLA-G-Deruxtecan conjugate was also able to effectively reduce the tumor volume as soon as 7 days after treatment at a concentration of about 6mg/kg.
  • the anti-HLA-G-DGN549C conjugate at 0.1 mg/kg was able to completely reduce tumor volume in the TOV-112D model with physiologically relevant HLA-G expression reflecting patient-derived tumors.
  • HLA-G antibodies were selected from a synthetic library of human antibodies presented on the surface of yeast cells in IgG format, as generally described, e.g., in W02009036379; W02010105256; WO2012009568; and Xu et al., Protein Eng. Des. Sel., 2013, 26:663-670 (each incorporated by reference in its entirety), and more specifically as provided below.
  • the antigen was biotinylated human HLA-G, decreasing concentrations of antigen were used in each subsequent round of selection.
  • some rounds of selection were employed to reduce the number of nonspecific binders utilizing soluble membrane proteins from CHO cells (see WO2014179363 and Xu et al., Protein Eng. Des. Sel., 2013, 26:663-670, each incorporated by reference in its entirety).
  • deselections against recombinant HLA- A/B/C proteins were performed to maintain specific binding to HLA-G. After the final round of sorting, yeast were plated and individual colonies were picked for characterization and for nomination of clones for affinity maturation.
  • Antibody variable domains of interest were synthesized, with codon optimization to maximize transient expression in host cells. The variable regions were cloned into expression vectors containing human immunoglobulin constant domains and their sequence confirmed. Antibody heavy and light chain vector pairings were transfected into Expi293 cells using the Expifectamine system (Invitrogen). Transient cultures were harvested on day 4 and clarified cell culture supernatant IgG titer was estimated using Bio- Layer Interferometry (BLI) using Octet (ForteBio) alongside standards. Antibodies were subsequently purified on a Protein A column and eluted using low pH glycine.
  • Light Chain Shuffling Heavy chain plasmids were extracted from na'ive outputs (described herein) and transformed into a pre-made naive light chain library with a diversity of 10E+06. Selections were performed as described above with one round of MACS sorting and three rounds of FACS sorting using decreasing amounts of biotinylated HLA-G antigen for respective rounds.
  • Example 6 Affinity Maturation [0252] Optimization of naive clones was carried out utilizing four maturation strategies; diversification of CDR-H1 and CDR-H2; diversification of CDR-H3; diversification of CDR-L1, L2 and L3; shuffling of diversified heavy and light chains. [0253] CDR-H1 and CDR-H2 Selection: The CDR-H3s from clones selected from light chain batch diversification, light chain diversification, and naive discovery efforts were independently recombined into premade libraries with CDR-H1 and CDR-H2 variants of a diversity of >10E+8. Selections were performed using HLA-G antigen.
  • CDR-H3 Selection After characterization of CDR-H1 and CDR-H2 variants, clones with binding to HLA antigens outside of HLA-G were removed. Chemical liabilities were also removed from the variable regions when applicable. The remaining clones obtained from the CDR-H1 and CDR-H2 selection procedure were subject to additional rounds of affinity maturation via walking dimer mutagenesis of the CDR-H3. Selections were performed using HLA-G as antigen generally as described above, except for employing FACS sorting for all selection rounds.
  • CDR-L1, L2, L3 Selection Clones obtained from the CDR-H1 and CDR-H2 selection procedure were subject to additional rounds of affinity maturation via mutagenesis of the light chain.
  • the CDR-L1 and CDR-L2 diversity was derived from a pre-made library while CDR-L3 diversity was derived from walking monomer mutagenesis. Selections were performed using HLA-G as antigen, starting with one round of MACS followed by three rounds of FACS in the CDR-L1, L2, L3 process described here.
  • HLA-G/32m/peptide heterotrimer was loaded onto streptavidin (SA) biosensors to a binding response of approximately 0.25 nm.
  • SA streptavidin
  • the biosensors were exposed to varying concentrations (1.5, 3.0, or 30 nM) of full-length anti-HLA-G mAbs for the association step. Dissociation of the complex was monitored upon dipping the sensors to running buffer once again for up to 30 min. Data was processed using ForteBio Octet DataAnalysis software (version 10) with background subtraction of biosensors without HLA-G.
  • a 1: 1 Langmuir binding model was fit to each sensorgram to obtain association and dissociation rates via local-full or local- partial fitting.
  • KD was calculated from the ratio of kd to ka.
  • Monovalent affinities were obtained using identical methods but Fabs were used instead of IgGs.
  • the avid KD values ranged from 11.7 nanomolar to sub picomolar with off-rates (koff) ranging from 0.007 sec -1 to the Octet off-rate limit (1.0 x 10-7 sec -1 ).
  • Monovalent KD values ranged from 0.187 nM to 208 nM, but monovalent affinities for clones that had weaker avid affinities were not determined.
  • Example 8 Synthesis of Antibody-Drug Conjugates [0260] All TTX-080 and isotype control antibody-drug conjugates (ADC) were synthesized at NJ Bio (Princeton, New Jersey, USA). ADCs with linker-payloads (LP) CL2A-SN38, Deruxtecan, mc-vc-PAB-MMAE, and DGN549-C were synthesized via cysteine conjugation with the LPs. ADCs with LP vc-SECO-DUBA were synthesized via stochastic maleimide conjugation to interchain cysteines of TTX-080 and isotype control with vc-SECO-DUBA.
  • ADCs with linker-payloads (LP) CL2A-SN38, Deruxtecan, mc-vc-PAB-MMAE, and DGN549-C were synthesized via cysteine conjugation with the LPs.
  • TTX-080 and isotype control were reduced with tris(2-carboxyethyl) phosphine ⁇ (TCEP) for 1.5 h at 37 °C to expose the thiol groups of the interchain cysteine residues, and then conjugated with the specific LP for 2 h at room temperature.
  • TCEP tris(2-carboxyethyl) phosphine ⁇
  • ADCs were purified by size exclusion chromatography (SEC) to remove residual LP and to produce the target drug antibody ratio (DAR): CL2A-SN38 (DAR 5.4- 6.4), Deruxtecan (DAR 6.4-8.6), mc-vc-PAB-MMAE (DAR 3.3-3.9), DGN549C (DAR 1.7- 1.74), and vc-SECO-DUBA (DAR 2.5-3.5).
  • DAR was assessed by HIC, RP-LC/MS, RP-LC, and/or UV/Vis.
  • All ADCs have monomeric purity of ⁇ 95% by SEC and endotoxin of ⁇ 1 EU/mg by LAL assay, and are in 1X PBS, pH 6.5 or 7.4, concentrated, and flash frozen for storage at -80 ⁇ °C.
  • Table 4 shows the chemical structure of some of the antibody-drug conjugates synthesized.
  • Example 10 Anti-HLA-G Antibody Drug Conjugates Show In Vivo Efficacy in Multiple Patient-Derived Xenograft Models
  • nude mice were implanted with HLA-G expressing patient-derived xenograft (PDX) tumor fragments. Treatment of mice started when tumors reach an average tumor volume of 150-300mm3. Mice received 3 weekly IV doses of anti-HLA-G ADC or isotype ADC.
  • FIGS.8A-8B show anti-tumor activity of anti-HLA-G ADCs.
  • Tumor growth curves show reduced tumor growth in mice treated with anti-HLA-G ADCs compared to isotype treated mice in melanoma PDX CRT00465 (FIGS.8A) and pancreatic PDX CRT0000 (8B) tumor models.
  • PDX Patient-derived tumor models (PDX) with verified HLA-G expression were evaluated to further explore the activity of an HLA-G antibody conjugated to DGN549C in a more physiological model.
  • the in vivo cytotoxicity of the conjugate provided herein is measured by the tumor volume changing with the days after tumor implantation, compared with the respective isotypes. The results show that when the isotypes were used, the tumor volume continued to grow with time. In contrast, the DGN549C conjugate provided herein were able to effectively suppress the growth of the tumor in a melanoma and a pancreatic patient derived tumor.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cell Biology (AREA)
  • Oncology (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Provided herein are antibody-drug conjugates with antibodies specifically binding HLA-G and compositions comprising the conjugates, including pharmaceutical compositions and kits. Also provided are methods of using the conjugates for therapeutic purposes and methods of producing the conjugates. The conjugates provided herein also include payloads such as DGN549C, Monomethyl auristatin E, Deruxtecan, SN-38, vc-SECO-DUBA, Calicheamicin, SPDB-DM4, and Tesirine. The conjugates provided herein can be used for treatment of a subject suffering from cancer, a chronic infection, or from an inflammatory disease, or for modulating immune system function in a subject in need thereof.

Description

HLA-G ANTIBODIES IN ANTIBODY-DRUG CONJUGATES RELATED APPLICATIONS [0001] This application claims priority to U.S. provisional application number 63/536,635, filed September 5, 2023, which is incorporated by reference herein in its entirety. FIELD [0002] Provided herein are antibody-drug conjugates with antibodies specifically binding HLA-G and compositions comprising the conjugates, including pharmaceutical compositions and kits. Also provided are methods of using the conjugates for therapeutic purposes and methods of producing the conjugates. REFERENCE TO ELECTRONIC SEQUENCE LISTING [0003] The application contains a Sequence Listing which has been submitted electronically in .XML format and is hereby incorporated by reference in its entirety. Said .XML copy, created on September 4, 2024, is named “1107368.00127.xml” and is 427,933 bytes in size. The sequence listing contained in this .XML file is part of the specification and is hereby incorporated by reference herein in its entirety. BACKGROUND [0004] An antibody-drug conjugate (ADC) is a type of targeted cancer therapy that combines the specificity of antibodies with the potency of cytotoxic drugs. This approach aims to selectively deliver a toxic payload to cancer cells while sparing healthy tissues, thereby enhancing the therapeutic index and reducing adverse effects associated with conventional chemotherapy. [0005] Antibodies recognize specific antigens present on the surface of cancer cells. They are highly specific and can bind to these antigens with high affinity. Antibodies act as vehicles for delivering the cytotoxic payload to the cancer cells. [0006] The cytotoxic payload is a potent drug designed to kill cancer cells. These drugs are highly toxic and can damage the DNA or interfere with cellular processes, leading to cell death. However, the challenge with conventional chemotherapy is that these drugs also affect healthy cells, causing side effects. ADCs overcome this limitation by selectively delivering the cytotoxic payload to cancer cells. [0007] The antibody and the cytotoxic payload are connected by a linker molecule. The linker molecule should be mostly stable in circulation but capable of releasing the drug once the ADC is internalized by the cancer cell. There are different types of linkers, such as cleavable and non-cleavable linkers, which determine how and when the payload is released. [0008] When the ADC is administered to the patient, it circulates in the patient’s bloodstream. When it encounters cancer cells expressing the target antigen, the antibody component binds specifically to the antigen on the cell surface. This binding triggers internalization of the ADC-antigen complex through endocytosis. [0009] Once inside the cancer cell, the ADC-antigen complex is transported to lysosomes, cellular compartments involved in degradation. Within the lysosomes, the linker is cleaved, releasing the cytotoxic payload. [0010] The released cytotoxic drug exerts its potent effect on the cancer cell. Depending on the type of drug used, it may interfere with DNA replication, protein synthesis, or other essential cellular processes, ultimately leading to cell death. [0011] The success of an ADC depends on several factors, including the choice of antibody, the specificity and expression level of the target antigen, the design of the linker, and the cytotoxic payload selected. [0012] HLA-G histocompatibility antigen, class I, G, also known as human leukocyte antigen G (HLA-G), is a protein that in humans is encoded by the HLA-G gene. HLA-G belongs to the HLA nonclassical class I heavy chain paralogues. HLA-G is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). There are membrane bound and soluble forms of HLA-G. [0013] HLA-G is normally expressed at the maternal-fetal interface and other immune-privileged sites. HLA-G may play a role in immune tolerance in pregnancy, being expressed in the placenta by extravillous trophoblast cells, while the classical MHC class I genes (HLA-A and HLA-B) are not. As HLA-G was first identified in placenta samples, many studies have evaluated its role in pregnancy disorders, such as preeclampsia and recurrent pregnancy loss. See, Michita, Rafael Tomoyaet al., Human Immunology.2016, 77 (10): 892-897, which is incorporated by reference herein in its entirety, including any drawings. [0014] HLA-G has been shown to be immune-suppressive. By binding receptors expressed on various myeloid and lymphoid cells, HLA-G may directly inhibit the functions of NK cells, cytotoxic T-lymphocytes, B cells, neutrophils, monocytes, macrophages, and dendritic cells. HLA-G also inhibits T and NK cell proliferation and cytolytic activities. HLA-G suppresses phagocytosis and induces the generation or expansion of regulatory T cells. [0015] HLA-G mediates immune function through at least three ITIM-containing inhibitory receptors, ILT2, ILT4, and KIR2DL4. On lymphoid and myeloid cells, for example, HLA-G mediates function through ILT2. On myeloid cells, HLA-G mediates function through ILT4. On decidual NK cells, HLA-G mediates immune function through KIR2DL4 and ILT2. [0016] HLA-G is an immune checkpoint target. HLA-G can directly inhibit immune cell function through receptor binding and/or trogocytosis and impairment of chemotaxis. HLA-G can lend tumor cells a higher invasive and metastatic potential. HLA-G promotes evasion of tumor immune surveillance and enhances metastasis and the progression of malignancies. During tumor progression, HLA-G has other effects, such as inhibition of immune cell cytolysis, induction of immune cell apoptosis, and/or the generation of regulatory cells through receptor binding and/or trogocytosis. [0017] HLA-G expression is upregulated on a broad spectrum of tumors and is associated with poor prognosis and disease progression. Serum HLA-G levels are elevated in breast, lung, colorectal cancer (CRC), gastric, esophageal, neuroblastoma, cervical, and hematological cancers. HLA-G has also been found to be correlated with clinical parameters in advanced disease, such as tumor metastasis, poor prognosis, immune escape, and tumor invasiveness. [0018] HLA-G is an attractive target for diseases especially in the context of an ADC. SUMMARY [0019] The present invention is drawn to antibody-drug conjugates with antibodies specifically binding HLA-G and compositions comprising the conjugates, including pharmaceutical compositions. The conjugates provided herein also include payloads such as DGN549C, Monomethyl auristatin E, Deruxtecan, SN-38, vc-SECO-DUBA, Calicheamicin, SPDB-DM4, and Tesirine. The conjugates provided herein can be used for treatment of a subject suffering from cancer, a chronic infection, or from an inflammatory disease, or for modulating immune system function in a subject in need thereof. [0020] A first aspect provides a conjugate comprising, consisting essentially of, or consisting of (i) an antibody that binds specifically to a human HLA-G (hHLA-G) and (ii) a molecule coupled to the antibody. [0021] In some embodiments, the antibody has 1, 2, 3, 4, 5, 6, or 7 of the following characteristics: a) is a monoclonal antibody; b) is a human antibody, a humanized antibody, or a chimeric antibody; c) is a bispecific antibody, a multi-specific antibody, a diabody, or a multivalent antibody; d) is of the IgA, IgGl, IgG2, IgG3, IgG4, or IgM type; e) is an antigen-binding antibody fragment; f) is a Fab fragment, a Fab' fragment, a F(ab')2 fragment, or an Fv fragment; and/or g) is a single chain antibody, a single domain antibody, or a nanobody. [0022] In some embodiments, the molecule coupled to the antibody comprises one selected from the group consisting of a detectable label, a drug, a toxin, a cytokine, a radionuclide, an enzyme, and combinations thereof. [0023] In some embodiments, the molecule coupled to the antibody comprises a DNA- alkylating cytotoxic molecule or an antineoplastic agent. [0024] In some embodiments, the molecule coupled to the antibody comprises one selected from the group consisting of Formulas I-VIII:
Figure imgf000006_0001
Formula I: DGN549-C
E
in) ormua V : S - , and
Formula VIII: Tesirine [0025] In some embodiments, the antibody binds to a human HLA-G polypeptide or a variant thereof with a KD of less than about 20 nM. [0026] In some embodiments, the antibody comprises, consists essentailly of, or consists of a human heavy chain constant region or fragment or a variant thereof and/or a light chain constant region or fragment or variant thereof; and the constant region or fragment of variant thereof comprises, consists essentailly of, or consists of up to 20 conservatively modified amino acid substitutions from any sequence set forth SEQ ID NOS: 170-200 and/or SEQ ID NOS: 204-228. [0027] In some embodiments, the antibody comprises, consists essentially of, or consists of : an isolated antibody molecule capable of binding to human HLA-G (hHLA- G), comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH and/or VL comprising 1, 2, 3, 4, 5, or 6 of: a VHCDR1 having the sequence set forth in SEQ ID NOS: 1 -14 or SEQ ID NOS: 18- 34, a VHCDR2 having the sequence set forth in SEQ ID NOS: 38-50 or SEQ ID NOS: 54-71 , a VHCDR3 having the sequence set forth in SEQ ID NOS: 76-101, a VLCDR1 having the sequence set forth in SEQ ID NOS: 105-124, a VLCDR2 having the sequence set forth in SEQ ID NOS: 128-145, and a VLCDR3 having the sequence set forth in SEQ ID NOS: 149-166. [0028] In some embodiments, the antibody comprises, consists essentially of, or consists of : an isolated antibody molecule capable of binding to human HLA-G (hHLA-G), comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising: a) a VHCDR1 having a sequence set forth in SEQ ID NOS: 1-14 or SEQ ID NOS: 18- 34, b) a VHCDR2 having a sequence set forth in SEQ ID NOS: 38-50 or SEQ ID NOS: 54- 71 , and c) a VHCDR3 having a sequence set forth in SEQ ID NOS: 76-101; and the VL comprising: d) a VLCDR1 having a sequence set forth in SEQ ID NO: 105-124, e) a VLCDR2 having a sequence set forth in SEQ ID NO: 128-145, and f) a VLCDR3 having a sequence set forth in SEQ ID NO: 149-166. [0029] In some embodiments, the antibody comprises, consists essentially of, or consists of : an isolated antibody molecule capable of binding to human HLA-G (hHLA-G), and comprising a heavy chain variable region (VH) and/or a light chain variable region (VL), the VH comprising at least one sequence set forth in any of SEQ ID NOS: 170-200 and the VL comprising at least one sequence set forth in any of SEQ ID NOS: 204-228. [0030] In some embodiments, the antibody comprises, consists essentially of, or consists of : an isolated antibody molecule capable of binding to human HLA-G (hHLA-G), the isolated antibody molecule comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising 1, 2, or 3 of: a VHCDR1 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOS: 1-14 or 18-34, a VHCDR2 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOS: 54-71, and a VHCDR3 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOS: 76-101; and the VL comprising 1, 2, or 3 of: a VLCDR1 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOS: 105-124, a VLCDR2 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOS: 128-145, and a VLCDR3 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOs 149-166. [0031] In some embodiments, the antibody comprises, consists essentially of, or consists of: an isolated antibody molecule capable of binding to human HLA-G (hHLA-G), the isolated antibody molecule comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising 1, 2, or 3 of: a VHCDR1 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 1-14 or SEQ ID NOS: 18-34, a VHCDR2 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 38-50 or SEQ ID NOS: 54-71, and a VHCDR3 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 76-101; and the VL comprising 1, 2, or 3 of: a VLCDR1 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 105-124, a VLCDR2 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 128-145, and a VLCDR3 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 149-166. [0032] In some embodiments, the antibody comprises, consists essentially of, or consists of : an isolated antibody molecule capable of binding to human HLA-G (hHLA-G), the isolated antibody molecule comprising a heavy chain and a light chain, the heavy chain comprising one or more molecules having a sequence consisting of one of SEQ ID NOS: 232-262 or SEQ ID NOS: 266-296, and the light chain comprising one or more molecules having a sequence consisting of one of SEQ ID NOS: 300-330. [0033] In some embodiments, the antibody comprises, consists essentially of, or consists of : an isolated antibody molecule capable of binding to human HLA-G (HLA-G), the isolated antibody molecule comprising a heavy chain and a light chain and being selected from the group consisting of: the heavy chain comprising one or more molecules each having a sequence consisting of SEQ ID NO: 232 and the light chain comprising one or more molecules each having a sequence consisting of SEQ ID NO: 300; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 233 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 301 ; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 234 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 302; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 235 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 303; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 236 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 304; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 237 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 305; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 238 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 306; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 239 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 307; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 240 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 308; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 241 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 309; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 242 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 310; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 243 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 311 ; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 244 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 312; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 245 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 313; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 246 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 314; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 247 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 315; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 248 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 316; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 249 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 317; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 250 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 318; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 251 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 319; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 252 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 320; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 253 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 321 ; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 254 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 322; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 255 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 323; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 256 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 324; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 257 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 325; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 258 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 326; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 259 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 327; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 260 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 328; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 261 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 329; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 262 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 330; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 266 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 300; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 267 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 301; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 268 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 302; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 269 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 303; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 270 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 304; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 271 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 305; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 272 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 306; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 273 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 307; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 274 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 308; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 275 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 309; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 276 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 310; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 277 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 311; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 278 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 312; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 279 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 313; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 280 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 314; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 281 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 315; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 282 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 316; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 283 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 317; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 284 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 318; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 285 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 319; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 286 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 320; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 287 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 321; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 288 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 322; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 289 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 323; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 290 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 324; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 291 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 325; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 292 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 326; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 293 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 327; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 294 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 328; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 295 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 329; and the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 296 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 330. [0034] In some embodiments, the antibody comprises, consists essentially of, or consists of : an isolated antibody molecule capable of binding to human HLA-G (hHLA-G), the isolated antibody molecule comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH and/or VL comprising 1, 2, 3, 4, 5, or 6 of: a) a VHCDR1 sequence comprising: a Kabat CDR-H1 sequence defined by the consensus sequence S-S-Δ3-Δ4-Y-W-Δ7 (SEQ ID NOS: 18-21, 23, and 34), where Δ3 is D or S; Δ4 is T or Y; and Δ7 is A, G, or S; a Kabat CDR-H1 sequence defined by the consensus sequence S-G-θ3-Y- W-θ6 (SEQ ID NOS: 24-29), where θ3 is F, H, or Y; and θ6 is F, G, I, L, or T; a Chothia CDR-H1 sequence defined by the consensus sequence G-G-S- -S-S-Ω7- Ω8- Ω9 (SEQ ID NOS: 1-4 and 13-14), where Ω 7 is S or A; Ω8 is D, S, or N; and Ω9 is T, N, Y, or is absent; or a Chothia CDR-H1 sequence defined by the consensus sequence G-F-T-F-κ5-κ6-κ7 (SEQ ID NOS: 10-12), where κ5 is D or s; κ6 is D, N, or S; and κ7 is S or Y, b) a VHCDR2 sequence comprising: a Kabat CDR-H2 sequence defined by the consensus sequence β1-I-β3- β4-β5-β6-β7-T-β9-Y-N- P-S-L-K-S (SEQ ID NOS: 54-65 and 69-70) where β1 is A, E, G, or S; β3 is A, H, S, or Y; β4 is H, S, or Y; β5 is N or S; β6 is A or G; β7 is A, L, or S; and β9 is A, N, L, V, or Y; a Chothia CDR-H2 sequence defined by the consensus sequence U-ε2- S-ε4-S (SEQ ID NOS: 38 and 44-45), where ε2 is H or Y and ε4 is A or G; a Chothia CDR-H2 sequence defined by the consensus sequence α1-α2-S-G-S (SEQ ID NOS: 39, 41-42, and 49), where α1 is A, H, or S; and α2 is S or Y; or a Chothia CDR-H2 sequence defined by the consensus sequence β1- β2- S-G- β5- β6 (SEQ ID NOS: 56-60), where β1 is A or S; β2 is G or S; β5 is I or S; and β6 is T or V, c) a VHCDR3 sequence comprising: a CDR-H3 sequence defined by the consensus sequence G-Υ2-Y3-R-A-V-P-F-Y9-Y10 (SEQ ID NOS: 76-84), where Y2 is I, P, Q, T, or V; Y3 is A, F, K, or R; Y9 is A, D, Q, or V; Y10 is D, R, or Y; or a CDR-H3 sequence defined by the consensus sequence G-G-Φ3-Φ4-Φ5-Y-S-R-G-P-Φ11-D-V (SEQ ID NOS: 85-93), where Φ3 is E, G, Q, or T; Φ4 is A, H, P, Q, or V; Φ5 is K or T; and Φ11 is F, L, or M, d) a VLCDR1 sequence comprising: a CDR-L1 sequence defined by the consensus sequence Φ1-A-S-Q-Φ5- V-S-S-Φ9-Φ10-L-A (SEQ ID NOS: 105-112 and 117), where Φ1 is E, G, K, Q, or R; Φ5 is A or S; Φ9 is A, D, N, S, or T; and Φ10 is F or Y; a CDR-L1 sequence defined by the consensus sequence R-A-S-Q-S-σ6-σ7-S-σ9-L-σ11 (SEQ ID NOS: 119 and 123-124), where σ6 is I or V; σ7 is N or S; σ9 is N, W, or Y; σ11 is A or N; or a CDR-L1 sequence defined by the consensus sequence Γ1-Γ2-S-Q-S-V-S-Γ8-Γ9-Y-L-A (SEQ ID NOS: 113-116), where Γ1 is E or R; Γ2 is A or V; Γ8 is A, D, or S; and Γ9 is A or S, e) a VLCDR2 sequence comprising: a CDR-L2 sequence defined by the consensus sequence ψ1-A-S-ψ4-R-A-ψ7 (SEQ ID NOS: 128, 130, 132, 134-138, 143, and 145), where ψ1 is D or G; ψ4 is A, D, N, R, S, T, or Y; and ψ7 is A, N, S, or T, and a VLCDR3 sequence comprising: a CDR-L3 sequence defined by the consensus sequence Q-π2-π3-π4-H-S-P-Y-T (SEQ ID NOS: 149-153), where π2 is Q or W; π3 is A, T, or V; and π4 is I or V; a CDR-L3 sequence defined by the consensus sequence Q-Q-λ3-S-λ5-Y-P-P-T (SEQ ID NOS: 154-158), where λ3 is F, H, or V; and λ5 is I, L, or S; or a CDR-L3 sequence defined by the consensus sequence Q-Q-ω3-ω4-ω5-ω6-P-I-T (SEQ ID NOS: 160-161 and 163-164), where ω3 is A, L, V, or Y; ω4 is G, P, V, or Y; ω5 is S, L, or F; and ω6 is D, L, S, or Y. [0035] A second aspect provides a pharmaceutical composition comprising, consisting essentailly of, or consisting of an effective amount of any of the conjugates provided herein; and a pharmaceutically acceptable diluent, carrier or excipient. [0036] In some embodiments, the pharmaceutical composition provided herein further comprises an effective amount of at least one of the following: a) an anti-ILT2 antibody; b) an anti-ILT3 antibody; c) an anti-ILT4 antibody; d) an anti-KIR2DL4 antibody; e) an anti-HLA-E antibody; f) an anti-NKG2A antibody; g) an anti-HLA-F antibody h) an anti-HLA-J antibody; i) an anti-PD-L1 antibody; j) an anti-PD-1 antibody; k) an anti-CD38 antibody; l) an anti-CD39 antibody; m) an anti-CD73 antibody; n) an anti-A2A receptor antibody; o) an anti-A2B receptor antibody; p) an anti-A2A/A2B dual receptor antibody or a combination thereof; q) an anti-CD47 antibody; r) a small molecule inhibitor; s) a bi-specific T cell engager and/or CAR-T therapy and or CAR-NK therapy, CAR- Macrophage therapy t) an oncolytic virus; u) a chemotherapy; v) ADCC capable therapies using an effector competent antibody selected from the group consisting of anti-CDl9, anti-CD20, anti-EGFR, anti-Her2, anti-SLAMF7, anti-CD52, anti-BCMA, anti-GD2, anti-CCR4, anti-CTLA4, and mixtures thereof. In some embodiments, any of the pharmaceutical compositions provided herein further comprises at least one of a) an antibody to an immune inhibitory receptor or ligand and/or b) an antibody to an immune stimulatory receptor or ligand. [0037] A third aspect provides a method for treatment of a subject suffering from cancer, a chronic infection, and/or from an inflammatory disease, the method comprising, consisting essentially of, or consisting of administering to the subject a pharmaceutical composition comprising an effective amount of the conjugate of any aspect and/or any embodiment described herein or the pharmaceutical composition of any aspect and/or any embodiment described herein. [0038] In some embodiments, the cancer is a solid cancer or a hematological cancer. [0039] In some embodiments, the subject is a human subject. [0040] In some embodiments, the method further comprises one or more of the following: a) administering chemotherapy; b) administering radiation therapy; and/or c) administering one or more additional therapeutic agents. [0041] In some embodiments, the one or more additional therapeutic agents comprise, consist essentially of, or consist of one or more immunostimulatory agents. [0042] In some embodiments, wherein the one or more immunostimulatory agents comprise, consist essentially of, or consist of an antagonist to an inhibitory receptor of an immune cell. [0043] In some embodiments, the inhibitory receptor is one of or is selected from the group consisting of ILT2, ILT3, ILT4, KIR2DL4, CTLA-4, PD-l , CD39, CD73, PD-L1, PD-L2, LAG-3, Tim3, TIGIT, B7-H3, B7-H4, neuritin, BTLA, CECAM-l , CECAM-5, VISTA, LAIR1, CD160, 2B4,TGF-B (including traps and GARP), NKG2A, a Killer-cell immunoglobulin-like receptor (KIR), and combinations thereof. [0044] In some embodiments, the one or more immunostimulatory agents comprise, consist essentially of, or consist of an agonist of a co-stimulatory receptor of an immune cell. [0045] In some embodiments, the co-stimulatory receptor is at least one of OX40, CD2, CD27, ICAM-l, LFA-l , ICOS (CD278), 4-1BB (CD 137), GITR, CD28, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp30, NKp46, NKp80, CD160, and/or a CD83 ligand. [0046] In some embodiments, the one or more immunostimulatory agents comprise, consist essentially of, or consist of an ADCC competent antibody selected from the group consisting of an anti-CD19, anti-CD20, anti-EGFR, anti-Her2, anti-SLAMF7, anti-CD52, anti-BCMA, anti-GD2, anti-CD38, anti-CCR4, anti-CTLA4, antibody, and combinations thereof. [0047] In some embodiments, the one or more immunostimulatory agents comprise, consist essentially of, or consist of a cytokine. [0048] In some embodiments, the cytokine is selected from the group consisting of IL-l, IL-2, IL-5, IL-7, IL-10, IL-l 2, IL-l5, IL-18, IL-21, IL-27, and combinations thereof. [0049] In some embodiments, the one or more immunostimulatory agents comprise, consist essentially of, or consist of an oncolytic virus. [0050] In some embodiments, the oncolytic virus is selected from the group consisting of a Herpes simplex virus, a Vesicular stomatitis virus, an adenovirus, a Newcastle disease virus, a vaccinia virus, and a maraba virus. In some embodiments, the oncolytic virus is a synthetic oncolytic virus. [0051] In some embodiments, the one or more immunostimulatory agents comprise, consist essentially of, or consist of a chimeric antigen receptor engineered T cell (CAR T cell). The antigen-binding domain of the CAR T cell recognizes specific cancer cell surface antigens, allowing the CAR T cell to target cancer cells with precision. This recognition leads to the activation and killing of cancer cells by the CAR T cell. [0052] In some embodiments, the one or more immunostimulatory agents comprise, consist essentially of, or consist of a natural killer cell. In some embodiments, the one or more immunostimulatory agents comprise, consist essentially of, or consist of a myeloid cell. [0053] In some embodiments, the one or more immunostimulatory agents comprise, consist essentially of, or consist of a bi- or multi-specific T cell directed antibody. The specificity of the bi- or multi-specific T cell directed antibody allows them to target cancer cells while minimizing the impact on healthy cells, potentially reducing side effects. Bi- or multi-specific antibodies can be used in combination with other immunotherapies, chemotherapy, and targeted therapies to enhance the overall anti-cancer effect. [0054] A fourth aspect provides a method for modulating immune system function in a subject in need thereof, the method comprising, consisting essentially of, or consisting of contacting a population of immune cells of the subject with any of the pharmaceutical compositions provided herein comprising an effective amount of any of the conjugates provided herein, under conditions such that the immune system is modulated. [0055] A fifth aspect provides a method for producing the conjugate of any aspect and/or any embodiment described herein, the method comprising conjugating the molecule to the antibody using an amino or sulfhydryl specific linker attached to the molecule that react with lysines or cysteines on the antibody surface. [0056] In some embodiments, the method comprises treating the antibody to create a conjugation site on the antibody surface and reacting the conjugation site with the amino or sulfhydryl specific linker attached to the molecule. BRIEF DESCRIPTION OF THE DRAWINGS [0057] FIGS.1A-1R show the cytotoxicity of multiple free payloads for HLA-G expressing cells. [0058] FIGS.2A-2K provide data showing target mediated killing by anti-HLA-G ADC (“α-HLA-G”) compared to isotype conjugated ADC. [0059] FIGS.3A-3F show the internalization of HLA-G specific antibodies on cells expressing HLA-G. [0060] FIGS.4A-4E show data on tumor growth inhibition with anti-HLA-G antibody (“α-HLA-G”) conjugated to different payloads compared to isotype control antibody (“Iso”) conjugated to payloads in JEG3 (FIGS.4A-4C) and A549 (FIGS.4D-4E) cells expressing HLA-G. [0061] FIG.5 shows data on in vivo antibody detection with anti-HLA-G antibody (“α-HLA-G”) conjugated to DGN549C compared to isotype control antibody (“Iso”) conjugated to DGN549C after 7 days. [0062] FIGS.6A-6F show data on tumor growth inhibition with anti-HLA-G antibody (“α-HLA-G”) conjugated to DGN549C compared to isotype control antibody (“Iso”) conjugated to DGN549C in admixture JEG3 (FIGS.6A-6C, 6F) and A549 (FIGS. 6D-6E) cells expressing 10-100% HLA-G. [0063] FIGS.7A-7D show data on tumor growth inhibition with anti-HLA-G antibody (“α-HLA-G”) conjugated to DGN549C compared to isotype control antibody (“Iso”) conjugated to DGN549C in admixture TOV-112D cells expressing 20-100% HLA-G. [0064] FIGS.8A and 8B show data on tumor growth inhibition with anti-HLA-G antibody (“α-HLA-G”) conjugated to DGN549C compared to isotype control antibody (“Iso”) conjugated to DGN549C in a melanoma PDX CRT00465 and pancreatic PDX CRT00400. DETAILED DESCRIPTION 1. Definitions [0065] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this disclosure pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art, such as, for example, the widely utilized molecular cloning methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 2nd ed. (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer defined protocols and/or parameters unless otherwise noted. [0066] As used herein, the singular form of a word includes the plural, unless the context clearly dictates otherwise. Thus, the references "a," "an" and "the" are generally inclusive of the plurals of the respective terms. For example, reference to "an ingredient" or "a method" includes a plurality of such "ingredients" or "methods." [0067] The term “about” indicates and encompasses an indicated value and a range above and below that value. As used herein, "about," "approximately" and "substantially" are understood to refer to numbers in a range of numerals, for example the range of -10% to +10% of the referenced number, preferably -5% to +5% of the referenced number, more preferably -1% to +1% of the referenced number, most preferably -0.1% to +0.1% of the referenced number. In certain embodiments, the term “about” indicates the designated value ± 10%, ± 5%, or ± 1%. In certain embodiments, the term “about” indicates the designated value ± one standard deviation of that value. [0068] Furthermore, all numerical ranges herein should be understood to include all integers, whole or fractions, within the range. Moreover, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range. For example, a disclosure of from 1 to 10 should be construed as supporting a range of from 1 to 8, from 3 to 7, from 1 to 9, from 3.6 to 4.6, from 3.5 to 9.9, and so forth. [0069] The words "comprise," "comprises," and "comprising" are to be interpreted inclusively rather than exclusively. Likewise, the terms "include," "including" and "or" should all be construed to be inclusive, unless such a construction is clearly prohibited from the context. However, the embodiments provided by the present disclosure may lack any element that is not specifically disclosed herein. Thus, a disclosure of an embodiment defined using the term "comprising" is also a disclosure of embodiments "consisting essentially of” and "consisting of” the disclosed components. The phrase "consisting essentially of” limits the scope of the disclosed components to the specified materials or steps and those that do not materially affect the basic and novel characteristics of the disclosed invention. The phrase "consisting of” excludes any element, step, or ingredient not specified. [0070] As used herein, the term "example," particularly when followed by a listing of terms, is merely exemplary and illustrative, and should not be deemed to be exclusive or comprehensive. Any embodiment disclosed herein can be combined with any other embodiment disclosed herein unless explicitly indicated otherwise. [0071] The term “combinations thereof” includes every possible combination of elements to which the term refers. [0072] The term "and/or" used in the context of "X and/or Y" should be interpreted as "X," or “Y,” or "X and Y." [0073] As used herein, a “conjugate” refers to an “antibody-drug conjugate (ADC),” formed by chemically linking an antibody, a cytotoxic drug, and a linker molecule. This creates a single molecule that can selectively deliver the drug to target cells. [0074] As used herein, “couple,” “coupled,” or “coupling” means two or more entities or elements are connected or joined together. Coupling reactions involve the combination of two molecules to form a larger molecule. [0075] The term “immunoglobulin” refers to a class of structurally related proteins generally comprising two pairs of polypeptide chains: one pair of light (L) chains and one pair of heavy (H) chains. In an “intact immunoglobulin,” all four of these chains are interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, e.g., Paul, Fundamental Immunology 7th ed., Ch.5 (2013) Lippincott Williams & Wilkins, Philadelphia, PA. Briefly, each heavy chain typically comprises a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region typically comprises three domains, CHI, CH2, and CH3. Each light chain typically comprises a light chain variable region (VL) and a light chain constant region. The light chain constant region typically comprises one domain, abbreviated CL. [0076] The term “antibody” describes a type of immunoglobulin molecule and is used herein in its broadest sense. An antibody specifically includes intact antibodies (e.g., intact immunoglobulins) and antibody fragments and antigen binding proteins. Antibodies comprise at least one antigen-binding domain. One example of an antigen-binding domain is an antigen binding domain formed by a VH –VL dimer. An “HLA-G antibody,” “anti-HLA-G antibody,” “HLA-G Ab,” “HLA-G-specific antibody,” or “anti-HLA-G Ab” is an antibody, as described herein, which binds specifically to the antigen HLA-G. [0077] The VH and VL regions may be further subdivided into regions of hypervariability (“hypervariable regions (HVRs);” also called “complementarity determining regions” (CDRs)) interspersed with regions that are more conserved. The more conserved regions are called framework regions (FRs). Each VH and VL generally comprises three CDRs and four FRs, arranged in the following order (from N-terminus to C-terminus): FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4. The CDRs are involved in antigen binding, and confer antigen specificity and binding affinity to the antibody. See Kabat et al., Sequences of Proteins of Immunological Interest 5th ed. (1991) Public Health Service, National Institutes of Health, Bethesda, MD, incorporated by reference in its entirety. [0078] The light chain from any vertebrate species can be assigned to one of two types, called kappa and lambda, based on the sequence of the constant domain. [0079] The heavy chain from any vertebrate species can be assigned to one of five different classes (or isotypes): IgA, IgD, IgE, IgG, and IgM. These classes are also designated α, δ, ε, γ, and μ, respectively. The IgG and IgA classes are further divided into subclasses on the basis of differences in sequence and function. Humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgAl, and IgA2. [0080] The amino acid sequence boundaries of a CDR can be determined by one of skill in the art using any of a number of known numbering schemes, including those described by Kabat et al., supra (“Kabat” numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-948 (“Chothia” numbering scheme); MacCallum et al., 1996, J. Mol. Biol.262:732-745 (“Contact” numbering scheme); Lefranc et al., Dev. Comp. Immunol., 2003, 27:55-77 (“IMGT” numbering scheme); and Honegge and Plückthun, J. Mol. Biol., 2001, 309:657-70 (“AHo” numbering scheme), each of which is incorporated by reference in its entirety. [0081] Table 1 provides the positions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 as identified by the Kabat and Chothia schemes. For CDR-H1, residue numbering is provided using both the Kabat and Chothia numbering schemes. [0082] Unless otherwise specified, the numbering scheme used for identification of a particular CDR herein is the Kabat/Chothia numbering scheme. Where the residues encompassed by these two numbering schemes diverge, the numbering scheme is specified as either Kabat or Chothia. [0083] Table 1. Residues in CDRs according to Kabat and Chothia numbering schemes. CDR Kabat Chothia L1 L24-L34 L24-L34 L2 L50-L56 L50-L56 L3 L89-L97 L89-L97 H1 (Kabat Numbering) H31-H35B H26-H32 or H34* H1 (Chothia Numbering) H31-H35 H26-H32 H2 H50-H65 H52-H56 H3 H95-H102 H95-H102 • The C-terminus of CDR-H1, when numbered using the Kabat numbering convention, varies between H32 and H34, depending on the length of the CDR. [0084] The “EU numbering scheme” is generally used when referring to a residue in an antibody heavy chain constant region (e.g., as reported in Kabat et al., supra). Unless stated otherwise, the EU numbering scheme is used to refer to residues in antibody heavy chain constant regions described herein. [0085] An “antibody fragment” comprises a portion of an intact antibody, such as the antigen binding or variable region of an intact antibody. Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab′)2 fragments, Fab′ fragments, scFv (sFv) fragments, and scFv-Fc fragments. [0086] “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain. [0087] “Fab” fragments comprise, in addition to the heavy and light chain variable domains, the constant domain of the light chain and the first constant domain (CHI) of the heavy chain. Fab fragments may be generated, for example, by papain digestion of a full- length antibody. [0088] “F(ab′)2” fragments contain two Fab′ fragments joined, near the hinge region, by disulfide bonds. F(ab′)2 fragments may be generated, for example, by pepsin digestion of an intact antibody. The F(ab′) fragments can be dissociated, for example, by treatment with ß-mercaptoethanol. [0089] “Single-chain Fv” or “sFv” or “scFv” antibody fragments comprise a VH domain and a VL domain in a single polypeptide chain. The VH and VL are generally linked by a peptide linker. See Plückthun A. (1994). Antibodies from Escherichia coli. In Rosenberg M. & Moore G.P. (Eds.), The Pharmacology of Monoclonal Antibodies vol.113 (pp.269- 315). Springer-Verlag, New York, incorporated by reference in its entirety. “scFv-Fc” fragments comprise an scFv attached to an Fc domain. For example, an Fc domain may be attached to the C-terminal of the scFv. The Fc domain may follow the VH or VL, depending on the orientation of the variable domains in the scFv (i.e., VH-VL or VL-VH). Any suitable Fc domain known in the art or described herein may be used. [0090] The term “monoclonal antibody” refers to an antibody from a population of substantially homogeneous antibodies. A population of substantially homogeneous antibodies comprises antibodies that are substantially similar and that bind the same epitope(s), except for variants that may normally arise during production of the monoclonal antibody. Such variants are generally present in only minor amounts. A monoclonal antibody is typically obtained by a process that includes the selection of a single antibody from a plurality of antibodies. For example, the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibody can be further altered, for example, to improve affinity for the target (“affinity maturation”), to humanize the antibody, to improve its production in cell culture, and/or to reduce its immunogenicity in a subject. [0091] The term “chimeric antibody” refers to an antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species. [0092] “Humanized” forms of non-human antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody. A humanized antibody is generally a human immunoglobulin (recipient antibody) in which residues from one or more CDRs are replaced by residues from one or more CDRs of a non-human antibody (donor antibody). The donor antibody can be any suitable non-human antibody, such as a mouse, rat, rabbit, chicken, or non-human primate antibody having a desired specificity, affinity, or biological effect. In some instances, selected framework region residues of the recipient antibody are replaced by the corresponding framework region residues from the donor antibody. Humanized antibodies may also comprise residues that are not found in either the recipient antibody or the donor antibody. Such modifications may be made to further refine antibody function. For further details, see Jones et al., Nature, 1986, 321:522-525; Riechmann et al., Nature, 1988, 332:323-329; and Presta, Curr. Op. Struct. Biol., 1992, 2:593-596, each of which is incorporated by reference in its entirety. [0093] A “human antibody” is one which possesses an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody-encoding sequences (e.g., obtained from human sources or designed de novo). Human antibodies specifically exclude humanized antibodies. [0094] An “isolated antibody” is one that has been separated and/or recovered from a component of its natural environment. Components of the natural environment may include enzymes, hormones, and other proteinaceous or nonproteinaceous materials. In some embodiments, an isolated antibody is purified to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence, for example by use of a spinning cup sequenator. In some embodiments, an isolated antibody is purified to homogeneity by gel electrophoresis (e.g., SDS-PAGE) under reducing or nonreducing conditions, with detection by Coomassie blue or silver stain. An isolated antibody includes an antibody in situ within recombinant cells, since at least one component of the antibody’s natural environment is not present. In some aspects, an isolated antibody is prepared by at least one purification step. [0095] In some embodiments, an isolated antibody is purified to at least 80%, 85%, 90%, 95%, or 99% by weight. In some embodiments, an isolated antibody is provided as a solution comprising at least 85%, 90%, 95%, 98%, 99% to 100% by weight of an antibody, the remainder of the weight comprising the weight of other solutes dissolved in the solvent. [0096] A “bispecific antibody” simultaneously target two different antigens or molecules. A bispecific antibody typically consists of two different antigen-binding regions, each with specificity for a distinct target. These regions can be derived from two different mAbs, and they are engineered to bind to specific molecules, such as antigens on the surface of cancer cells or immune cells. [0097] A “multi-specific antibody” has the ability to simultaneously bind to and interact with multiple antigens or molecules. Similar to bispecific antibodies, multi-specific antibodies target more than two different molecules or epitopes. [0098] A “diabody” is a type of engineered antibody fragment that consists of two antibody variable domains (one heavy chain and one light chain) connected by a short linker. It has a compact structure and retains the ability to bind to a specific antigen, but it lacks the constant domains present in full-length antibodies. A diabody is composed of two single- chain variable fragments (scFv), each containing the variable regions of both heavy and light antibody chains. These scFvs are connected by a short peptide linker that allows the two variable domains to associate and form the diabody structure. Diabodies are much smaller than full-length antibodies and lack the Fc region responsible for effector functions like antibody-dependent cellular cytotoxicity (ADCC) and complement activation. Despite their size, diabodies are bivalent, meaning they can bind to two identical or different antigen molecules simultaneously due to the presence of two binding sites. They can be designed to target specific antigens on cancer cells or other disease-related molecules. [0099] A “multivalent antibody” is an antibody that possesses multiple antigen- binding sites or paratopes. These antibodies are capable of simultaneously binding to multiple copies of the same antigen or to different antigens. The “valency” of an antibody refers to the number of antigen-binding sites it has. Standard, full-length antibodies found in the immune system typically have two antigen-binding sites, one on each of the two arms of the Y-shaped molecule. Multivalent antibodies can be engineered to have three or four antigen-binding sites, respectively, by fusing multiple antibody fragments or domains together. [0100] A “single domain antibody (sdAb),” also known as a “nanobody” or “VHH antibody,” is a small antibody fragment consisting of a single, independently folded domain that retains antigen-binding properties. This variable domain contains complementarity- determining regions (CDRs) responsible for antigen binding. Their smaller size and simpler structure make sdAbs more stable and less prone to aggregation than traditional antibodies. Single domain antibodies are derived from heavy-chain-only antibodies found in camelids (llamas, camels, and alpacas) and cartilaginous fish. sdAbs are around one-tenth the size of traditional antibodies, making them suitable for accessing and binding to unique epitopes, including those that might be challenging for larger antibodies. [0101] “Affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). 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 molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including those described herein. Affinity can be determined, for example, using surface plasmon resonance (SPR) technology, such as a Biacore® instrument, or using bio-layer interferometry technology, such as an Octet® instrument. [0102] With regard to the binding of an antibody to a target molecule, the terms “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule. Specific binding can also be determined by competition with a control molecule that is similar to the target, such as an excess of non-labeled target. In that case, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by the excess non-labeled target. [0103] The term “kd” (sec-1), as used herein, refers to the dissociation rate constant of a particular antibody-antigen interaction. This value is also referred to as the koff value. [0104] The term “ka” (M-1 xsec-1), as used herein, refers to the association rate constant of a particular antibody-antigen interaction. This value is also referred to as the kon value. [0105] The term “KD” (M), as used herein, refers to the dissociation equilibrium constant of a particular antibody-antigen interaction. KD = kd/ka. [0106] The term “KA” (M-1), as used herein, refers to the association equilibrium constant of a particular antibody-antigen interaction. KA = ka/kd. [0107] The term “epitope” means a portion of an antigen capable of specific binding to an antibody. Epitopes frequently consist of surface-accessible amino acid residues and/or sugar side chains and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents. An epitope may comprise amino acid residues that are directly involved in the binding, and other amino acid residues, which are not directly involved in the binding. The epitope to which an antibody binds can be determined using known techniques for epitope determination such as, for example, testing for antibody binding to HLA-G variants with different point-mutations. [0108] Percent “identity” between a polypeptide sequence and a reference sequence (and the related word “identical”), is defined as the percentage of amino acid residues in the polypeptide sequence that are identical to the amino acid residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, or CLUSTAL OMEGA software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. [0109] A “conservative substitution” or a “conservative amino acid substitution,” refers to the substitution of one or more amino acids with one or more chemically or functionally similar amino acids. Conservative substitution tables providing similar amino acids are well known in the art. Polypeptide sequences having such substitutions are known as “conservatively modified variants.” By way of example, the following groups of amino acids are considered conservative substitutions for one another. Acidic Residues D and E Basic Residues K, R, and H Hydrophilic Uncharged Residues S, T, N, and Q Aliphatic Uncharged Residues G, A, V, L, and I Non polar Uncharged Residues C, M, and P Aromatic Residues F, Y, and W Alcohol Group-Containing Residues S and T Aliphatic Residues I, L, V, and M Cycloalkenyl-associated Residues F, H, W, and Y Hydrophobic Residues A, C, F, G, H, I, L, M, V, W, and Y Negatively Charged Residues D and E Polar Residues C, D, E, H, K, N, Q, R, S, and T Positively Charged Residues H, K, and R Small Residues A, C, D, G, N, P, S, T, and V Very Small Residues A, G, and S Residues Involved in Turn Formation A, C, D, E, G, H, K, N, Q, R, S, P, and T Flexible Residues Q, T, K, S, G, P, D, E, and R Group 1 A, S, and T Group 2 D and E Group 3 N and Q Group 4 R and K Group 5 I, L, and M Group 6 F, Y, and W Group A A and G Group B D and E Group C N and Q Group D R, K, and H Group E I, L, M, V Group F F, Y, and W Group G S and T Group H C and M [0110] Additional conservative substitutions may be found, for example, in Creighton, Proteins: Structures and Molecular Properties 2nd ed. (1993) W. H. Freeman & Co., New York, NY. An antibody generated by making one or more conservative substitutions of amino acid residues in a parent antibody is referred to as a “conservatively modified variant.” [0111] The term “amino acid” refers to the twenty common naturally occurring amino acids. Naturally occurring amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C); glutamic acid (Glu; E), glutamine (Gln; Q), Glycine (Gly; G); histidine (His; H), isoleucine (Ile; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V). [0112] As used herein, a "warhead" refers to the active component of the ADCs or conjugates provided herein that produces the desired outcome, such as killing cancer cells, inhibiting a disease pathway, or blocking the activity of a specific protein. In the ADCs or conjugates provided herein, the toxic drug payload linked to the antibody is the warhead. [0113] A “detectable label” refers to a molecule or substance that is attached to a target molecule (such as a biomolecule or cell) to enable its easy visualization, quantification, or detection. Detectable labels are used to tag or mark a target molecule, especially molecules that are not directly visible or detectable, such as proteins, nucleic acids, and cells, enabling its detection in assays, experiments, or clinical settings. [0114] A “cytokine” is a small protein or signaling molecule that plays a crucial role in cell communication and immune responses. They are produced by various cells, especially immune cells, and are involved in coordinating the body's defense mechanisms, inflammation, and cellular interactions. Cytokines act as messengers, transmitting signals between cells to regulate various physiological and immune processes. They regulate immune responses, inflammation, cell growth, differentiation, and tissue repair. [0115] A “radionuclide,” also known as a radioactive nuclide or radioisotope, is an atom that has an unstable nucleus and undergoes radioactive decay, emitting radiation in the process. This radiation emission can include alpha particles, beta particles, gamma rays, or other particles, depending on the type of radioactive decay occurring within the nucleus. “Enzymes” are biological molecules, typically proteins, which act as catalysts to facilitate and accelerate chemical reactions in living organisms. Enzymes lower the activation energy required for reactions to occur, thereby increasing the rate of these reactions. Enzymes are essential for metabolism, growth, and various cellular functions and play a critical role in various biochemical processes, including digestion, energy production, DNA replication, and cellular signaling. [0116] A “DNA-alkylating cytotoxic molecule” is a type of chemical compound that attaches alkyl groups to the DNA molecules in cells, disrupting the normal functioning of DNA and leading to cell death. These molecules form covalent bonds with DNA bases by attaching alkyl groups to the nitrogen or oxygen atoms of DNA bases, primarily guanine. This alters the DNA's structure and prevents the strands from pairing correctly during replication and transcription, causing structural damage and interfering with DNA replication and transcription. [0117] An “antineoplastic agent,” also known as an anticancer or chemotherapy drug, is a type of medication used to treat cancer by inhibiting the growth and spread of cancerous cells. Some inhibit DNA replication and cell division, while others target signaling pathways essential for cancer cell survival. [0118] The term "pharmaceutically acceptable" describes substances, formulations, or components that meet the necessary criteria for safety, quality, and suitability for use in pharmaceutical products. These substances are deemed suitable for inclusion in drug products intended for human consumption and have a minimal risk of causing harm or adverse effects, based on established standards and guidelines set by regulatory authorities. They are also free from impurities, contaminants, and substances that might compromise the quality and safety of the final pharmaceutical product. Pharmaceutically acceptable substances, including active pharmaceutical ingredients (APIs), excipients, solvents, and other components, must meet established quality standards, such as those outlined in pharmacopeias (e.g., United States Pharmacopeia, European Pharmacopoeia). Components that are pharmaceutically acceptable are compatible with each other and maintain stability over the intended shelf life of the pharmaceutical product. They do not interact in ways that would compromise the safety or efficacy of the product. Different routes of administration (oral, injectable, topical, etc.) may have specific requirements for substances to be considered pharmaceutically acceptable for that route. Substances must meet the relevant regulatory and quality standards for the intended route of administration. [0119] A pharmaceutically acceptable diluent is a substance used to dilute or reduce the concentration of an active pharmaceutical ingredient (API) or other components in a pharmaceutical formulation, making it suitable for administration to patients. Diluents are added to drug formulations for various reasons, including achieving the desired dosage strength, improving stability, aiding in drug delivery, and enhancing patient acceptance. IDiluents should be compatible with the active ingredient and other excipients in the formulation. They should not adversely affect the stability, solubility, or bioavailability of the drug product. Diluents, like other excipients used in pharmaceutical formulations, must meet established regulatory standards for safety, quality, and purity. The choice of a pharmaceutically acceptable diluent can depend on the intended route of administration. Different routes (oral, injectable, topical, etc.) may have specific requirements for diluents. The choice of diluent may vary depending on the intended dosage form, such as tablets, capsules, solutions, suspensions, or injectable formulations. For oral formulations, diluents can impact the taste, texture, and ease of swallowing, which can influence patient compliance and acceptance. [0120] A pharmaceutically acceptable carrier, also referred to as an excipient or vehicle, is a substance used in pharmaceutical formulations to provide a suitable medium or matrix for delivering active pharmaceutical ingredients (APIs) to patients. Carriers are inert substances that help achieve the desired physical characteristics, stability, and ease of administration of the final drug product. Carriers are used to formulate APIs into various dosage forms, such as tablets, capsules, creams, solutions, and injections. They provide a stable matrix for the API, aiding in its dispersion, dissolution, and overall effectiveness. [0121] A pharmaceutically acceptable excipient is a substance added to a pharmaceutical formulation alongside the active pharmaceutical ingredient (API) to facilitate the preparation of the final dosage form, enhance stability, improve patient acceptance, or aid in the delivery of the medication. Excipients are inert substances that serve various functional roles in pharmaceutical products. Excipients are used for various purposes, such as binding, dilution, disintegration, dissolution, coloration, flavoring, preservation, and enhancing patient acceptability. They help achieve the desired physical and chemical properties of the final dosage form. [0122] A “small molecule inhibitor” is a type of chemical compound that binds to a specific target molecule in cells and interferes with its activity, often by blocking or reducing its function. [0123] An “effector competent antibody,” also known as a functional antibody or effector-active antibody, is an antibody that is capable of engaging with the immune system's effector mechanisms to elicit specific immune responses against its target. Effector mechanisms are processes by which antibodies activate immune responses to eliminate target cells or pathogens. These mechanisms involve interactions with immune cells or proteins that enhance the immune response's effectiveness. Effector mechanisms include processes like antibody-dependent cellular cytotoxicity (ADCC), complement activation, and immune cell recruitment. In ADCC, antibodies bind to a target cell's surface antigens. Immune cells, particularly natural killer (NK) cells, recognize the bound antibodies and subsequently target and destroy the antibody-coated cells. In complement activation, antibodies activate the complement system, a cascade of proteins that leads to cell lysis, opsonization (enhancement of phagocytosis), and inflammation. In immune cell recruitment, antibodies facilitate the recruitment of immune cells, such as macrophages and neutrophils, to the site of infection or inflammation. Effector competent antibodies are employed in various therapeutic strategies, including antibody-based cancer therapies and treatments for infectious diseases. Monoclonal antibodies that can induce ADCC or complement activation have been developed to target cancer cells, enhancing the immune system's ability to eliminate tumors. [0124] “Treating” or “treatment” of any disease or disorder refers, in certain embodiments, to ameliorating a disease or disorder that exists in a subject. In another embodiment, “treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible by the subject. In yet another embodiment, “treating” or “treatment” includes modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In yet another embodiment, “treating” or “treatment” includes delaying or preventing the onset of the disease or disorder. [0125] As used herein, the term “therapeutically effective amount” or “effective amount” refers to an amount of an antibody or composition that when administered to a subject is effective to treat a disease or disorder. [0126] As used herein, the term “subject” means a mammalian subject. Exemplary subjects include, but are not limited to humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, avians, goats and sheep. In certain embodiments, the subject is a human. In some embodiments, the subject has cancer, an autoimmune disease or condition, and/or an infection that can be treated with an antibody provided herein. In some embodiments, the subject is a human that is suspected to have cancer, an autoimmune disease or condition, and/or an acute infection and chronic infection. [0127] A “solid cancer,” also known as solid tumor, is a type of cancer that form in the body's tissues and organs, resulting in the development of masses or lumps of abnormal cells. Solid cancers can occur in virtually any organ or tissue in the body. Common examples include but are not limted to breast cancer, lung cancer, colorectal cancer, prostate cancer, and ovarian cancer. [0128] A “hematological cancer,” also known as hematologic cancer or blood cancer, refers to cancers that originate in the cells of the blood, bone marrow, or lymphatic system. Unlike solid cancers, hematological cancers primarily involve the production and function of blood cells and often affect the bone marrow's ability to produce healthy blood cells. Hematological cancers are broadly categorized into three main types: leukemia, lymphoma, and myeloma. Leukemia is a cancer of the bone marrow and blood, characterized by the rapid production of abnormal white blood cells. These abnormal cells crowd out healthy cells, leading to reduced production of red blood cells and platelets. Lymphoma is a cancer of the lymphatic system, which includes lymph nodes, lymphocytes (a type of white blood cell), and lymphatic vessels. There are two main types: Hodgkin lymphoma and non-Hodgkin lymphoma. Myeloma is a cancer that affects plasma cells, a type of white blood cell responsible for producing antibodies. In myeloma, abnormal plasma cells accumulate in the bone marrow and interfere with normal cell production. [0129] An “immunostimulatory agent,” also known as an immune modulator or immunomodulatory agent, is a substance that influences the immune system's response, either by enhancing or suppressing its activity. [0130] An “antagonist” is a type of molecule or substance that binds to a receptor or target in the body, blocking or inhibiting its activity. Antagonists work by preventing the natural or intended interactions between the receptor and its ligands, which are molecules that normally bind to the receptor to produce a response, leading to a reduction or inhibition of the receptor's signaling pathway. [0131] An “agonist” is a type of molecule or substance that binds to a receptor or target in the body and activates its function. When an agonist binds to its specific receptor, it triggers a biological response or signal within the cell or tissue. This activation leads to downstream cellular responses, which can include changes in gene expression, enzyme activity, ion channel opening, or the release of signaling molecules. Agonists exhibit specificity for certain receptors, as their chemical structure allows them to interact with complementary binding sites on those receptors. Endogenous agonists are naturally produced molecules in the body that bind to receptors and regulate physiological functions. Synthetic agonists are artificially designed molecules that mimic the effects of endogenous agonists. Partial agonists bind to receptors but only activate them to a limited extent compared to full agonists. [0132] An “oncolytic virus” is a type of virus that has been genetically modified or naturally evolved to selectively infect and destroy cancer cells while sparing normal healthy cells. [0133] A chimeric antigen receptor (CAR) engineered T cell, often referred to as CAR T cell therapy, is an immunotherapy approach that involves genetically modifying a patient's own T cells to enhance their ability to recognize and attack cancer cells. A CAR is a synthetic receptor that combines an antigen-binding domain derived from an antibody with T cell signaling components. [0134] Bi- or multi-specific T cell-directed antibodies are antibodies that simultaneously engage T cells and cancer cells, bringing T cells in close proximity to cancer cells, facilitating the immune system's ability to recognize and destroy cancer cells with high specificity. By bringing T cells into direct contact with cancer cells, these antibodies help activate T cells and trigger their cytotoxic response against the cancer cells. Bi-specific antibodies can be designed as T cell engagers (TCEs) or bispecific T cell engagers (BiTEs). BiTEs are a type of bi-specific antibody that binds to both a tumor-specific antigen and a T cell receptor. 2. Conjugates [0135] Provided herein are conjugates that include antibodies selectively bind human HLA-G and molecules coupled to the antibodies. [0136] One aspect herein provides a conjugate comprising, consisting essentially of, or consisting of (i) an antibody that binds specifically to a human HLA-G (hHLA-G) and (ii) a molecule coupled to the antibody. [0137] In some embodiments, the antibody has any of the following characteristics: a) is a monoclonal antibody; b) is a human antibody, a humanized antibody, or a chimeric antibody; c) is a bispecific antibody, a multi-specific antibody, a diabody, or a multivalent antibody; d) is of the IgA, IgGl, IgG2, IgG3, IgG4, or IgM type; e) is an antigen-binding antibody fragment; f) is a Fab fragment, a Fab' fragment, a F(ab')2 fragment, or an Fv fragment; and/or g) is a single chain antibody, a single domain antibody, or a nanobody. [0138] In some embodiments, the antibody has one of these characteristics. In some embodiments, the antibody has two of these characteristics. In some embodiments, the antibody has three of these characteristics. In some embodiments, the antibody has four of these characteristics. In some embodiments, the antibody has five of these characteristics. In some embodiments, the antibody has six of these characteristics. In some embodiments, the antibody has seven of these characteristics. [0139] In some embodiments, the antibody is a bispecific antibody. By simultaneously binding to two different targets, bispecific antibodies can create connections between cells or molecules that might not naturally interact. This can be used to direct immune cells toward cancer cells, enhance immune responses, or modify signaling pathways. In cancer immunotherapy, bispecific antibodies can be designed to engage both cancer cells and immune cells. This facilitates the immune system's recognition of cancer cells, triggering immune responses that lead to the destruction of the cancer cells. Some bispecific antibodies are designed to "redirect" immune cells, such as T cells, towards cancer cells. These antibodies bridge the gap between the immune cell and the cancer cell, enabling the immune cell to attack and eliminate the cancer cell. Bispecific antibodies can also be used to interfere with signaling pathways by binding to different components of those pathways. This has applications in various diseases where abnormal signaling contributes to the disease's progression. Bispecific antibodies have shown promise in treating hematological disorders like certain types of leukemia and lymphoma. By targeting both malignant cells and immune cells, they can enhance the immune system's ability to eliminate cancerous cells. Bispecific antibodies are used for precise and targeted therapies, offering the potential to modulate complex biological interactions and improve treatment outcomes for various diseases, particularly cancers and autoimmune disorders. [0140] In some embodiments, the antibody is a multi-specific antibody. Multi- specific antibodies can simultaneously engage multiple targets, which can enhance their specificity and potency. This is particularly valuable when dealing with complex diseases or therapeutic strategies that require interactions with multiple cellular components. In scenarios where diseases involve intricate signaling networks, multi-specific antibodies can be engineered to engage different molecules within these networks, allowing for fine-tuned modulation of signaling pathways. Multi-specific antibodies are used in cancer immunotherapy to target multiple antigens on cancer cells or to simultaneously engage immune cells and cancer cells. This approach can potentially increase the immune response against cancer and improve therapeutic outcomes. Multi-specific antibodies can be designed to bind to various molecules involved in autoimmune responses, with the goal of regulating the immune system and reducing inflammation. Multi-specific antibodies can come in various formats, such as "tri-specific" (binding to three targets) or more complex designs. These formats are designed based on the therapeutic goal and the molecular interactions being targeted. [0141] In some embodiments, the antibody is a multivalent antibody. Multivalent antibodies can offer enhanced binding affinity and avidity. They can potentially bind more strongly to antigens due to multiple interactions between binding sites and antigens. Multivalent antibodies can neutralize pathogens more effectively by binding to multiple epitopes on the pathogen's surface. Multivalent antibodies are used in cancer immunotherapy to enhance the immune response against cancer cells. They can engage immune cells more effectively, leading to improved tumor cell killing. [0142] In some embodiments, the antibody is a single domain antibody. sdAbs often exhibit excellent thermal and chemical stability, making them suitable for various applications, including harsh conditions. sdAbs have therapeutic potential, especially in scenarios where small size, stability, and novel epitope targeting are advantageous. They can be used for cancer therapy, autoimmune diseases, and more. [0143] In some embodiments, the antibody binds to a human HLA-G polypeptide or a variant thereof with a KD of less than about 20 nM. [0144] In some embodiments, the antibody comprises, consists essentailly of, or consists of a human heavy chain constant region or fragment or a variant thereof and/or a light chain constant region or fragment or variant thereof; and the constant region or fragment of variant thereof comprises, consists essentailly of, or consists of up to 20 conservatively modified amino acid substitutions from any sequence set forth in SEQ ID NOS: 170-200 and/or SEQ ID NOS: 204-228. [0145] In some embodiments, the antibody comprises, consists essentilly of or consists of: an isolated antibody molecule capable of binding to human HLA-G (hHLA- G), comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH and/or VL comprising 1, 2, 3, 4, 5, or 6 of: a VHCDR1 having the sequence set forth in SEQ ID NOS: 1 -14 or SEQ ID NOS: 18-34, a VHCDR2 having the sequence set forth in SEQ ID NOS: 38-50 or SEQ ID NOS: 54-71 , a VHCDR3 having the sequence set forth in SEQ ID NOS: 76-101, a VLCDR1 having the sequence set forth in SEQ ID NOS: 105-124, a VLCDR2 having the sequence set forth in SEQ ID NOS: 128-145, and a VLCDR3 having the sequence set forth in SEQ ID NOS: 149-166. [0146] In some embodiments, the antibody comprises, consists essentilly of or consists of: an isolated antibody molecule capable of binding to human HLA-G (hHLA-G), comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising: a VHCDR1 having a sequence set forth in SEQ ID NOS: 1-14 or SEQ ID NOS: 18-34, a VHCDR2 having a sequence set forth in SEQ ID NOS: 38-50 or SEQ ID NOS: 54-71 , and c) a VHCDR3 having a sequence set forth in SEQ ID NOS: 76-101; and the VL comprising: a VLCDR1 having a sequence set forth in SEQ ID NO: 105-124, a VLCDR2 having a sequence set forth in SEQ ID NO: 128-145, and a VLCDR3 having a sequence set forth in SEQ ID NO: 149-166. [0147] In some embodiments, the antibody comprises, consists essentilly of or consists of: an isolated antibody molecule capable of binding to human HLA-G (hHLA-G), and comprising a heavy chain variable region (VH) and/or a light chain variable region (VL), the VH comprising at least one sequence set forth in any of SEQ ID NOS: 170-200 and the VL comprising at least one sequence set forth in any of SEQ ID NOS: 204-228;. [0148] In some embodiments, the antibody comprises, consists essentilly of or consists of: an isolated antibody molecule capable of binding to human HLA-G (hHLA-G), the isolated antibody molecule comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising 1, 2, or 3 of: a VHCDR1 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOS: 1-14 or 18-34, a VHCDR2 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOS: 54-71, and a VHCDR3 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOS: 76-101; and the VL comprising 1, 2, or 3 of: a VLCDR1 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOS: 105-124, a VLCDR2 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOS: 128-145, and a VLCDR3 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOs 149-166. [0149] In some embodiments, the antibody comprises, consists essentilly of or consists of: an isolated antibody molecule capable of binding to human HLA-G (hHLA-G), the isolated antibody molecule comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising 1, 2, or 3 of: a VHCDR1 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 1-14 or SEQ ID NOS: 18-34, a VHCDR2 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 38-50 or SEQ ID NOS: 54-71, and a VHCDR3 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 76-101; and the VL comprising 1, 2, or 3 of: a VLCDR1 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 105-124, a VLCDR2 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 128-145, and a VLCDR3 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 149-166. [0150] In some embodiments, the antibody comprises, consists essentilly of or consists of: an isolated antibody molecule capable of binding to human HLA-G (hHLA-G), the isolated antibody molecule comprising a heavy chain and a light chain, the heavy chain comprising one or more molecules having a sequence consisting of one of SEQ ID NOS: 232-262 or SEQ ID NOS: 266-296, and the light chain comprising one or more molecules having a sequence consisting of one of SEQ ID NOS: 300-330. [0151] In some embodiments, the antibody comprises, consists essentilly of or consists of: an isolated antibody molecule capable of binding to human HLA-G (HLA-G), the isolated antibody molecule comprising a heavy chain and a light chain and being selected from the group consisting of: the heavy chain comprising one or more molecules each having a sequence consisting of SEQ ID NO: 232 and the light chain comprising one or more molecules each having a sequence consisting of SEQ ID NO: 300; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 233 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 301 ; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 234 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 302; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 235 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 303; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 236 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 304; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 237 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 305; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 238 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 306; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 239 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 307; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 240 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 308; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 241 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 309; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 242 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 310; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 243 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 311 ; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 244 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 312; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 245 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 313; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 246 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 314; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 247 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 315; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 248 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 316; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 249 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 317; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 250 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 318; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 251 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 319; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 252 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 320; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 253 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 321 ; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 254 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 322; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 255 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 323; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 256 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 324; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 257 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 325; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 258 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 326; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 259 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 327; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 260 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 328; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 261 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 329; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 262 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 330; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 266 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 300; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 267 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 301; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 268 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 302; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 269 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 303; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 270 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 304; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 271 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 305; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 272 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 306; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 273 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 307; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 274 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 308; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 275 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 309; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 276 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 310; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 277 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 311; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 278 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 312; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 279 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 313; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 280 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 314; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 281 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 315; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 282 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 316; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 283 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 317; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 284 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 318; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 285 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 319; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 286 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 320; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 287 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 321; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 288 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 322; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 289 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 323; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 290 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 324; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 291 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 325; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 292 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 326; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 293 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 327; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 294 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 328; the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 295 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 329; and the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 296 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 330. [0152] In some embodiments, the antibody comprises, consists essentilly of or consists ofan isolated antibody molecule capable of binding to human HLA-G (hHLA-G), the isolated antibody molecule comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH and/or VL comprising 1, 2, 3, 4, 5, or 6 of: a) a VHCDR1 sequence comprising: Kabat CDR-H1 sequence defined by the consensus sequence S-S-Δ3-Δ4-Y-W-Δ7 (SEQ ID NOS: 18-21, 23, and 34), where Δ3 is D or S; Δ4 is T or Y; and Δ7 is A, G, or S; a Kabat CDR-H1 sequence defined by the consensus sequence S-G-θ3-Y- W-θ6 (SEQ ID NOS: 24-29), where θ3 is F, H, or Y; and θ6 is F, G, I, L, or T; a Chothia CDR-H1 sequence defined by the consensus sequence G-G-S- -S-S-Ω7- Ω8- Ω9 (SEQ ID NOS: 1-4 and 13-14), where Ω 7 is S or A; Ω8 is D, S, or N; and Ω9 is T, N, Y, or is
Figure imgf000047_0001
a Chothia CDR-H1 sequence defined by the consensus sequence G-F-T-F-κ5-κ6-κ7 (SEQ ID NOS: 10-12), where κ5 is D or s; κ6 is D, N, or S; and κ7 is S or Y, b) a VHCDR2 sequence comprising: a Kabat CDR-H2 sequence defined by the consensus sequence β1-I-β3- β4-β5-β6-β7-T-β9-Y-N- P-S-L-K-S (SEQ ID NOS: 54-65 and 69-70) where β1 is A, E, G, or S; β3 is A, H, S, or Y; β4 is H, S, or Y; β5 is N or S; β6 is A or G; β7 is A, L, or S; and β9 is A, N, L, V, or Y; a Chothia CDR-H2 sequence defined by the consensus sequence U-ε2- S-ε4-S (SEQ ID NOS: 38 and 44-45), where ε2 is H or Y and ε4 is A or G; a Chothia CDR-H2 sequence defined by the consensus sequence α1-α2-S-G-S (SEQ ID NOS: 39, 41-42, and 49), where α1 is A, H, or S; and α2 is S or Y; or a Chothia CDR-H2 sequence defined by the consensus sequence β1- β2- S-G- β5- β6 (SEQ ID NOS: 56-60), where β1 is A or S; β2 is G or S; β5 is I or S; and β6 is T or V, c) a VHCDR3 sequence comprising: a CDR-H3 sequence defined by the consensus sequence G-Υ2-Y3-R-A-V-P-F-Y9-Y10 (SEQ ID NOS: 76-84), where Y2 is I, P, Q, T, or V; Y3 is A, F, K, or R; Y9 is A, D, Q, or V; Y10 is D, R, or Y; or a CDR-H3 sequence defined by the consensus sequence G-G-Φ3-Φ4-Φ5-Y-S-R-G-P-Φ11-D-V (SEQ ID NOS: 85-93), where Φ3 is E, G, Q, or T; Φ4 is A, H, P, Q, or V; Φ5 is K or T; and Φ11 is F, L, or M, d) a VLCDR1 sequence comprising: a CDR-L1 sequence defined by the consensus sequence Φ1-A-S-Q-Φ5- V-S-S-Φ9-Φ10-L-A (SEQ ID NOS: 105-112 and 117), where Φ1 is E, G, K, Q, or R; Φ5 is A or S; Φ9 is A, D, N, S, or T; and Φ10 is F or Y; a CDR-L1 sequence defined by the consensus sequence R-A-S-Q-S-σ6-σ7-S-σ9-L-σ11 (SEQ ID NOS: 119 and 123-124), where σ6 is I or V; σ7 is N or S; σ9 is N, W, or Y; σ11 is A or N; or a CDR-L1 sequence defined by the consensus sequence Γ1-Γ2-S-Q-S-V-S-Γ8-Γ9-Y-L-A (SEQ ID NOS: 113-116), where Γ1 is E or R; Γ2 is A or V; Γ8 is A, D, or S; and Γ9 is A or S, e) a VLCDR2 sequence comprising: a CDR-L2 sequence defined by the consensus sequence ψ1-A-S-ψ4-R-A-ψ7 (SEQ ID NOS: 128, 130, 132, 134-138, 143, and 145), where ψ1 is D or G; ψ4 is A, D, N, R, S, T, or Y; and ψ7 is A, N, S, or T, and a VLCDR3 sequence comprising: a CDR-L3 sequence defined by the consensus sequence Q-π2-π3-π4-H-S-P-Y-T (SEQ ID NOS: 149-153), where π2 is Q or W; π3 is A, T, or V; and π4 is I or V; a CDR-L3 sequence defined by the consensus sequence Q-Q-λ3-S-λ5-Y-P-P-T (SEQ ID NOS: 154-158), where λ3 is F, H, or V; and λ5 is I, L, or S; or a CDR-L3 sequence defined by the consensus sequence Q-Q-ω3-ω4-ω5-ω6-P-I-T (SEQ ID NOS: 160-161 and 163-164), where ω3 is A, L, V, or Y; ω4 is G, P, V, or Y; ω5 is S, L, or F; and ω6 is D, L, S, or Y. [0153] In some embodiments, in any conjugate provided herein, the molecule coupled to the antibody comprises a cytotoxic payload or warhead. In some embodiments, the conjugate provided herein further comprises a linker molecule, and the cytotoxic payload or warhead is coupled to the antibody by the linker molecule. [0154] In some embodiments, in any conjugate provided herein, the molecule coupled to the antibody comprises a cytotoxic payload or warhead and further comprises a linker molecule. The cytotoxic payload or warhead is coupled to the antibody by the linker molecule. [0155] In some embodiments, the linker molecule is cleavable. In some other embodiments, the linker molecule is non-cleavable. [0156] In some embodiments, in any conjugate provided herein, the molecule coupled to the antibody comprises one selected from the group consisting of a detectable label, a drug, a toxin, a cytokine, a radionuclide, an enzyme, and combinations thereof. [0157] In some embodiments, in any conjugate provided herein, the molecule coupled to the antibody comprises a cytokine. Cytokines are categorized into different groups based on their functions: Interleukins (ILs) mainly act on immune cells and are involved in inflammation, cell proliferation, and differentiation. Tumor Necrosis Factors (TNFs) are involved in inflammation and cell death. Interferons (IFNs) play a role in antiviral responses and regulating immune cell activities. Chemokines attract immune cells to specific sites of infection or inflammation. Growth Factors stimulate cell growth, proliferation, and tissue repair. Cytokines help regulate the intensity and duration of immune responses. They can stimulate or inhibit immune cell activities based on the context. They are vital for maintaining a balanced immune response, preventing excessive inflammation, and avoiding immune-related diseases. Dysregulation of cytokines can contribute to various diseases, including autoimmune disorders, allergies, and chronic inflammatory conditions. [0158] In some embodiments, in any conjugate provided herein, the molecule coupled to the antibody comprises a DNA-alkylating cytotoxic molecule or an antineoplastic agent. [0159] In some embodiments, in any conjugate provided herein, the molecule coupled to the antibody comprises a DNA-alkylating cytotoxic molecule. DNA-alkylating cytotoxic molecules induce cytotoxicity by causing DNA damage that triggers cell cycle arrest and apoptosis (programmed cell death). Rapidly dividing cells, such as cancer cells, are particularly sensitive to these alkylating agents, as these agents interfere with their ability to replicate their DNA. These alkylating agents are used to treat various types of cancer. Examples of alkylating agents used in cancer treatment include, for example, cyclophosphamide, temozolomide, and cisplatin. [0160] In some embodiments, in any conjugate provided herein, the molecule coupled to the antibody comprises an antineoplastic agent. The antineoplastic agent targets rapidly dividing cells, which includes cancer cells, to disrupt their growth, division, and survival. Antineoplastic agents can be used alone or in combination with other therapies. Cytotoxic antineoplastic agents directly kill rapidly dividing cells; and examples include alkylating agents, antimetabolites, and microtubule inhibitors. Targeted antineoplastic agents specifically target proteins or pathways involved in cancer growth; and examples include tyrosine kinase inhibitors and monoclonal antibodies. Immunotherapeutic antineoplastic agents stimulate the immune system to recognize and attack cancer cells; and examples include immune checkpoint inhibitors and CAR-T cell therapy. [0161] In some embodiments, in any of the conjugates provided herein, the molecule coupled to the antibody comprises a warhead selected from the group consisting of DGN549C, Monomethyl auristatin E (MMAE), Deruxtecan, SN-38, vc-SECO-DUBA (duocarmycin), Calicheamicin, SPDB-DM4, and Tesirine. [0162] In some embodiments, in any of the conjugates provided herein, the molecule coupled to the antibody comprises one selected from the group consisting of Formulas I-VIII:
Figure imgf000050_0001
Formula I: DGN549-C
E
nd 3. Pharmaceutical Compositions [0163] Also provided herein are pharmaceutical compositions comprising, consisting essentailly of, or consisting of any of the conjugates provided herein. [0164] One aspect herein provides a pharmaceutical composition comprising, consisting essentailly of, or consisting of an effective amount of any of the conjugates provided herein. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable diluent, carrier, or excipient. [0165] In some embodiments, the pharmaceutical composition further comprises an effective amount of at least one of the following: a) an anti-ILT2 antibody; b) an anti-ILT3 antibody; c) an anti-ILT4 antibody; d) an anti-KIR2DL4 antibody; e) an anti-HLA-E antibody; f) an anti-NKG2A antibody; g) an anti-HLA-F antibody; h) an anti-HLA-J antibody; i) an anti-PD-L1 antibody; j) an anti-PD-1 antibody; k) an anti-CD38 antibody; l) an anti-CD39 antibody; m) an anti-CD73 antibody; n) an anti-A2A receptor antibody; o) an anti-A2B receptor antibody; p) an anti-A2A/A2B dual receptor antibody or a combination thereof; q) an anti-CD47 antibody; r) a small molecule inhibitor; s) a bi-specific T cell engager and/or CAR-T therapy and or CAR-NK therapy, CAR- Macrophage therapy t) an oncolytic virus; u) a chemotherapy; v) ADCC capable therapies using an effector competent antibody selected from the group consisting of anti-CDl9, anti-CD20, anti-EGFR, anti-Her2, anti-SLAMF7, anti-CD52, anti-BCMA, anti-GD2, anti-CCR4, anti-CTLA4, and mixtures thereof. [0166] In some embodiments, the pharmaceutical composition further comprises an effective amount of a small molecule inhibitor. The small molecule inhibitor binds to a specific target molecule, such as an enzyme, receptor, or signaling protein, and altering its structure or function. By binding to the target, the inhibitor can disrupt the target's activity, signaling pathways, or interactions with other molecules. The small molecule inhibitor preferably target specific signaling pathways that are overactive in cancer cells leading to growth inhibition or cell death. Examples include tyrosine kinase inhibitors, such as imatinib for chronic myeloid leukemia, and proteasome inhibitors, such as bortezomib for multiple myeloma. [0167] In some embodiments, the pharmaceutical composition further comprises an effective amount of an oncolytic virus. Oncolytic viruses exploit the unique characteristics of cancer cells, such as their altered signaling pathways, weakened antiviral defenses, and impaired ability to respond to viral infections. The viruses replicate preferentially within cancer cells, leading to their lysis (destruction) and release of new viral particles that can infect nearby cancer cells. Oncolytic viruses can kill cancer cells through multiple mechanisms, including direct cell lysis, induction of apoptosis (programmed cell death), stimulation of anti-tumor immune responses, and disruption of tumor vasculature (blood vessels). There are various types of oncolytic viruses, including adenoviruses, herpes simplex viruses, reoviruses, vaccinia viruses, and vesicular stomatitis viruses. Some viruses are naturally selective for cancer cells, while others are engineered to enhance their tumor- targeting capabilities. Oncolytic virotherapy can be combined with other treatment modalities, such as chemotherapy, radiation therapy, and immunotherapy, to enhance the overall anti-cancer effect. Oncolytic viruses can stimulate the immune system to recognize and attack cancer cells by releasing tumor antigens and promoting the activation of immune cells. [0168] In some embodiments, the pharmaceutical composition further comprises at least one of a) an antibody to an immune inhibitory receptor or ligand and/or b) an antibody to an immune stimulatory receptor or ligand. [0169] The pharmaceutical composition may comprise one or more pharmaceutical excipients or pharmaceutically acceptable excipients. Any suitable pharmaceutical excipient may be used, and one of ordinary skill in the art is capable of selecting suitable pharmaceutical excipients. Accordingly, the pharmaceutical excipients provided below are intended to be illustrative, and not limiting. Additional pharmaceutical excipients include, for example, those described in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), incorporated by reference in its entirety. [0170] The pharmaceutical composition may comprise an anti-foaming agent. Any suitable anti-foaming agent may be used. The anti-foaming agent may be one of an alcohol, an ether, an oil, a wax, a silicone, a surfactant, or combinations thereof. The anti-foaming agent may be one of a mineral oil, a vegetable oil, ethylene bis stearamide, a paraffin wax, an ester wax, a fatty alcohol wax, a long chain fatty alcohol, a fatty acid soap, a fatty acid ester, a silicon glycol, a fluorosilicone, a polyethylene glycol-polypropylene glycol copolymer, polydimethylsiloxane-silicon dioxide, ether, octyl alcohol, capryl alcohol, sorbitan trioleate, ethyl alcohol, 2-ethyl-hexanol, dimethicone, oleyl alcohol, simethicone, or combinations thereof. [0171] The pharmaceutical composition may comprise a cosolvent. Illustrative examples of cosolvents include ethanol, poly(ethylene) glycol, butylene glycol, dimethylacetamide, glycerin, and propylene glycol. [0172] The pharmaceutical composition may comprise a buffer. Illustrative examples of buffers include acetate, borate, carbonate, lactate, malate, phosphate, citrate, hydroxide, diethanolamine, monoethanolamine, glycine, methionine, guar gum, and monosodium glutamate. [0173] The pharmaceutical composition may comprise a carrier or filler. Illustrative examples of carriers or fillers include lactose, maltodextrin, mannitol, sorbitol, chitosan, stearic acid, xanthan gum, and guar gum. [0174] The pharmaceutical composition may comprise a surfactant. Illustrative examples of surfactants include d-alpha tocopherol, benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride, docusate sodium, glyceryl behenate, glyceryl monooleate, lauric acid, macrogol 15 hydroxystearate, myristyl alcohol, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxylglycerides, sodium lauryl sulfate, sorbitan esters, and vitamin E polyethylene(glycol) succinate. [0175] The pharmaceutical composition may comprise an anti-caking agent. Illustrative examples of anti-caking agents include calcium phosphate (tribasic), hydroxymethyl cellulose, hydroxypropyl cellulose, and magnesium oxide. [0176] Other excipients that may be used with the pharmaceutical compositions include, for example, albumin, antioxidants, antibacterial agents, antifungal agents, bioabsorbable polymers, chelating agents, controlled release agents, diluents, dispersing agents, dissolution enhancers, emulsifying agents, gelling agents, ointment bases, penetration enhancers, preservatives, solubilizing agents, solvents, stabilizing agents, and sugars. Specific examples of each of these agents are described, for example, in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), The Pharmaceutical Press, incorporated by reference in its entirety. [0177] The pharmaceutical composition may comprise a solvent. The solvent may be saline solution, such as a sterile isotonic saline solution or dextrose solution. The solvent may be water for injection. [0178] The pharmaceutical composition provided herein may be in a single unit dosage form. 3.1. Parenteral Dosage Forms [0179] The pharmaceutical compositions provided herein may be in parenteral dosage forms administered to subjects via intravenous injection. Because their administration typically bypasses subjects’ natural defenses against contaminants, parenteral dosage forms are typically, sterile or capable of being sterilized prior to administration to a subject. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions. [0180] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection; water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. [0181] Excipients that increase the solubility of one or more of the conjugates disclosed herein can also be incorporated into the parenteral dosage forms. 3.2. Dosage and Unit Dosage Forms [0182] In human therapeutics, the doctor will determine the dosology which they consider most appropriate according to the treatment and according to the age, weight, condition and other factors specific to the subject to be treated. [0183] The amount of the conjugate or pharmaceutical composition provided herein which will be effective in the treatment of a disorder or one or more symptoms thereof will vary with the nature and severity of the disease or condition. The frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy administered, the severity of the disorder, disease, or condition, as well as age, body, weight, response, and the past medical history of the subject. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems. [0184] In some embodiments, exemplary doses of the pharmaceutical composition provided herein include milligram or microgram amounts of the conjugate per kilogram of subject or sample weight (e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 microgram per kilogram to about 10 milligrams per kilogram). [0185] In some embodiments, the dosage of the pharmaceutical composition provided herein, based on weight of the conjugate, is about 0.1 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 10 mg/kg, or about 15 mg/kg or more of a subject’s body weight. In some embodiments, the dosage of the pharmaceutical composition provided herein, based on weight of the conjugate, is 0.1 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 10 mg/kg, or 15 mg/kg or more of a subject’s body weight. [0186] In some embodiments, the dosage of the pharmaceutical composition is about 0.1 mg to about 200 mg, about 0.1 mg to about 100 mg, about 0.1 mg to about 50 mg, about 0.1 mg to about 25 mg, about 0.1 mg to about 20 mg, about 0.1 mg to about 15 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 7.5 mg, about 0.1 mg to about 5 mg, about 0.1 to about 2.5 mg, about 0.25 mg to about 20 mg, about 0.25 to about 15 mg, about 0.25 to about 12 mg, about 0.25 to about 10 mg, about 0.25 mg to about 7.5 mg, about 0.25 mg to about 5 mg, about 0.25 mg to about 2.5 mg, about 0.5 mg to about 20 mg, about 0.5 to 15 mg, about 0.5 to 12 mg, about 0.5 to about 10 mg, about 0.5 mg to about 7.5 mg, about 0.5 mg to about 5 mg, about 0.5 mg to about 2.5 mg, about 1 mg to about 20 mg, about 1 mg to about 15 mg, about 1 mg to about 12 mg, about 1 mg to about 10 mg, about 1 mg to about 7.5 mg, about 1 mg to about 5 mg, or about 1 mg to about 2.5 mg. In some embodiments, the dosage of the pharmaceutical composition is 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.25 mg to 2.5 mg, 0.5 mg to 20 mg, 0.5 to 15 mg, 0.5 to 12 mg, 0.5 to 10 mg, 0.5 mg to 7.5 mg, 0.5 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg. [0187] The dose can be administered according to a suitable schedule, for example, once, two times, three times, or four times weekly. It may be necessary to use dosages of the conjugate or pharmaceutical composition outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with subject response. [0188] Different therapeutically effective amounts may be applicable for different diseases and conditions, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to manage, treat, or ameliorate such disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the conjugate provided herein are also encompassed by the herein described dosage amounts and dose frequency schedules. Further, when a subject is administered multiple dosages of a conjugate or pharmaceutical composition provided herein, not all of the dosages need be the same. For example, the dosage administered to the subject may be increased to improve the effect of the conjugate or pharmaceutical composition, or it may be decreased to reduce one or more side effects that a particular subject is experiencing. [0189] In some embodiments, treatment can be initiated with one or more loading doses of a pharmaceutical composition or conjugate provided herein followed by one or more maintenance doses. [0190] In some embodiments, administration of the same conjugate or pharmaceutical composition may be repeated, and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. 4. Therapeutic Applications [0191] For therapeutic applications, the conjugates provided herein are administered to a mammal, generally a human, in a pharmaceutically acceptable dosage form such as those known in the art and those discussed herein. For example, the conjugates or pharmaceutical compositions provided herein may be administered to a human intravenously as a bolus or by continuous infusion over a period of time. The conjugates or pharmaceutical compositions provided herein also are suitably administered by peritumoral, intralesional, or perilesional routes, to exert local as well as systemic therapeutic effects. The intraperitoneal route may be particularly useful, for example, in the treatment of ovarian tumors. [0192] One aspect herein provides a method for treatment of a subject suffering from cancer, a chronic infection, and/or from an inflammatory disease, the method comprising, consisting essentially of, or consisting of administering to the subject a pharmaceutical composition comprising, consisting essentially of, or consisting of an effective amount of a conjugate provided herein or a pharmaceutical composition provided herein. [0193] The conjugates or pharmaceutical compositions provided herein may be useful for the treatment of any disease or condition involving HLA-G, such as cancer, autoimmune disease, and infection. [0194] Any suitable cancer may be treated with the conjugates or pharmaceutical compositions provided herein. Illustrative suitable cancers include, for example, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, basal cell carcinoma, brain tumor, bile duct cancer, bladder cancer, bone cancer, breast cancer, bronchial tumor, Burkitt Lymphoma, carcinoma of unknown primary origin, cardiac tumor, cervical cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasm, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, fibrous histiocytoma, Ewing sarcoma, eye cancer, germ cell tumor, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gestational trophoblastic disease, glioma, head and neck cancer, hairy cell leukemia, hepatocellular cancer, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer with occult primary, midline tract carcinoma involving NUT gene, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasm, nasal cavity and par nasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytomas, pituitary tumor, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell cancer, renal pelvis and ureter cancer, retinoblastoma, rhabdoid tumor, salivary gland cancer, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, spinal cord tumor, stomach cancer, T-cell lymphoma, teratoid tumor, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, vulvar cancer, and Wilms tumor. In some embodiments, the cancer is selected from breast, lung, CRC, gastric, esophageal, neuroblastoma, cervical, and hematological cancers. [0195] Any suitable autoimmune disease may be treated with the conjugates or pharmaceutical compositions provided herein. Illustrative suitable autoimmune diseases, or diseases with an autoimmune component, include, for example, acute disseminated encephalomyelitis (ADEM), acute necrotizing hemorrhagic leukoencephalitis, Addison’s disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti- GBM/anti-TBM nephritis, antiphospholipid syndrome (APS), autoimmune angioedema, autoimmune aplastic anemia, autoimmune dysautonomia, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura (ATP), autoimmune thyroid disease, autoimmune urticarial, axonal & neuronal neuropathies, Balo disease, Behcet’s disease, bullous pemphigoid, cardiomyopathy, Castleman disease, Celiac disease, Chagas disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal ostomyelitis (CRMO), Churg-Strauss syndrome, cicatricial pemphigoid/benign mucosal pemphigoid, Crohn’s disease, Cogans syndrome, cold agglutinin disease, colitis, congenital heart block, coxsackie myocarditis, CREST disease, essential mixed cryoglobulinemia, demyelinating neuropathies, dermatitis herpetiformis, dermatomyositis, Devic’s disease (neuromyelitis optica), discoid lupus, Dressler’s syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, experimental allergic encephalomyelitis, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture’s syndrome, granulomatosis with polyangiitis (GPA) (formerly called Wegener’s Granulomatosis), Graves’ disease, Guillain-Barre syndrome, Hashimoto’s encephalitis, Hashimoto’s thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpes gestationis, hypogammaglobulinemia, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease, immunoregulatory lipoproteins, inclusion body myositis, inflammatory bowel disease. interstitial cystitis, juvenile arthritis, juvenile diabetes (Type 1 diabetes), juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), lupus (SLE), Lyme disease (chronic), Meniere’s disease, microscopic polyangiitis, mixed connective tissue disease (MCTD), Mooren’s ulcer, Mucha-Habermann disease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica (Devic’s), neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Parsonnage-Turner syndrome, pars planitis (peripheral uveitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, type I, II, & III autoimmune polyglandular syndromes, polymyalgia rheumatic, polymyositis, postmyocardial infarction syndrome, postpericardiotomy syndrome, progesterone dermatitis, primary biliary cirrhosis, rimary sclerosing cholangitis, psoriasis, psoriatic arthritis, idiopathic pulmonary fibrosis, pyoderma gangrenosum, pure red cell aplasia, Raynauds phenomenon, reactive arthritis, reflex sympathetic dystrophy, Reiter’s syndrome, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjogren’s syndrome, sperm & testicular autoimmunity, stiff person syndrome, subacute bacterial endocarditis (SBE), Susac’s syndrome, sympathetic ophthalmia, Takayasu’s arteritis, temporal arteritis/giant cell arteritis, thrombotic disease, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, transverse myelitis, type 1 diabetes, ulcerative colitis, undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vesiculobullous dermatosis, vitiligo, and Wegener’s granulomatosis (now termed Granulomatosis with Polyangiitis (GPA). [0196] Any suitable infection may be treated with the conjugates or pharmaceutical compositions provided herein. Illustrative suitable infections include, for example, hepatitis A virus, hepatitis B virus, hepatitis C virus (HCV), human immunodeficiency virus (HIV), and other viral infections. [0197] In some embodiments, the cancer is a solid cancer or a hematological cancer. [0198] In some embodiments, the subject is a human subject. [0199] In some embodiments, the method of treatment provided herein further comprises one or more of the following: a) administering chemotherapy; b) administering radiation therapy; and/or c) administering one or more additional therapeutic agents. [0200] In some embodiments, the method of treatment provided herein comprises administering one or more additional therapeutic agents. [0201] In some embodiments, the one or more additional therapeutic agents comprise, consist essentially of, or consist of one or more immunostimulatory agents. Immunostimulatory agents enhance the immune system's response against pathogens, cancer cells, or other antigens. They can boost immune cell activation, proliferation, and the production of cytokines and antibodies. Immunostimulatory agents can also suppress the immune system, often used to manage autoimmune diseases or prevent transplant rejection. Immunostimulatory agents are a key component of cancer immunotherapy, which aims to harness the immune system to target and eliminate cancer cells. Immune checkpoint inhibitors, cancer vaccines, and adoptive T cell therapies are examples of immunostimulatory approaches used in cancer treatment. In autoimmune diseases, where the immune system attacks the body's own tissues, immunostimulatory agents can be used to suppress immune responses and reduce inflammation. [0202] In some embodiments, the one or more immunostimulatory agents comprise, consist essentially of, or consist of an antagonist to an inhibitory receptor of an immune cell. [0203] In some embodiments, the inhibitory receptor is one of or is selected from the group consisting of ILT2, ILT3, ILT4, KIR2DL4, CTLA-4, PD-l, CD39, CD73, PD-L1, PD- L2, LAG-3, Tim3, TIGIT, B7-H3, B7-H4, neuritin, BTLA, CECAM-l , CECAM-5, VISTA, LAIR1, CD160, 2B4,TGF-B (including traps and GARP), NKG2A, a Killer-cell immunoglobulin-like receptor (KIR), and combinations thereof. [0204] In some embodiments, the one or more immunostimulatory agents comprise, consist essentially of, or consist of an agonist of a co-stimulatory receptor of an immune cell. [0205] In some embodiments, the co-stimulatory receptor is at least one of OX40, CD2, CD27, ICAM-l, LFA-l, ICOS (CD278), 4-1BB (CD 137), GITR, CD28, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp30, NKp46, NKp80, CD160, and/or a CD83 ligand. [0206] In some embodiments, the one or more immunostimulatory agents comprise, consist essentially of, or consist of an ADCC competent antibody selected from the group consisting of an anti-CD19, anti-CD20, anti-EGFR, anti-Her2, anti-SLAMF7, anti-CD52, anti-BCMA, anti-GD2, anti-CD38, anti-CCR4, anti-CTLA-4 antibody, and combinations thereof. [0207] In some embodiments, the one or more immunostimulatory agents comprise, consist essentially of, or consist of a cytokine. [0208] In some embodiments, the cytokine is one of or is selected from the group consisting of IL-l, IL-2, IL-5, IL-7, IL-10, IL-12, IL-15, IL-21, IL-27, and combinations thereof. [0209] In some embodiments, the one or more immunostimulatory agents comprise, consist essentially of, or consist of an oncolytic virus. [0210] In some embodiments, the oncolytic virus is one of or is selected from the group consisting of a Herpes simplex virus, a Vesicular stomatitis virus, an adenovirus, a Newcastle disease virus, a vaccinia virus, and a maraba virus. [0211] In some embodiments, the one or more immunostimulatory agents comprise, consist essentially of, or consist of a chimeric antigen engineered T cell. [0212] In some embodiments, the one or more immunostimulatory agents comprise, consist essentially of, or consist of a bi- or multi-specific T cell directed antibody. [0213] Another aspect herein provides a method for modulating immune system function in a subject in need thereof, the method comprising, consisting essentially of, or consisting of contacting a population of immune cells of the subject with a pharmaceutical composition comprising an effective amount of any of the conjugates provided herein, under conditions such that the immune system is modulated. [0214] Modulating the immune system function involves intentionally influencing the activity and responses of the immune system to achieve specific outcomes. This can include enhancing immune responses to fight infections or cancer, as well as suppressing immune responses to manage autoimmune diseases and prevent transplant rejection. The strategies and approaches employed to modulate immune system function depend on the desired outcome and the context in which it is being applied. [0215] In some embodiments, the subject is a human subject. [0216] In some embodiments, the method for modulating immune system function in a subject in need thereof provided herein further comprises administering chemotherapy, administering radiation therapy, and/or administering one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents comprise one or more immunostimulatory agents. In some embodiments, the one or more immunostimulatory agents comprise an antagonist to an inhibitory receptor of an immune cell. In some embodiments, the inhibitory receptor is at least one of ILT2, ILT3, ILT4, KIR2DL4, CTLA- 4, PD-1, CD39, CD73, PD-L1, PD-L2, LAG-3, TIGIT, B7-H3, B7-H4, Tim3, neuritin, BTLA, CECAM-1, CECAM-5, VISTA, LAIR1, CD160, 2B4, TGF-B (including traps and GARP), NKG2A, and/or a Killer-cell immunoglobulin-like receptor (KIR). [0217] In some embodiments, the one or more immunostimulatory agents comprise an agonist of a co-stimulatory receptor of an immune cell. In some embodiments, the co- stimulatory receptor comprises one or more of OX40, CD2, CD27, ICAM-1, LFA-1, ICOS (CD278), 4-1BB (CD137), GITR, CD28, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp30, NKp46, NKp80, CD160, and/or a CD83 ligand. [0218] In some embodiments, the one or more immunostimulatory agents comprise a cytokine. In some embodiments, the cytokine is at least one of IL-1, IL-2, IL-5, IL-7, IL-10, IL-12, IL-15, IL-21, and/or IL-27. In some embodiments, the one or more immunostimulatory agents comprise an oncolytic virus. In some embodiments, the oncolytic virus comprises one or more of the oncolytic virus is a Herpes simplex virus, a Vesicular stomatitis virus, an adenovirus, a Newcastle disease virus, a vaccinia virus, or a maraba virus. In some embodiments, the one or more immunostimulatory agents comprise a chimeric antigen engineered T cell. In some embodiments, the immunostimulatory agents comprise a bi- or multi-specific T cell directed antibody. In some embodiments, the one or more immunostimulatory agents comprises or consists of an ADCC competent antibody that may target CD19, CD20, EGFR, Her2, SLAMF7, CD52, BCMA, GD2, CD38, CCR4, or CTLA- 4. In some embodiments, the ADCC competent antibody is effector enhanced through afucosylation, point mutations, or otherwise. [0219] In some embodiments, the one or more immunostimulatory agents comprise a bi-specific T cell engager and/or CAR-T therapy, CAR-NK therapy, CAR-macrophage therapy, adoptive T cell therapy. 5. Kits [0220] In some embodiments, a conjugate or pharmaceutical composition provided herein is provided in the form of a kit, i.e., a packaged combination of reagents in predetermined amounts with instructions for performing a procedure. In some embodiments, the procedure is a therapeutic procedure. 6. Production of the conjugates [0221] Provided herein are also methods of production of the conjugates described herein. [0222] The development of an ADC can be challenging due to considerations such as antibody selection, linker stability, drug potency, and overall safety. Creating an ADC involves a series of complex steps that combine the antibody, the cytotoxic drug, and a linker molecule to form a single molecule capable of targeting and killing specific cells, such as cancer cells. After the antibody is selected, the linker molecule can be designed to connect the antibody and the cytotoxic drug. The linker molecule should be stable in circulation but may be cleavable within the target cell to release the drug. The drug may usually be modified with a functional group that can be conjugated to the linker molecule. The modified drug may be attached to the linker molecule, forming a drug-linker complex. The drug-linker complex may then be conjugated to the antibody using specific conjugation chemistry, which may involve chemical reactions like thiol-maleimide or click chemistry. The ADC then may be purified to remove unreacted components and byproducts. [0223] The ADC can then be analyzed using various analytical techniques to ensure that the conjugation was successful and that the desired drug-to-antibody ratio is achieved. The stability of the ADC can be assessed under various conditions, including temperature, pH, and storage time, and the appropriate formulation to maintain ADC stability can be determined. The ADC can be tested in cell culture to confirm its ability to selectively bind to target cells and induce cell death. Preclinical studies can be conducted in animal models to evaluate the ADC's efficacy, safety, and pharmacokinetics. If preclinical studies are successful, clinical trials can then be conducted to evaluate the safety and effectiveness of the ADC in humans. [0224] Thiol-maleimide and click chemistry are two distinct chemical reactions frequently used in the context of creating ADCs or other bioconjugates. These reactions enable the specific and efficient attachment of molecules while maintaining the stability and activity of the final product. [0225] Thiol-maleimide chemistry is a reaction between a thiol (-SH) group and a maleimide functional group. The reaction is highly selective and occurs efficiently under mild conditions, making it suitable for bioconjugation applications. In ADC development, maleimide groups are often introduced to the cytotoxic drug or linker, while thiol groups are introduced to the antibody. When a maleimide-modified drug or linker is mixed with a thiol- modified antibody, the thiol-maleimide reaction forms a covalent bond, conjugating the drug or linker to the antibody. [0226] Click chemistry refers to a set of reactions that are highly efficient, specific, and bioorthogonal (meaning they occur selectively in biological systems without interfering with other processes). Click chemistry is often used in the development of ADCs because of its versatility, efficiency, and compatibility with biological systems. [0227] Both thiol-maleimide and click chemistry offer advantages in terms of selectivity, efficiency, and mild reaction conditions. The choice between these chemistries may depend on factors such as the specific functional groups available for modification, the stability of the conjugate under physiological conditions, and the overall design of the ADC. When developing an ADC, selecting the appropriate conjugation chemistry is a critical decision that can influence the stability, activity, and therapeutic potential of the final product. Factors to be considered include the characteristics of the components being conjugated, the desired drug-to-antibody ratio, and the potential impact of the chemistry on the antibody's binding affinity and biological function. [0228] Popular conjugation methods and recent approaches including the “click” conjugation and enzymatic ligation are described in “Antibody Drug Conjugates: Design and Selection of Linker, Payload and Conjugation Chemistry,” McCombs et al, AAPS J.2015 Mar; 17(2): 339–351. “Recent advances in antibody-drug conjugates produced using chemical conjugation technology,” Matsuda Y, J. ADC. January 5, 2023 also provides an overview of established full chemical conjugation methods that have already been applied in the scale-up phase for ADC production. The conjugates provided herein may be produced by any suitable established method. [0229] One aspect herein provides a method for producing an ADC. In some embodiments of the methods provided here, the cytotoxic payload of the ADC may be conjugated to an HLA-G antibody via a covalent linker. In some embodiments, the conjugate may be produced by conjugating the cytotoxic payload to the antibody using an amino or sulfhydryl specific linker that reacts with lysines or cysteines on the antibody surface. In some embodiments, the conjugation reaction happens in a closed system. In the closed system, no reactants or products can escape, only heat can be exchanged freely. In some embodiments, the method comprises treating the antibody to create a conjugation site on the antibody surface and reacting the conjugation site with the amino or sulfhydryl specific linker attached to the molecule. [0230] There are commercially available kits for ADC conjugation. Some ADC kits apply to general payloads with certain functional groups. Some ADC kits supply the selected, standard linkage molecules conjugated to a selected payload, ready with the appropriate reactive modifications to directly attach the payload and linker to the specific antibody of interest. The kits may be complete with all reagents and procedures for attaching the selected payload directly to the antibody of interest and purifying the final ADC. [0231] The cytotoxic payloads used herein, such as DGN549C, Monomethyl auristatin E (MMAE), Deruxtecan, SN-38, vc-SECO-DUBA (duocarmycin), Calicheamicin, SPDB-DM4, or Tesirine, may be commercially available. The cytotoxic payloads used herein may include a linker moiety that can react with the lysines or cysteines of the antibody provided herein to creat a covalent linkage between the cytotoxic payload and the antibody to thereby produce the conjugates provided here. EXAMPLES Example 1: HLA-G Expressing Cells Are Sensitive to Multiple Free Cytotoxic Payloads [0232] To determine the sensitivity of HLA-G expressing cell lines for multiple free payloads, cells were treated with each payload and cytotoxicity was assessed by measuring cell viability. Briefly, 5000 cells were plated in 75 µl of RPMI, 10% fetal bovine serum (FBS), 1% penicillin streptomycin (Pen Strep) in opaque flat bottom plates. Cells were allowed to attach to the plates for two hours followed by addition of payload compounds.25 µl of payload was added and the plates were transferred to an incubator for 72 hours at 37° C, 5% CO2. After 72 hours, plates were removed from the incubator, 70 µl of CellTiter-Glo mix was added to the wells, and the plates were placed on a shaker for 1 minute. Plates were allowed to sit at room temperature for 10 minutes before reading the luminescence on the Biotek Cytation5 plate reader. [0233] FIGS.1A-1R show killing curves of CL2A-SN38, Deruxtecan, PABC- MMAE, calcheamicin, SPDB-DM4, teserine, seco-DUBA, and DGN549-C on multiple HLA-G endogenous (BICR6, HUP-T3, RERF, JEG3, HT1376) and over-expressing (AU565, OV90, TOV-112D, HEC-1-B, SK-MES-1, 22RV1, 721.221, A549, SKOV3) cells. [0234] The half-maximal inhibitory concentration (IC50) values of the payloads were measured. IC50 is the most widely used and informative measure of a drug's efficacy. It indicates how much drug is needed to inhibit a biological process by half, thus providing a measure of potency of an antagonist drug. The lower the IC50 value, the more potent the drug. [0235] Table 1 provides IC50 values (in nM) of different payloads on HLA-G expressing cell lines. Example 2: Anti-HLA-G Antibody Conjugated to Different Payloads Demonstrates Increased Cytotoxicity in Multiple Tumor Cell Lines [0236] To determine the in vitro cytotoxic potential of combining anti-HLA-G antibody with different cytotoxic payloads, HLA-G expressing cells were plated at 4000 cells per well in 50 µl of RPMI and 10% FBS and allowed to adhere overnight at 37° C, 5% CO2. Cells were treated with increasing concentration of either isotype conjugated ADC or anti- HLA-G conjugated ADC molecules. Cells were incubated for six days at 37° C, 5% CO2 and viability was determined by CellTiter-Glo. Luminescence was read on Biotek Cytation5 plate reader. [0237] Anti-HLA-G and isotype (hIgG1 AAA) antibodies were conjugated to DGN549C (FIGS.2A-2G), MMAE (FIGS.2H-2J) and Deruxtecan (FIG.2K), respectively. FIGS.2A-2K show that an anti-HLA-G antibody conjugated to a cytotoxic payload can significantly increase the target mediated cytotoxicity of multiple HLA-G expressing tumor cell lines compared to an isotype control conjugated molecule. [0238] Table 2 provides IC50 values (in nM) of anti-HLA-G ADCs on multiple HLA- G expressing cell lines. Example 3: Anti-HLA-G Antibodies Demonstrate Target Specific Internalization [0239] To determine whether anti-HLA-G antibodies can efficiently deliver payloads to the lysosome, cells over-expressing HLA-G or wildtype cells were cultured in 50 µl RPMI, 10% FBS, 1% Pen Strep and incubated overnight at 37° C, 5% CO2. Equal amounts of Fabfluor-pH Red antibody labeling reagent and anti-HLA-G antibody were mixed and incubated at 37° C for one hour.50 µl of Fabfluor/antibody premix was added to the cells for a final concentration of 4 µg/ml and the plate was transferred to the Incucyte Live-Cell Analysis System for real-time evaluation of antibody internalization. Antibody internalization into the lysosome was measured hourly by red florescence for 48 hours. [0240] FIGS.3A-3F show internalization of anti-HLA-G antibodies on HLA-G expressing cells. Cells expressing HLA-G internalize Fabfluor-conjugated anti-HLA-G antibodies in the lysosome. Upon internalization of the antibody in the acidic environment of the endosome and lysosome, red florescence is observed. Parental (wildtype) cells lacking expression of HLA-G do not bind anti-HLA-G antibodies and show minimal red florescence compared to HLA-G expressing cells. Example 4: Anti-HLA-G Antibody Drug Conjugates Show In Vivo Efficacy in Multiple Tumor Models [0241] To evaluate the tumor growth inhibition capacity of anti-HLA-G ADC molecules, nude mice were implanted with 1-5 × 106 HLA-G expressing tumor cell lines. Treatment of mice started between days 9 and 15 when mice had palpable tumors. Mice received either a single IV dose or one dose once weekly of anti-HLA-G ADC or isotype ADC for between one and three weeks. [0242] FIGS.4A-4E show anti-tumor activity of anti-HLA-G ADCs. Mice treated with either isotype (hIgG1 AAA) or anti-HLA-G conjugated to VcMMAE (3 mg/kg), Deruxtecan (6 mg/kg), DGN549C (1 mg/kg or 0.3 mg/kg) or SN38 (30 mg/kg), and tumors were measured biweekly. Tumor growth curves show reduced tumor growth in mice treated with anti-HLA-G ADCs compared to isotype treated mice in JEG3 (FIGS.4A-4C) and A549 (FIGS.4D-4E) tumor model. [0243] FIGS.6A-6F show anti-tumor activity of the anti-HLA-G-DGN549C conjugate (0.3 mg/kg) in admixture tumor models with 10-100% HLA-G expression. Cells for an admixture implantation were prepared by normalizing HLA-G positive and HLA-G negative (parental or HLA-G KO) cell lines to the same concentration of cells/ml, and then mixing the cell lines at the desired ratio of HLA-G positive and negative cells. Mice were treated with three doses of anti-HLA-G-DGN549C weekly. Tumor growth curves show reduced tumor growth in mice treated with anti-HLA-G-DGN549C compared to isotype treated mice in JEG3 (FIGS.6A-6C) and A549 (FIGS.6D-6E) tumor model. FIG.6F shows increased survival in mice treated with anti-HLA-G-DGN549C compared to isotype treated mice in JEG3 admixture tumor model. [0244] FIGS.7A-7D show anti-tumor activity of the anti-HLA-G-DGN549C conjugate (0.3 mg/kg or 0.1 mg/kg) in TOV-112D admixture tumor models with 100% or 20% HLA-G expression. Mice were treated with one dose of anti-HLA-G-DGN549C at 0.3 mg/kg or two doses of anti-HLA-G-DGN549C at 0.1 mg/kg. Tumor growth curves show reduced tumor growth in mice treated with anti-HLA-G-DGN549C compared to isotype treated mice (FIGS.7A-7B). FIGS.7C-7D show increased survival in mice treated with anti-HLA-G-DGN549C compared to isotype treated mice in TOV-112D admixture tumor model. [0245] The in vivo cytotoxicity of the conjugates provided herein is measured by the tumor volume changing with the days after tumor implantation, compared with the respective isotypes. The results show that when the isotypes were used, the tumor volume continued to grow with time. In contrast, all the conjugates provided herein were able to effectively suppress the growth of the tumor, especially after a short period, such as after the first 13, 16, 20, or 24 days after the tumor implantation, depending on the conjugate used. For example, the anti-HLA-G-DGN549C conjugate, at 1mg/kg, or at 0.3mg/kg on a single dose, was able to effectively reduce the tumor volume as soon as 6 days after treatment in established tumors. Similarly, the anti-HLA-G-Deruxtecan conjugate was also able to effectively reduce the tumor volume as soon as 7 days after treatment at a concentration of about 6mg/kg. In addition, the anti-HLA-G-DGN549C conjugate at 0.1 mg/kg was able to completely reduce tumor volume in the TOV-112D model with physiologically relevant HLA-G expression reflecting patient-derived tumors. Lastly, anti-tumor activity of the anti- HLA-G-DGN549C conjugate in admixture tumor models with 10-50% HLA-G expression indicates in vivo bystander activity in models with low and heterogeneous HLA-G expression. [0246] Example 5: Selection of HLA-G Antibodies [0247] HLA-G antibodies were selected from a synthetic library of human antibodies presented on the surface of yeast cells in IgG format, as generally described, e.g., in W02009036379; W02010105256; WO2012009568; and Xu et al., Protein Eng. Des. Sel., 2013, 26:663-670 (each incorporated by reference in its entirety), and more specifically as provided below. The sequences and characteristics of the antibodies isolated from the recombinant library are provided in Table S. [0248] Eight naive human synthetic yeast libraries each of ~10E+09 diversity were propagated as described in W02009036379; WO2010105256; WO2012009568; and Xu et al., Protein Eng. Des. Sel., 2013, 26:663-670; each incorporated by reference in its entirety. For the first two rounds of selection, a magnetic bead sorting technique utilizing the Miltenyi MACS® system was performed, as described in Siegel et al., J. Immunol. Meth., 2004, 286:141-153. The following rounds of selection were performed using flow cytometry-based sorting. For all rounds of selection, the antigen was biotinylated human HLA-G, decreasing concentrations of antigen were used in each subsequent round of selection. In addition to selection on antigen, some rounds of selection were employed to reduce the number of nonspecific binders utilizing soluble membrane proteins from CHO cells (see WO2014179363 and Xu et al., Protein Eng. Des. Sel., 2013, 26:663-670, each incorporated by reference in its entirety). In addition to the CHO cell proteins, deselections against recombinant HLA- A/B/C proteins were performed to maintain specific binding to HLA-G. After the final round of sorting, yeast were plated and individual colonies were picked for characterization and for nomination of clones for affinity maturation. [0249] Antibody variable domains of interest were synthesized, with codon optimization to maximize transient expression in host cells. The variable regions were cloned into expression vectors containing human immunoglobulin constant domains and their sequence confirmed. Antibody heavy and light chain vector pairings were transfected into Expi293 cells using the Expifectamine system (Invitrogen). Transient cultures were harvested on day 4 and clarified cell culture supernatant IgG titer was estimated using Bio- Layer Interferometry (BLI) using Octet (ForteBio) alongside standards. Antibodies were subsequently purified on a Protein A column and eluted using low pH glycine. Purified antibody samples were then buffer-exchanged or dialyzed into downstream assay-compatible buffers. [0250] Antibody purity was assessed by running samples on SDS-PAGE and on an analytical size exclusion chromatography column. [0251] Light Chain Shuffling: Heavy chain plasmids were extracted from na'ive outputs (described herein) and transformed into a pre-made naive light chain library with a diversity of 10E+06. Selections were performed as described above with one round of MACS sorting and three rounds of FACS sorting using decreasing amounts of biotinylated HLA-G antigen for respective rounds. Example 6: Affinity Maturation [0252] Optimization of naive clones was carried out utilizing four maturation strategies; diversification of CDR-H1 and CDR-H2; diversification of CDR-H3; diversification of CDR-L1, L2 and L3; shuffling of diversified heavy and light chains. [0253] CDR-H1 and CDR-H2 Selection: The CDR-H3s from clones selected from light chain batch diversification, light chain diversification, and naive discovery efforts were independently recombined into premade libraries with CDR-H1 and CDR-H2 variants of a diversity of >10E+8. Selections were performed using HLA-G antigen. Affinity pressures were applied by using decreasing concentrations of antigen and HLA-G specificity was maintained with deselections against HLA-A/B/C antigens. [0254] CDR-H3 Selection: After characterization of CDR-H1 and CDR-H2 variants, clones with binding to HLA antigens outside of HLA-G were removed. Chemical liabilities were also removed from the variable regions when applicable. The remaining clones obtained from the CDR-H1 and CDR-H2 selection procedure were subject to additional rounds of affinity maturation via walking dimer mutagenesis of the CDR-H3. Selections were performed using HLA-G as antigen generally as described above, except for employing FACS sorting for all selection rounds. [0255] CDR-L1, L2, L3 Selection: Clones obtained from the CDR-H1 and CDR-H2 selection procedure were subject to additional rounds of affinity maturation via mutagenesis of the light chain. The CDR-L1 and CDR-L2 diversity was derived from a pre-made library while CDR-L3 diversity was derived from walking monomer mutagenesis. Selections were performed using HLA-G as antigen, starting with one round of MACS followed by three rounds of FACS in the CDR-L1, L2, L3 process described here. [0256] Diversified Heavy Chain and Light Chain Shuffling: Outputs from CDR-H3 diversification and CDR-L1, L2, L3 diversification described above were recombined and selections were performed using HLA-G as antigen generally as described above, except for employing FACS sorting for all selection rounds. Example 7: Binding Affinity of Anti-HLA-G Antibodies to Recombinant HLA-G [0257] Binding kinetics were measured using the Octet Red96 system (Pall ForteBio) at 30°C in running buffer (lx Pall ForteBio Kinetics Buffer diluted into lx PBS pH 7.4). In brief, 0.16 pg/ml of biotinylated recombinant HLA-G/32m/peptide heterotrimer was loaded onto streptavidin (SA) biosensors to a binding response of approximately 0.25 nm. After a short baseline step in running buffer, the biosensors were exposed to varying concentrations (1.5, 3.0, or 30 nM) of full-length anti-HLA-G mAbs for the association step. Dissociation of the complex was monitored upon dipping the sensors to running buffer once again for up to 30 min. Data was processed using ForteBio Octet DataAnalysis software (version 10) with background subtraction of biosensors without HLA-G. A 1: 1 Langmuir binding model was fit to each sensorgram to obtain association and dissociation rates via local-full or local- partial fitting. KD was calculated from the ratio of kd to ka. Monovalent affinities were obtained using identical methods but Fabs were used instead of IgGs.
[0258] Table 3 shows avid and monovalent affinities of anti-HLA-G antibodies to recombinant HLA-G protein. [0259] Data shown in Table 3 had R2 >0.98. ND= not determined using Fabs. The avid KD values ranged from 11.7 nanomolar to sub picomolar with off-rates (koff) ranging from 0.007 sec-1 to the Octet off-rate limit (1.0 x 10-7 sec-1). Monovalent KD values ranged from 0.187 nM to 208 nM, but monovalent affinities for clones that had weaker avid affinities were not determined. Example 8: Synthesis of Antibody-Drug Conjugates [0260] All TTX-080 and isotype control antibody-drug conjugates (ADC) were synthesized at NJ Bio (Princeton, New Jersey, USA). ADCs with linker-payloads (LP) CL2A-SN38, Deruxtecan, mc-vc-PAB-MMAE, and DGN549-C were synthesized via cysteine conjugation with the LPs. ADCs with LP vc-SECO-DUBA were synthesized via stochastic maleimide conjugation to interchain cysteines of TTX-080 and isotype control with vc-SECO-DUBA. [0261] For cysteine conjugations, TTX-080 and isotype control were reduced with tris(2-carboxyethyl) phosphine^(TCEP) for 1.5 h at 37 °C to expose the thiol groups of the interchain cysteine residues, and then conjugated with the specific LP for 2 h at room temperature. For maleimide conjugations, TTX-080 and isotype control were reduced with TCEP, and then conjugated with maleimide-functionalized vc-SECO-DUBA. [0262] ADCs were purified by size exclusion chromatography (SEC) to remove residual LP and to produce the target drug antibody ratio (DAR): CL2A-SN38 (DAR 5.4- 6.4), Deruxtecan (DAR 6.4-8.6), mc-vc-PAB-MMAE (DAR 3.3-3.9), DGN549C (DAR 1.7- 1.74), and vc-SECO-DUBA (DAR 2.5-3.5). DAR was assessed by HIC, RP-LC/MS, RP-LC, and/or UV/Vis. All ADCs have monomeric purity of ≥95% by SEC and endotoxin of ≤1 EU/mg by LAL assay, and are in 1X PBS, pH 6.5 or 7.4, concentrated, and flash frozen for storage at -80^°C. [0263] Table 4 shows the chemical structure of some of the antibody-drug conjugates synthesized. Chemical Structure 1 TTX-080- DGN549-C 2 TTX-080- CL2A- SN38 3 TTX-080- mc-vc- PAB- MMAE TTX-80- DXD Isotype Control- DGN549-C Isotype Control- CL2A- SN38 Isotype Control- mc-vc- PAB- MMAE Isotype Control- DXD
9 TTX-080- vc-SECO- DUBA Example 9: In vivo Detection of Anti-HLA-G Antibody Drug Conjugates in Mouse Serum [0264] BALB/c mice were IV dosed with 0.3 mg/kg of anti-HLA-G antibody or anti- HLA-G-DGN549C conjugate and serum was collected 2 hours, 1 day, 3 days, and 7 days post injection. Antibodies were quantified in mouse serum using a human/non-human primate IgG detection kit from Meso Scale Discovery. [0265] FIG.5 shows similar in vivo antibody levels and kinetics between 0.3 mg/kg of anti-HLA-G antibody and anti-HLA-G-DGN549C conjugate after 7 days. Example 10: Anti-HLA-G Antibody Drug Conjugates Show In Vivo Efficacy in Multiple Patient-Derived Xenograft Models [0266] To evaluate the tumor growth inhibition capacity of anti-HLA-G ADC molecules, nude mice were implanted with HLA-G expressing patient-derived xenograft (PDX) tumor fragments. Treatment of mice started when tumors reach an average tumor volume of 150-300mm³. Mice received 3 weekly IV doses of anti-HLA-G ADC or isotype ADC. [0267] FIGS.8A-8B show anti-tumor activity of anti-HLA-G ADCs. Mice treated with either isotype (hIgG1 AAA) or anti-HLA-G conjugated to DGN549C (0.3 mg/kg) and tumors were measured biweekly. Tumor growth curves show reduced tumor growth in mice treated with anti-HLA-G ADCs compared to isotype treated mice in melanoma PDX CRT00465 (FIGS.8A) and pancreatic PDX CRT0000 (8B) tumor models. [0268] Patient-derived tumor models (PDX) with verified HLA-G expression were evaluated to further explore the activity of an HLA-G antibody conjugated to DGN549C in a more physiological model. The in vivo cytotoxicity of the conjugate provided herein is measured by the tumor volume changing with the days after tumor implantation, compared with the respective isotypes. The results show that when the isotypes were used, the tumor volume continued to grow with time. In contrast, the DGN549C conjugate provided herein were able to effectively suppress the growth of the tumor in a melanoma and a pancreatic patient derived tumor. For example, the anti-HLA-G-DGN549C conjugate at 0.3mg/kg (3 weekly-doses), was able to effectively reduce the tumor volume as in established tumors 15 days after dosing in the melanoma PDX CRT00465 (FIG 8 A.) and 25 days after dosing in the pancreatic PDX CRT00400 (FIG 8B.) Example S: Sequences [0269] Table S provides sequences referred to herein. Table S Sequences. SEQ Region Scheme/Clone Sequence ID NO: 1 CDR-H1 Chothia GGSISSSDY 2 CDR-H1 Chothia GGSISSSST 3 CDR-H1 Chothia GGSISSSDT 4 CDR-H1 Chothia GGSISSADN 5 CDR-H1 Chothia GGSVSSSST 6 CDR-H1 Chothia GYSISSGY 7 CDR-H1 Chothia GYSILSGY 8 CDR-H1 Chothia GYSISSGH 9 CDR-H1 Chothia GYSISSGF 10 CDR-H1 Chothia GFTFDNY 11 CDR-H1 Chothia GFTFSDY 12 CDR-H1 Chothia GFTFSSS 13 CDR-H1 Chothia GGSISSSN CDR-H1 Chothia GGSISSSSY CDR-H1 Kabat SSDYYWG CDR-H1 Kabat SSSTYWA CDR-H1 Kabat SSSTYWG CDR-H1 Kabat SSDTYWG CDR-H1 Kabat SADNYWG CDR-H1 Kabat SSSTYWS CDR-H1 Kabat SGYYWG CDR-H1 Kabat SGYYWF CDR-H1 Kabat SGHYWI CDR-H1 Kabat SGFYWT CDR-H1 Kabat SGYYWL CDR-H1 Kabat SGHYWT CDR-H1 Kabat NYAMH CDR-H1 Kabat DYYMS CDR-H1 Kabat SSAMA CDR-H1 Kabat SSNWWS CDR-H1 Kabat SSSYYWG CDR-H2 Chothia YYSGS CDR-H2 Chothia SSSGS CDR-H2 Chothia HHSGA CDR-H2 Chothia HYSGS CDR-H2 Chothia AYSGS CDR-H2 Chothia SYNAL CDR-H2 Chothia YHSGS CDR-H2 Chothia YHSAS CDR-H2 Chothia SARGI CDR-H2 Chothia ASSGSV CDR-H2 Chothia SGSGIT CDR-H2 Chothia SYSGS CDR-H2 Chothia SSSGST CDR-H2 Kabat SIYYSGSTYYNPSLKS CDR-H2 Kabat SISSSGSTYYNPSLKS CDR-H2 Kabat SIHHSGATYYNPSLKS CDR-H2 Kabat SIHYSGSTLYNPSLKS CDR-H2 Kabat SIHYSGSTYYNPSLKS CDR-H2 Kabat GIAYSGSTYYNPSLKS CDR-H2 Kabat SISYNALTYYNPSLKS CDR-H2 Kabat SIYHSGSTYYNPSLKS CDR-H2 Kabat GIYHSASTAYNPSLKS CDR-H2 Kabat GIYHSGSTYYNPSLKS CDR-H2 Kabat AIYHSGSTVYNPSLKS CDR-H2 Kabat GIYHSGSTAYNPSLKS CDR-H2 Kabat AISARAGITYYADSVKG CDR-H2 Kabat YIASSGSVIYYADSVKG CDR-H2 Kabat TISGSGITTWYADSVKG CDR-H2 Kabat EIYHSGSTNYNPSLKS CDR-H2 Kabat SISYSGSTYYNPSLKS CDR-H2 Kabat YISSSGSTIYYADSVKG CDR-H3 GVRRAVPFDY CDR-H3 GIARAVPFDY CDR-H3 GPKRAVPFDY CDR-H3 GVRRAVPFVD CDR-H3 GVRRAVPFQR CDR-H3 GTRRAVPFDY CDR-H3 GVRRAVPFAD CDR-H3 GIRRAVPFDY CDR-H3 GQFRAVPFDY CDR-H3 GGTHTYSRGPMDV CDR-H3 GGTHTYSRGPFDV CDR-H3 GGTPIYSRGPLDV CDR-H3 GGGQTYSRGPLDV CDR-H3 GGGATYSRGPLDV CDR-H3 GGTHTYSRGPLDV CDR-H3 GGTVKYSRGPLDV CDR-H3 GGQVTYSRGPLDV CDR-H3 GGEVTYSRGPLDV CDR-H3 RIGYSYGTAPPFDV CDR-H3 HGTPRAFDI CDR-H3 GSRHLNAFNR CDR-H3 GVYHYDPYGMDV CDR-H3 TELGKMHFDY CDR-H3 GSPRYMQD CDR-H3 HSSLGTHNWFDP CDR-H3 EGALSYSWLAAFDI CDR-L1 RASQSVSSSYLA CDR-L1 GASQSVSSDYLA CDR-L1 QASQAVSSNYLA CDR-L1 GASQSVSSAFLA CDR-L1 RASQSVSSTYLA CDR-L1 QASQSVSSSYLA CDR-L1 KASQAVSSSYLA CDR-L1 EASQSVSSSYLA CDR-L1 EASQSVSASYLA CDR-L1 EASQSVSSAYLA CDR-L1 RVSQSVSDAYLA CDR-L1 EVSQSVSASYLA CDR-L1 RASQSVSSAYLA CDR-L1 RASNAVSSSYLA CDR-L1 RASQSINSWLA CDR-L1 AASQGISSDLA CDR-L1 RASQDISTYLN CDR-L1 RSSQSLLHSNGYNYLD CDR-L1 RASQSISSYLN CDR-L1 RASQSVSSNLA CDR-L2 GASSRAT CDR-L2 GAYSLAT CDR-L2 GASARAT CDR-L2 GASSREA CDR-L2 GASNRAA CDR-L2 GASSRQD CDR-L2 GASNRAT CDR-L2 DASSRAS CDR-L2 DASTRAT CDR-L2 GASDRAN CDR-L2 GASYRAT CDR-L2 DASSLES CDR-L2 SASSTQS CDR-L2 DAFNLET CDR-L2 LGSNRAS CDR-L2 GASRRAT CDR-L2 AASSLQS CDR-L2 GASTRAT CDR-L3 QQAVHSPYT CDR-L3 QWAVHSPYT CDR-L3 QQVVHSPYT CDR-L3 QQTVHSPYT CDR-L3 QQAIHSPYT CDR-L3 QQHSSYPPT CDR-L3 QQHSLYPPT CDR-L3 QQFSSYPPT CDR-L3 QQVSSYPPT CDR-L3 QQHSIYPPT CDR-L3 QQYDSHIT CDR-L3 QQAYLYPIT CDR-L3 QQLPFLPIT CDR-L3 MQALGGPWT CDR-L3 QQYVSDPIT CDR-L3 QQVGSSPIT CDR-L3 QQSHLVPRT CDR-L3 QQANHHPPFT VH QLQLQESGPGLVKPSETLSLTCTVSGGSISS SD YYWGWIRQPPGKGLEWIGSIYYSGSTYYN PSLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GVRRAVPFDYWGQGTLVTVSS VH QLQLQESGPGLVKPSETLSLTCTVSGGSISS SS TYWAWIRQPPGKGLEWIGSISSSGSTYYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GIARAVPFDYWGQGTLVTVSS VH QLQLQESGPGLVKPSETLSLTCTVSGGSISS SS TYWGWIRQSPGKGLEWIGSIHHSGATYYN PSLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GPKRAVPFDYWGQGTLVTVSS VH QLQLQESGPGLVKPSETLSLTCTVSGGSISS SD TYWGWIRQPPGKGLEWIGSIHYSGSTLYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GVRRAVPFVDWGQGTLVTVSS VH QLQLQESGPGLVKPSETLSLTCTVSGGSISS AD NYWGWIRQPPGKGLEWIGSIHYSGSTYYN PSLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GVRRAVPFQRWGQGTLVTVSS VH QLQLQESGPGLVKPSETLSLTCTVSGGSISS SD TYWGWIRQPPGKGPEWIGSIHYSGSTLYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GVRRAVPFDYWGQGTLVTVSS VH QLQLQESGPGLVKPSETLSLTCTVSGGSISS SS TYWSWIRQPPGKGLEWIGGIAYSGSTYYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GVRRAVPFDYWGQGTLVTVSS VH QLQLQESGPGLVKPSETLSLTCTVSGGSISS SS TYWSWIRQPPGKGLEWIGSISYNALTYYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GTRRAVPFDYWGQGTLVTVSS VH QLQLQESGPGLVKPSETLSLTCTVSGGSISS SS TYWSWIRQPPGKGLEWIGGIAYSGSTYYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GVRRAVPFADWGQGTLVTVSS VH QLQLQESGPGLVKPSETLSLTCTVSGGSVSS SS TYWSWIRQPPGKGLEWIGGIAYSGSTYYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GVRRAVPFDYWGQGTLVTVSS VH QLQLQESGPGLVKPSETLSLTCTVSGGSISS SS TYWSWIRQPPGKGLEWIGGIAYSGSTYYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GTRRAVPFDYWGQGTLVTVSS VH QLQLQESGPGLVKPSETLSLTCTVSGGSISS SD TYWGWIRQPPGKGLEWIGSIHYSGSTLYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GIRRAVPFDYWGQGTLVTVSS VH QLQLQESGPGLVKPSETLSLTCTVSGGSISS SD TYWGWIRQPPGKGLEWIGSIHYSGSTLYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GQFRAVPFDYWGQGTLVTVSS VH QVQLQESGPGLVKPSETLSLTCAVSGYSISS GY YWGWIRQPPGKGLEWIGSIYHSGSTYYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GTHTYSRGPMDVWGQGTTVTVSS VH QLQLQESGPRLVKPSETLSLTCAVSGYSISS GY YWGWIRQPPGKGLEWIGSIYHSGSTYYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GTHTYSRGPFDVWGQGTTVTVSS VH LVQLQESGPGLVKPSETLSLTCAVSGYSILS GY YWFWIRQPPGKGLEWIGGIYHSASTAYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GTPIYSRGPLDVWGQGTTVTVSS VH QVQLQESGPGLVKPSETLSLTCAVSGYSISS GH YWIWIRQPPGKGLEWIGGIYHSGSTYYNPS LKS RVTISVDTSKDQFSLKLSSVTAADTAVYYC ARG GGQTYSRGPLDVWGQGTTVTVSS VH QVQLQESGPGLVKPPETLSLTCAVSGYSISS GH YWIWIRQPPGKGLEWIGGIYHSGSTYYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GGATYSRGPLDVWGQGTTVTVSS VH QVQLQESGPGLVKPSETLSLTCAVSGYSILS GY YWFWIRQPPGKGLEWIGGIYHSGSTYYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GTHTYSRGPLDVWGQGTTVTVSS VH QVQLQESGPGLVKPSETLSLTCAVSGYSISS GF YWTWIRQPPGKGLEWIGAIYHSGSTVYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GTHTYSRGPLDVWGQGTTVTVSS VH QVQLQESGPGLVKPSETLSLTCAVSGYSISS GY YWLWIRQPPGKGLEWIGGIYHSASTAYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GTVKYSRGPLDVWGQGTTVTVSS VH QVQLQESGPGLVKPSETLSLTCAVSGYSISS GH YWTWIRQPPGKGLEWIGAIYHSGSTVYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GQVTYSRGPLDVWGQGTTVTVSS VH QVQLQESGPGLVKPSETLSLTCAVSGYSILS GY YWFWIRQPPGKGLEWIGGIYHSGSTAYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GEVTYSRGPLDVWGQGTTVTVSS VH EVQLLESGGGLVQPGGSLRLSCAASGFTFD NYA MHWVRQAPGKGLEWVSAISARAGITYYA DSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYY CARR IGYSYGTAPPFDVWGQGTTVTVSS VH QVQLVESGGGLVQPGGSLRLSCAASGFTFS DYY MSWIRQAPGKGLEWVSYIASSGSVIYYADS VKG RFTISRDNAKNSLYLQMNSLRAEDTAVYY CARH GTPRAFDIWGQGTTVTVSS VH EVQLLESGGGLVQPGGSLRLSCAASGFTFS SSA MAWVRQAPGKGLEWVSTISGSGITTWYAD SVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYY CAKG SRHLNAFNRWGQGTTVTVSS
VH QVQLQESGPGLVKPSGTLSLTCAVSGGSISS SN WWSWVRQPPGKGLEWIGEIYHSGSTNYNP SLKS RVTISVDKSKNQFSLKLSSVTAADTAVYYC ARG VYHYDPYGMDVWGQGTTVTVSS VH QLQLQESGPGLVKPSETLSLTCTVSGGSISS SS YYWGWIRQPPGKGLEWIGSISYSGSTYYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR TELGKMHFDYWGQGTLVTVSS VH QLQLQESGPGLVKPSETLSLTCTVSGGSISS SD YYWGWIRQPPGKGLEWIGSIYYSGSTYYN PSLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GSPRYMQDWGQGTLVTVSS VH QVQLVESGGGLVKPGGSLRLSCAASGFTFS DYY MSWIRQAPGKGLEWVSYISSSGSTIYYADS VKG RFTISRDNAKNSLYLQMNSLRAEDTAVYY CARH SSLGTHNWFDPWGQGTLVTVSS VH QVQLQESGPGLVKPSETLSLTCAVSGYSISS GY YWGWIRQPPGKGLEWIGSIYHSGSTYYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARE GALSYSWLAAFDIWGQGTMVTVSS VL EIVLTQSPGTLSLSPGERATLSCRASQSVSS SY LAWYQQKPGQAPRLLIYGASSRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQAVHSP YTF GGGTKVEIK VL EIVLTQSPGTLSLSPGERATLSCGASQSVSS DY LAWYQQKPGQAPRLLIYGAYSLATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQWAVHSP YTF GGGTKVEIK VL EIVLTQSPGTLSLSPGERATLSCQASQAVSS NY LAWYQQKPGQAPRLLIYGASSRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQVVHSP YTF GGGTKVEIK VL EIVLTQSPGTLSLSPGERATLSCGASQSVSS AF LAWYQQKPGQAPRLLIYGASARATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQVVHSP YTF GGGTKVEIK VL EIVLTQSPGTLSLSPGERATLSCRASQSVSS TY LAWYQQKPGQAPRLLIYGASSREAGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQTVHSP YTF GGGTKVEIK VL EIVLTQSPGTLSLSPGERATLSCQASQAVSS NY LAWYQQKPGQAPRLLIYGASNRAAGIPDR FSGS GSGTDFTLTISRLEPEDFAVYYCQQAIHSPY TF GGGTKVEIK VL EIVLTQSPGTLSLSPGERATLSCQASQSVSS SY LAWYQQKPGQAPRLLIYGASNRAAGIPDR FSGS GSGTDFTLTISRLEPEDFAVYYCQQVVHSP YTF GGGTKVEIK VL EIVLTQSPGTLSLSPGERATLSCKASQAVSS SY LAWYQQKPGQAPRLLIYGASSRQDGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQVVHSP YTF GGGTKVEIK VL EIVLTQSPGTLSLSPGERATLSCRASQSVSS SY LAWYQQKPGQAPRLLIYGASSRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQHSSYPP TF GGGTKVEIK VL EIVLTQSPGTLSLSPGERATLSCEASQSVSSS Y LAWYQQKPGQAPRLLIYGASNRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQHSLYPP TF GGGTKVEIK VL EIVLTQSPGTLSLSPGERATLSCEASQSVSA SY LAWYQQKPGQAPRLLIYDASSRASGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQFSSYPP TF GGGTKVEIK VL EIVLTQSPGTLSLSPGERATLSCEASQSVSS AY LAWYQQKPGQAPRLLIYDASTRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQVSSYPP TF GGGTKVEIK VL EIVLTQSPGTLSLSPGERAALSCRVSQSVSD AY LAWYQQKPGQAPRLLIYDASSRASGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQVSSYPP TF GGGTKVEIK VL EIVLTQSPGTLSLSPGERATLSCEVSQSVSA SY LAWYQQKPGQAPRLLIYGASSRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQHSLYPP TF GGGTKVEIK VL EIVLTQSPGTLSLSPGERATLSCRASQSVSS AY LAWYQQKPGQAPRLLIYGASDRANGIPDR FSGS GSGTDFTLTISRLEPEDFAVYYCQQHSLYPP TF GGGTKVEIK VL EIVLTQSPGTLSLSPGERATLSCRASNAVSS SY LAWYQQKPGQAPRLLIYGASDRANGIPDR FSGS GSGTDFTLTISRLEPEDFAVYYCQQHSIYPP TF GGGTKVEIK VL EIVLTQSPGTLSLSPGERATLSCRASNAVSS SY LAWYQQKPGQAPRLLIYGASYRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQHSLYPP TF GGGTKVEIK VL DIQMTQSPSTLSASVGDRVTITCRASQSINS WL AWYQQKPGKAPKLLISDASSLESGVPSRFS GSG SGTEFTLTISSLQPDDFATYYCQQYDSHITF GG GTKVEIK VL DIQMTQSPSSVSASVGDRVTITCAASQGISS DL AWYQQKPGKAPKLLIYSASSTQSGVPSRFS GSG SGTDFTLTISSLQPEDFATYYCQQAYLYPIT FG GGTKVEIK VL GVQMTQSPSSLSASVGDRVTITCRASQDIS TYL NWYQQKPGKAPKLLIYDAFNLETGVPSRFS GSG SGTDFTFTISSLQPEDIATYYCQQLPFLPITF G GGTKVEIK VL DIVMTQSPLSLPVTPGEPASISCRSSQSLLHS N GYNYLDWYLQKPGQSPQLLIYLGSNRASG VPDR FSGSGSGTDFTLKISRVEAEDVGVYYCMQ ALGG PWTFGGGTKVEIK VL EIVLTQSPGTLSLSPGERATLSCRASQSVSS SY LAWYQQKPGQAPRLLIYGASRRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQYVSDPI TF GGGTKVEIK VL EIVLTQSPGTLSLSPGERATLSCRASQSVSS SY LAWYQQKPGQAPRLLIYGASRRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQVGSSPI TF GGGTKVEIK VL DIQMTQSPSSLSASVGDRVTITCRASQSISS YL NWYQQKPGKAPKLLIYAASSLQSGVPSRFS GSG SGTDFTLTISSLQPEDFATYYCQQSHLVPRT FG GGTKVEIK VL EIVMTQSPATLSVSPGERATLSCRASQSVSS NL AWYQQKPGQAPRLLIYGASTRATGIPARFS GSG SGTEFTLTISSLQSEDFAVYYCQQANHHPPF TF GGGTKVEIK IGG1 AAA 33343 QLQLQESGPGLVKPSETLSLTCTVSGGSISS HC SD YYWGWIRQPPGKGLEWIGSIYYSGSTYYN PSLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GVRRAVPFDYWGQGTLVTVSSASTKGPSV FPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT QTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPP CPAPEAAGAPSVFLFPPKPKDTLMISRTPEV TC VVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKA LPAPIEKTISKAKGQPREPQVYTLPPSREEM TK NQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCS VMHEALHNHYTQKSLSLSPGK IGG1 AAA 37268 QLQLQESGPGLVKPSETLSLTCTVSGGSISS HC SS TYWAWIRQPPGKGLEWIGSISSSGSTYYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GIARAVPFDYWGQGTLVTVSSASTKGPSVF PLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT QTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPP CPAPEAAGAPSVFLFPPKPKDTLMISRTPEV TC VVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKA LPAPIEKTISKAKGQPREPQVYTLPPSREEM TK NQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCS VMHEALHNHYTQKSLSLSPGK IGGI AAA 37269 QLQLQESGPGLVKPSETLSLTCTVSGGSISS HC SS TYWGWIRQSPGKGLEWIGSIHHSGATYYN PSLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GPKRAVPFDYWGQGTLVTVSSASTKGPSV FPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT QTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPP CPAPEAAGAPSVFLFPPKPKDTLMISRTPEV TC VVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKA LPAPIEKTISKAKGQPREPQVYTLPPSREEM TK NQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCS VMHEALHNHYTQKSLSLSPGK IGG1 AAA 37271 QLQLQESGPGLVKPSETLSLTCTVSGGSISS HC SD TYWGWIRQPPGKGLEWIGSIHYSGSTLYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GVRRAVPFVDWGQGTLVTVSSASTKGPSV FPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT QTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPP CPAPEAAGAPSVFLFPPKPKDTLMISRTPEV TC VVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKA LPAPIEKTISKAKGQPREPQVYTLPPSREEM TK NQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCS VMHEALHNHYTQKSLSLSPGK IGG1 AAA 37272 QLQLQESGPGLVKPSETLSLTCTVSGGSISS HC AD NYWGWIRQPPGKGLEWIGSIHYSGSTYYN PSLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GVRRAVPFQRWGQGTLVTVSSASTKGPSV FPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT QTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPP CPAPEAAGAPSVFLFPPKPKDTLMISRTPEV TC VVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKA LPAPIEKTISKAKGQPREPQVYTLPPSREEM TK NQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCS VMHEALHNHYTQKSLSLSPGK IGG1 AAA 37277 QLQLQESGPGLVKPSETLSLTCTVSGGSISS HC SD TYWGWIRQPPGKGPEWIGSIHYSGSTLYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GVRRAVPFDYWGQGTLVTVSSASTKGPSV FPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT QTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPP CPAPEAAGAPSVFLFPPKPKDTLMISRTPEV TC VVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKA LPAPIEKTISKAKGQPREPQVYTLPPSREEM TK NQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCS VMHEALHNHYTQKSLSLSPGK IGG1 AAA 38373 QLQLQESGPGLVKPSETLSLTCTVSGGSISS HC SS TYWSWIRQPPGKGLEWIGGIAYSGSTYYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GVRRAVPFDYWGQGTLVTVSSASTKGPSV FPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT QTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPP CPAPEAAGAPSVFLFPPKPKDTLMISRTPEV TC VVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKA LPAPIEKTISKAKGQPREPQVYTLPPSREEM TK NQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCS VMHEALHNHYTQKSLSLSPGK IGG1 AAA 38375 QLQLQESGPGLVKPSETLSLTCTVSGGSISS HC SS TYWSWIRQPPGKGLEWIGSISYNALTYYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GTRRAVPFDYWGQGTLVTVSSASTKGPSV FPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSWTVPSSSL GT QTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPP CPAPEAAGAPSVFLFPPKPKDTLMISRTPEV TC WVDVSHEDPEVKFNWYVDGVEVHNAKTK PREE QYNSTYRWSVLTVLHQDWLNGKEYKCKV SNKA LPAPIEKTISKAKGQPREPQVYTLPPSREEM TK NQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCS VMHEALHNHYTQKSLSLSPGK IGG1 AAA 38379 QLQLQESGPGLVKPSETLSLTCTVSGGSISS HC SS TYWSWIRQPPGKGLEWIGGIAYSGSTYYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GVRRAVPFADWGQGTLVTVSSASTKGPSV FPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSWTVPSSSL GT QTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPP CPAPEAAGAPSVFLFPPKPKDTLMISRTPEV TC VVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKA LPAPIEKTISKAKGQPREPQVYTLPPSREEM TK NQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCS VMHEALHNHYTQKSLSLSPGK IGG1 AAA 38381 QLQLQESGPGLVKPSETLSLTCTVSGGSVSS HC SS TYWSWIRQPPGKGLEWIGGIAYSGSTYYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GVRRAVPFDYWGQGTLVTVSSASTKGPSV FPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT QTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPP CPAPEAAGAPSVFLFPPKPKDTLMISRTPEV TC VVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKA LPAPIEKTISKAKGQPREPQVYTLPPSREEM TK NQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCS VMHEALHNHYTQKSLSLSPGK IGG1 AAA 38383 QLQLQESGPGLVKPSETLSLTCTVSGGSISS HC SS TYWSWIRQPPGKGLEWIGGIAYSGSTYYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GTRRAVPFDYWGQGTLVTVSSASTKGPSV FPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT QTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPP CPAPEAAGAPSVFLFPPKPKDTLMISRTPEV TC VVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKA LPAPIEKTISKAKGQPREPQVYTLPPSREEM TK NQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCS VMHEALHNHYTQKSLSLSPGK IGG1 AAA 38386 QLQLQESGPGLVKPSETLSLTCTVSGGSISS HC SD TYWGWIRQPPGKGLEWIGSIHYSGSTLYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GIRRAVPFDYWGQGTLVTVSSASTKGPSVF PLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT QTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPP CPAPEAAGAPSVFLFPPKPKDTLMISRTPEV TC VVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNK ALPAPIEKTISKAKGQPREPQVYTLPPSREE MTK NQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCS VMHEALHNHYTQKSLSLSPGK IGG1 AAA 37273 QLQLQESGPGLVKPSETLSLTCTVSGGSISS HC SD TYWGWIRQPPGKGLEWIGSIHYSGSTLYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GQFRAVPFDYWGQGTLVTVSSASTKGPSV FPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSWTVPSSSL GT QTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPP CPAPEAAGAPSVFLFPPKPKDTLMISRTPEV TC WVDVSHEDPEVKFNWYVDGVEVHNAKTK PREE QYNSTYRWSVLTVLHQDWLNGKEYKCKV SNKA LPAPIEKTISKAKGQPREPQVYTLPPSREEM TK NQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCS VMHEALHNHYTQKSLSLSPGK IGG1 AAA 33361 QVQLQESGPGLVKPSETLSLTCAVSGYSISS HC GY YWGWIRQPPGKGLEWIGSIYHSGSTYYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GTHTYSRGPMDVWGQGTTVTVSSASTKGP SVFP LAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNS GALTSGVHTFPAVLQSSGLYSLSSWTVPSS SL GTQTYICNVNHKPSNTKVDKKVEPKSCDK THTC PPCPAPEAAGAPSVFLFPPKPKDTLMISRTP EV TCVWDVSHEDPEVKFNWYVDGVEVHNAK TKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKC KVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRE EM TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFS CSVMHEALHNHYTQKSLSLSPGK IGG1 AAA 35624 QLQLQESGPRLVKPSETLSLTCAVSGYSISS HC GY YWGWIRQPPGKGLEWIGSIYHSGSTYYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GTHTYSRGPFDVWGQGTTVTVSSASTKGP SVFP LAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNS GALTSGVHTFPAVLQSSGLYSLSSWTVPSS SL GTQTYICNVNHKPSNTKVDKKVEPKSCDK THTC PPCPAPEAAGAPSVFLFPPKPKDTLMISRTP EV TCWVDVSHEDPEVKFNWYVDGVEVHNAK TKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKC KVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRE EM TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFS CSVMHEALHNHYTQKSLSLSPGK IGG1 AAA 38410 LVQLQESGPGLVKPSETLSLTCAVSGYSILS HC GY YWFWIRQPPGKGLEWIGGIYHSASTAYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GTPIYSRGPLDVWGQGTTVTVSSASTKGPS VFP LAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSL GTQTYICNVNHKPSNTKVDKKVEPKSCDK THTC PPCPAPEAAGAPSVFLFPPKPKDTLMISRTP EV TCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRE EM TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFS CSVMHEALHNHYTQKSLSLSPGK IGG1 AAA 38418 QVQLQESGPGLVKPSETLSLTCAVSGYSISS HC GH YWIWIRQPPGKGLEWIGGIYHSGSTYYNPS LKS RVTISVDTSKDQFSLKLSSVTAADTAVYYC ARG GGQTYSRGPLDVWGQGTTVTVSSASTKGP SVFP LAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNS GALTSGVHTPAVLQSSGLYSLSSVVTVPSS SL GTQTYICNVNHKPSNTKVDKKVEPKSCDK THTC PPCPAPEAAGAPSVFLFPPKPKDTLMISRTP EV TCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRE EM TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFS CSVMHEALHNHYTQKSLSLSPGK IG G1 38420 QVQLQESGPGLVKPPETLSLTCAVSGYSISS AAA HC GH YWIWIRQPPGKGLEWIGGIYHSGSTYYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GGATYSRGPLDVWGQGTTVTVSSASTKGP SVFP LAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSL GTQTYICNVNHKPSNTKVDKKVEPKSCDK THTC PPCPAPEAAGAPSVFLFPPKPKDTLMISRTP EV TCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRE EM TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFS CSVMHEALHNHYTQKSLSLSPGK IGG1 AAA 38421 QVQLQESGPGLVKPSETLSLTCAVSGYSILS HC GY YWFWIRQPPGKGLEWIGGIYHSGSTYYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GTHTYSRGPLDVWGQGTTVTVSSASTKGP SVFP LAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSL GTQTYICNVNHKPSNTKVDKKVEPKSCDK THTC PPCPAPEAAGAPSVFLFPPKPKDTLMISRTP EV TCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRE EM TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFS CSVMHEALHNHYTQKSLSLSPGK IGG1 AAA 38422 QVQLQESGPGLVKPSETLSLTCAVSGYSISS HC GF YWTWIRQPPGKGLEWIGAIYHSGSTVYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GTHTYSRGPLDVWGQGTTVTVSSASTKGP SVFP LAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSL GTQTYICNVNHKPSNTKVDKKVEPKSCDK THTC PPCPAPEAAGAPSVFLFPPKPKDTLMISRTP EV TCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRE EM TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFS CSVMHEALHNHYTQKSLSLSPGK IGG1 AAA 38424 QVQLQESGPGLVKPSETLSLTCAVSGYSISS HC GY YWLWIRQPPGKGLEWIGGIYHSASTAYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GTVKYSRGPLDVWGQGTTVTVSSASTKGP SVFP LAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSL GTQTYICNVNHKPSNTKVDKKVEPKSCDK THTC PPCPAPEAAGAPSVFLFPPKPKDTLMISRTP EV TCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRE EM TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFS CSVMHEALHNHYTQKSLSLSPGK IGG1 AAA 38425 QVQLQESGPGLVKPSETLSLTCAVSGYSISS HC GH YWTWIRQPPGKGLEWIGAIYHSGSTVYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GQVTYSRGPLDVWGQGTTVTVSSASTKGP SVFP LAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSL GTQTYICNVNHKPSNTKVDKKVEPKSCDK THTC PPCPAPEAAGAPSVFLFPPKPKDTLMISRTP EV TCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRE EM TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFS CSVMHEALHNHYTQKSLSLSPGK IGG1 AAA 38426 QVQLQESGPGLVKPSETLSLTCAVSGYSILS HC GY YWFWIRQPPGKGLEWIGGIYHSGSTAYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GEVTYSRGPLDVWGQGTTVTVSSASTKGP SVFP LAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSL GTQTYICNVNHKPSNTKVDKKVEPKSCDK THTC PPCPAPEAAGAPSVFLFPPKPKDTLMISRTP EV TCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRE EM TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFS CSVMHEALHNHYTQKSLSLSPGK IGG1 AAA 37323 EVQLLESGGGLVQPGGSLRLSCAASGFTFD HC NYA MHWVRQAPGKGLEWVSAISARAGITYYA DSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYY CARR IGYSYGTAPPFDVWGQGTTVTVSSASTKGP SVF PLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVP SSS LGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHT CPPCPAPEAAGAPSVFLFPPKPKDTLMISRT PE VTCVVVDVSHEDPEVKFNWYVDGVEVHN AKTKP REEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVS NKALPAPIEKTISKAKGQPREPQVYTLPPSR EE MTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENN YKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVF SCSVMHEALHNHYTQKSLSLSPGK IGG1 AAA 38389 QVQLVESGGGLVQPGGSLRLSCAASGFTFS HC DYY MSWIRQAPGKGLEWVSYIASSGSVIYYADS VKG RFTISRDNAKNSLYLQMNSLRAEDTAVYY CARH GTPRAFDIWGQGTTVTVSSASTKGPSVFPL APS SKSTSGGTAALGCLVKDYFPEPVTVSWNS GALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT QT YICNVNHKPSNTKVDKKVEPKSCDKTHTC PPCP APEAAGAPSVFLFPPKPKDTLMISRTPEVTC VV VDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQY NSTYRVVSVLTVLHQDWLNGKEYKCKVS NKALP APIEKTISKAKGQPREPQVYTLPPSREEMTK NQ VSLTCLVKGFYPSDIAVEWESNGQPENNY KTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVM HEALHNHYTQKSLSLSPGK IGG1 AAA 38358 EVQLLESGGGLVQPGGSLRLSCAASGFTFS HC SSA MAWVRQAPGKGLEWVSTISGSGITTWYAD SVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYY CAKG SRHLNAFNRWGQGTTVTVSSASTKGPSVF PLAP SSKSTSGGTAALGCLVKDYFPEPVTVSWNS GAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TQ TYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPC PAPEAAGAPSVFLFPPKPKDTLMISRTPEVT CV VVDVSHEDPEVKFNWYVDGVEVHNAKTK PREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKAL PAPIEKTISKAKGQPREPQVYTLPPSREEMT KN QVSLTCLVKGFYPSDIAVEWESNGQPENN YKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVF SCSV MHEALHNHYTQKSLSLSPGK IGG1 AAA 33303 QVQLQESGPGLVKPSGTLSLTCAVSGGSISS HC SN WWSWVRQPPGKGLEWIGEIYHSGSTNYNP SLKS RVTISVDKSKNQFSLKLSSVTAADTAVYYC ARG VYHYDPYGMDVWGQGTTVTVSSASTKGP SVFPL APSSKSTSGGTAALGCLVKDYFPEPVTVSW NSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LG TQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCP PCPAPEAAGAPSVFLFPPKPKDTLMISRTPE VT CVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSREE MT KNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSC SVMHEALHNHYTQKSLSLSPGK IGG1 AAA 33342 QLQLQESGPGLVKPSETLSLTCTVSGGSISS HC SS YYWGWIRQPPGKGLEWIGSISYSGSTYYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR TELGKMHFDYWGQGTLVTVSSASTKGPSV FPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT QTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPP CPAPEAAGAPSVFLFPPKPKDTLMISRTPEV TC VVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKA LPAPIEKTISKAKGQPREPQVYTLPPSREEM TK NQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCS VMHEALHNHYTQKSLSLSPGK IGG1 AAA 33299 QLQLQESGPGLVKPSETLSLTCTVSGGSISS HC SD YYWGWIRQPPGKGLEWIGSIYYSGSTYYN PSLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GSPRYMQDWGQGTLVTVSSASTKGPSVFP LAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNS GALT SGVHTFPAVLQSSGLYSLSSWTVPSSSLGT QT YICNVNHKPSNTKVDKKVEPKSCDKTHTC PPCP APEAAGAPSVFLFPPKPKDTLMISRTPEVTC W VDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQY NSTYRWSVLTVLHQDWLNGKEYKCKVSN KALP APIEKTISKAKGQPREPQVYTLPPSREEMTK NQ VSLTCLVKGFYPSDIAVEWESNGQPENNY KTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVM HEALHNHYTQKSLSLSPGK IGG1 AAA 33351 QVQLVESGGGLVKPGGSLRLSCAASGFTFS HC DYY MSWIRQAPGKGLEWVSYISSSGSTIYYADS VKG RFTISRDNAKNSLYLQMNSLRAEDTAVYY CARH SSLGTHNWFDPWGQGTLVTVSSASTKGPS VFPL APSSKSTSGGTAALGCLVKDYFPEPVTVSW NSG ALTSGVHTFPAVLQSSGLYSLSSWTVPSSS LG TQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCP PCPAPEAAGAPSVFLFPPKPKDTLMISRTPE VT CWVDVSHEDPEVKFNWYVDGVEVHNAKT KPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCK VSNK ALPAPIEKTISKAKGQPREPQVYTLPPSREE MT KNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSC SVMHEALHNHYTQKSLSLSPGK IGG1 AAA 33357 QVQLQESGPGLVKPSETLSLTCAVSGYSISS HC GY YWGWIRQPPGKGLEWIGSIYHSGSTYYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARE GALSYSWLAAFDIWGQGTMVTVSSASTKG PSVF PLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPS SS LGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHT CPPCPAPEAAGAPSVFLFPPKPKDTLMISRT PE VTCVVVDVSHEDPEVKFNWYVDGVEVHN AKTKP REEQYNSTYRWSVLTVLHQDWLNGKEYK CKVS NKALPAPIEKTISKAKGQPREPQVYTLPPSR EE MTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENN YKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVF SCSVMHEALHNHYTQKSLSLSPGK IGG4 HC 33343 QLQLQESGPGLVKPSETLSLTCTVSGGSISS SD YYWGWIRQPPGKGLEWIGSIYYSGSTYYN PSLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GVRRAVPFDYWGQGTLVTVSSASTKGPSV FPLA PCSRSTSESTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPA PEFLGGPSVFLFPPKPKDTLMISRTPEVTCV VV DVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSN KGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTKN QV SLTCLVKGFYPSDIAVEWESNGQPENNYKT TPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCS VMH EALHNHYTQKSLSLSPGK IGG4 HC 37268 QLQLQESGPGLVKPSETLSLTCTVSGGSISS SS TYWAWIRQPPGKGLEWIGSISSSGSTYYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GIARAVPFDYWGQGTLVTVSSASTKGPSVF PLA PCSRSTSESTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPA PEFLGGPSVFLFPPKPKDTLMISRTPEVTCV VV DVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSN KGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTKN QV SLTCLVKGFYPSDIAVEWESNGQPENNYKT TPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCS VMH EALHNHYTQKSLSLSPGK IGG4 HC 37269 QLQLQESGPGLVKPSETLSLTCTVSGGSISS SS TYWGWIRQSPGKGLEWIGSIHHSGATYYN PSLK ı22 SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GPKRAVPFDYWGQGTLVTVSSASTKGPSV FPLA PCSRSTSESTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPA PEFLGGPSVFLFPPKPKDTLMISRTPEVTCV VV DVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSN KGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTKN QV SLTCLVKGFYPSDIAVEWESNGQPENNYKT TPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCS VMH EALHNHYTQKSLSLSPGK IGG4 HC 37271 QLQLQESGPGLVKPSETLSLTCTVSGGSISS SD TYWGWIRQPPGKGLEWIGSIHYSGSTLYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GVRRAVPFVDWGQGTLVTVSSASTKGPSV FPLA PCSRSTSESTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPA PEFLGGPSVFLFPPKPKDTLMISRTPEVTCV VV DVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSN KGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTKN QV SLTCLVKGFYPSDIAVEWESNGQPENNYKT TPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCS VMH EALHNHYTQKSLSLSPGK IGG4 HC 37272 QLQLQESGPGLVKPSETLSLTCTVSGGSISS AD NYWGWIRQPPGKGLEWIGSIHYSGSTYYN PSLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GVRRAVPFQRWGQGTLVTVSSASTKGPSV FPLA PCSRSTSESTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPA PEFLGGPSVFLFPPKPKDTLMISRTPEVTCV VV DVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSN KGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTKN QV SLTCLVKGFYPSDIAVEWESNGQPENNYKT TPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCS VMH EALHNHYTQKSLSLSPGK IGG4 HC 37277 QLQLQESGPGLVKPSETLSLTCTVSGGSISS SD TYWGWIRQPPGKGPEWIGSIHYSGSTLYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GVRRAVPFDYWGQGTLVTVSSASTKGPSV FPLA PCSRSTSESTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPA PEFLGGPSVFLFPPKPKDTLMISRTPEVTCV VV DVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSN KGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTKN QV SLTCLVKGFYPSDIAVEWESNGQPENNYKT TPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCS VMH EALHNHYTQKSLSLSPGK IGG4 HC 38373 QLQLQESGPGLVKPSETLSLTCTVSGGSISS SS TYWSWIRQPPGKGLEWIGGIAYSGSTYYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GVRRAVPFDYWGQGTLVTVSSASTKGPSV FPLA PCSRSTSESTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPA PEFLGGPSVFLFPPKPKDTLMSRTPEVTCV VV DVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSN KGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTKN QV SLTCLVKGFYPSDIAVEWESNGQPENNYKT TPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCS VMH EALHNHYTQKSLSLSPGK IGG4 HC 38375 QLQLQESGPGLVKPSETLSLTCTVSGGSISS SS TYWSWIRQPPGKGLEWIGSISYNALTYYNP SLK ı26 SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GTRRAVPFDYWGQGTLVTVSSASTKGPSV FPLA PCSRSTSESTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPA PEFLGGPSVFLFPPKPKDTLMISRTPEVTCV VV DVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSN KGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTKN QV SLTCLVKGFYPSDIAVEWESNGQPENNYKT TPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCS VMH EALHNHYTQKSLSLSPGK IGG4 HC 38379 QLQLQESGPGLVKPSETLSLTCTVSGGSISS SS TYWSWIRQPPGKGLEWIGGIAYSGSTYYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GVRRAVPFADWGQGTLVTVSSASTKGPSV FPLA PCSRSTSESTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL ı27 GT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPA PEFLGGPSVFLFPPKPKDTLMISRTPEVTCV VV DVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSN KGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTKN QV SLTCLVKGFYPSDIAVEWESNGQPENNYKT TPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCS VMH EALHNHYTQKSLSLSPGK IGG4 HC 38381 QLQLQESGPGLVKPSETLSLTCTVSGGSVSS SS TYWSWIRQPPGKGLEWIGGIAYSGSTYYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GVRRAVPFDYWGQGTLVTVSSASTKGPSV FPLA PCSRSTSESTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPA PEFLGGPSVFLFPPKPKDTLMISRTPEVTCV VV DVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSN KGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTKN QV SLTCLVKGFYPSDIAVEWESNGQPENNYKT TPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCS VMH EALHNHYTQKSLSLSPGK IGG4 HC 38383 QLQLQESGPGLVKPSETLSLTCTVSGGSISS SS TYWSWIRQPPGKGLEWIGGIAYSGSTYYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GTRRAVPFDYWGQGTLVTVSSASTKGPSV FPLA PCSRSTSESTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPA PEFLGGPSVFLFPPKPKDTLMISRTPEVTCV VV DVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSN KGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTKN QV SLTCLVKGFYPSDIAVEWESNGQPENNYKT TPP ı29 VLDSDGSFFLYSRLTVDKSRWQEGNVFSCS VMH EALHNHYTQKSLSLSPGK IGG4 HC 38386 QLQLQESGPGLVKPSETLSLTCTVSGGSISS SD TYWGWIRQPPGKGLEWIGSIHYSGSTLYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GIRRAVPFDYWGQGTLVTVSSASTKGPSVF PLA PCSRSTSESTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPA PEFLGGPSVFLFPPKPKDTLMISRTPEVTCV VV DVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSN KGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTKN QV SLTCLVKGFYPSDIAVEWESNGQPENNYKT TPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCS VMH EALHNHYTQKSLSLSPGK IGG4 HC 37273 QLQLQESGPGLVKPSETLSLTCTVSGGSISS SD TYWGWIRQPPGKGLEWIGSIHYSGSTLYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GQFRAVPFDYWGQGTLVTVSSASTKGPSV FPLA PCSRSTSESTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPA PEFLGGPSVFLFPPKPKDTLMISRTPEVTCV VV DVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSN KGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTKN QV SLTCLVKGFYPSDIAVEWESNGQPENNYKT TPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCS VMH EALHNHYTQKSLSLSPGK IGG4 HC 33361 QVQLQESGPGLVKPSETLSLTCAVSGYSISS GY YWGWIRQPPGKGLEWIGSIYHSGSTYYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GTHTYSRGPMDVWGQGTTVTVSSASTKGP SVFP LAPCSRSTSESTAALGCLVKDYFPEPVTVS WNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSL GTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPC PAPEFLGGPSVFLFPPKPKDTLMISRTPEVT CV VVDVSQEDPEVQFNWYVDGVEVHNAKTK PREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKGL PSSIEKTISKAKGQPREPQVYTLPPSQEEMT KN QVSLTCLVKGFYPSDIAVEWESNGQPENN YKTT PPVLDSDGSFFLYSRLTVDKSRWQEGNVFS CSV MHEALHNHYTQKSLSLSPGK IGG4 HC 35624 QLQLQESGPRLVKPSETLSLTCAVSGYSISS GY YWGWIRQPPGKGLEWIGSIYHSGSTYYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GTHTYSRGPFDVWGQGTTVTVSSASTKGP SVFP LAPCSRSTSESTAALGCLVKDYFPEPVTVS WNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSL GTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPC PAPEFLGGPSVFLFPPKPKDTLMISRTPEVT CV VVDVSQEDPEVQFNWYVDGVEVHNAKTK PREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKGL PSSIEKTISKAKGQPREPQVYTLPPSQEEMT KN QVSLTCLVKGFYPSDIAVEWESNGQPENN YKTT PPVLDSDGSFFLYSRLTVDKSRWQEGNVFS CSV MHEALHNHYTQKSLSLSPGK IGG4 HC 38410 LVQLQESGPGLVKPSETLSLTCAVSGYSILS GY YWFWIRQPPGKGLEWIGGIYHSASTAYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GTPIYSRGPLDVWGQGTTVTVSSASTKGPS VFP LAPCSRSTSESTAALGCLVKDYFPEPVTVS WNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSL GTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPC PAPEFLGGPSVFLFPPKPKDTLMISRTPEVT CV VVDVSQEDPEVQFNWYVDGVEVHNAKTK PREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKGL PSSIEKTISKAKGQPREPQVYTLPPSQEEMT KN QVSLTCLVKGFYPSDIAVEWESNGQPENN YKTT PPVLDSDGSFFLYSRLTVDKSRWQEGNVFS CSV MHEALHNHYTQKSLSLSPGK IGG4 HC 38418 QVQLQESGPGLVKPSETLSLTCAVSGYSISS GH YWIWIRQPPGKGLEWIGGIYHSGSTYYNPS LKS RVTISVDTSKDQFSLKLSSVTAADTAVYYC ARG GGQTYSRGPLDVWGQGTTVTVSSASTKGP SVFP LAPCSRSTSESTAALGCLVKDYFPEPVTVS WNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSL GTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPC PAPEFLGGPSVFLFPPKPKDTLMISRTPEVT CV VVDVSQEDPEVQFNWYVDGVEVHNAKTK PREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKGL PSSIEKTISKAKGQPREPQVYTLPPSQEEMT KN QVSLTCLVKGFYPSDIAVEWESNGQPENN YKTT PPVLDSDGSFFLYSRLTVDKSRWQEGNVFS CSV MHEALHNHYTQKSLSLSPGK IGG4 HC 38420 QVQLQESGPGLVKPPETLSLTCAVSGYSISS GH YWIWIRQPPGKGLEWIGGIYHSGSTYYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GGATYSRGPLDVWGQGTTVTVSSASTKGP SVFP LAPCSRSTSESTAALGCLVKDYFPEPVTVS WNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSL GTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPC PAPEFLGGPSVFLFPPKPKDTLMISRTPEVT CV VVDVSQEDPEVQFNWYVDGVEVHNAKTK PREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKGL PSSIEKTISKAKGQPREPQVYTLPPSQEEMT KN QVSLTCLVKGFYPSDIAVEWESNGQPENN YKTT PPVLDSDGSFFLYSRLTVDKSRWQEGNVFS CSV MHEALHNHYTQKSLSLSPGK IGG4 HC 38421 QVQLQESGPGLVKPSETLSLTCAVSGYSILS GY YWFWIRQPPGKGLEWIGGIYHSGSTYYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GTHTYSRGPLDVWGQGTTVTVSSASTKGP SVFP LAPCSRSTSESTAALGCLVKDYFPEPVTVS WNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSL GTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPC PAPEFLGGPSVFLFPPKPKDTLMISRTPEVT CV VVDVSQEDPEVQFNWYVDGVEVHNAKTK PREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKGL PSSIEKTISKAKGQPREPQVYTLPPSQEEMT KN QVSLTCLVKGFYPSDIAVEWESNGQPENN YKTT PPVLDSDGSFFLYSRLTVDKSRWQEGNVFS CSV MHEALHNHYTQKSLSLSPGK IGG4 HC 38422 QVQLQESGPGLVKPSETLSLTCAVSGYSISS GF YWTWIRQPPGKGLEWIGAIYHSGSTVYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GTHTYSRGPLDVWGQGTTVTVSSASTKGP SVFP LAPCSRSTSESTAALGCLVKDYFPEPVTVS WNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSL GTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPC PAPEFLGGPSVFLFPPKPKDTLMISRTPEVT CV VVDVSQEDPEVQFNWYVDGVEVHNAKTK PREEQ ı36 FNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKGL PSSIEKTISKAKGQPREPQVYTLPPSQEEMT KN QVSLTCLVKGFYPSDIAVEWESNGQPENN YKTT PPVLDSDGSFFLYSRLTVDKSRWQEGNVFS CSV MHEALHNHYTQKSLSLSPGK IGG4 HC 38424 QVQLQESGPGLVKPSETLSLTCAVSGYSISS GY YWLWIRQPPGKGLEWIGGIYHSASTAYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GTVKYSRGPLDVWGQGTTVTVSSASTKGP SVFP LAPCSRSTSESTAALGCLVKDYFPEPVTVS WNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSL GTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPC PAPEFLGGPSVFLFPPKPKDTLMISRTPEVT CV VVDVSQEDPEVQFNWYVDGVEVHNAKTK PREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKGL PSSIEKTISKAKGQPREPQVYTLPPSQEEMT KN QVSLTCLVKGFYPSDIAVEWESNGQPENN YKTT ı37 PPVLDSDGSFFLYSRLTVDKSRWQEGNVFS CSV MHEALHNHYTQKSLSLSPGK IGG4 HC 38425 QVQLQESGPGLVKPSETLSLTCAVSGYSISS GH YWTWIRQPPGKGLEWIGAIYHSGSTVYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GQVTYSRGPLDVWGQGTTVTVSSASTKGP SVFP LAPCSRSTSESTAALGCLVKDYFPEPVTVS WNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSL GTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPC PAPEFLGGPSVFLFPPKPKDTLMISRTPEVT CV VVDVSQEDPEVQFNWYVDGVEVHNAKTK PREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKGL PSSIEKTISKAKGQPREPQVYTLPPSQEEMT KN QVSLTCLVKGFYPSDIAVEWESNGQPENN YKTT PPVLDSDGSFFLYSRLTVDKSRWQEGNVFS CSV MHEALHNHYTQKSLSLSPGK IGG4 HC 38426 QVQLQESGPGLVKPSETLSLTCAVSGYSILS GY YWFWIRQPPGKGLEWIGGIYHSGSTAYNPS LKS ı38 RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARG GEVTYSRGPLDVWGQGTTVTVSSASTKGP SVFP LAPCSRSTSESTAALGCLVKDYFPEPVTVS WNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSL GTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPC PAPEFLGGPSVFLFPPKPKDTLMISRTPEVT CV VVDVSQEDPEVQFNWYVDGVEVHNAKTK PREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKGL PSSIEKTISKAKGQPREPQVYTLPPSQEEMT KN QVSLTCLVKGFYPSDIAVEWESNGQPENN YKTT PPVLDSDGSFFLYSRLTVDKSRWQEGNVFS CSV MHEALHNHYTQKSLSLSPGK IGG4 HC 37323 EVQLLESGGGLVQPGGSLRLSCAASGFTFD NYA MHWVRQAPGKGLEWVSAISARAGITYYA DSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYY CARR IGYSYGTAPPFDVWGQGTTVTVSSASTKGP SVF PLAPCSRSTSESTAALGCLVKDYFPEPVTVS WN SGALTSGVHTFPAVLQSSGLYSLSSVVTVP ı39 SSS LGTKTYTCNVDHKPSNTKVDKRVESKYGP PCPP CPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TC VVVDVSQEDPEVQFNWYVDGVEVHNAKT KPREE QFNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKG LPSSIEKTISKAKGQPREPQVYTLPPSQEEM TK NQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKT TPPVLDSDGSFFLYSRLTVDKSRWQEGNVF SCS VMHEALHNHYTQKSLSLSPGK IGG4 HC 38389 QVQLVESGGGLVQPGGSLRLSCAASGFTFS DYY MSWIRQAPGKGLEWVSYIASSGSVIYYADS VKG RFTISRDNAKNSLYLQMNSLRAEDTAVYY CARH GTPRAFDIWGQGTTVTVSSASTKGPSVFPL APC SRSTSESTAALGCLVKDYFPEPVTVSWNSG ALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT KT YTCNVDHKPSNTKVDKRVESKYGPPCPPC PAPE FLGGPSVFLFPPKPKDTLMISRTPEVTCVVV DV SQEDPEVQFNWYVDGVEVHNAKTKPREE QFNST YRVVSVLTVLHQDWLNGKEYKCKVSNKG LPSSI EKTISKAKGQPREPQVYTLPPSQEEMTKNQ VSL TCLVKGFYPSDIAVEWESNGQPENNYKTTP PVL DSDGSFFLYSRLTVDKSRWQEGNVFSCSV MHEA LHNHYTQKS LSLSPGK IGG4 HC 38358 EVQLLESGGGLVQPGGSLRLSCAASGFTFS SSA MAWVRQAPGKGLEWVSTISGSGITTWYAD SVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYY CAKG SRHLNAFNRWGQGTTVTVSSASTKGPSVF PLAP CSRSTSESTAALGCLVKDYFPEPVTVSWNS GAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TK TYTCNVDHKPSNTKVDKRVESKYGPPCPP CPAP EFLGGPSVFLFPPKPKDTLMISRTPEVTCVV VD VSQEDPEVQFNWYVDGVEVHNAKTKPRE EQFNS TYRVVSVLTVLHQDWLNGKEYKCKVSNK GLPSS IEKTISKAKGQPREPQVYTLPPSQEEMTKN QVS LTCLVKGFYPSDIAVEWESNGQPENNYKTT PPV LDSDGSFFLYSRLTVDKSRWQEGNVFSCSV MHE ALHNHYTQKSLSLSPGK IGG4 HC 33303 QVQLQESGPGLVKPSGTLSLTCAVSGGSISS SN WWSWVRQPPGKGLEWIGEIYHSGSTNYNP SLKS RVTISVDKSKNQFSLKLSSVTAADTAVYYC ARG VYHYDPYGMDVWGQGTTVTVSSASTKGP SVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSW NSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LG TKTYTCNVDHKPSNTKVDKRVESKYGPPC PPCP APEFLGGPSVFLFPPKPKDTLMISRTPEVTC VV VDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVS NKGLP SSIEKTISKAKGQPREPQVYTLPPSQEEMTK NQ VSLTCLVKGFYPSDIAVEWESNGQPENNY KTTP PVLDSDGSFFLYSRLTVDKSRWQEGNVFSC SVM HEALHNHYTQKSLSLSPGK IG G4 HC 33342 QLQLQESGPGLVKPSETLSLTCTVSGGSISS SS YYWGWIRQPPGKGLEWIGSISYSGSTYYNP SLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR TELGKMHFDYWGQGTLVTVSSASTKGPSV FPLA PCSRSTSESTAALGCLVKDYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPA PEFLGGPSVFLFPPKPKDTLMISRTPEVTCV VV DVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSN KGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTKN QV SLTCLVKGFYPSDIAVEWESNGQPENNYKT TPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCS VMH EALHNHYTQKSLSLSPGK QLQLQESGPGLVKPSETLSLTCTVSGGSISS SD YYWGWIRQPPGKGLEWIGSIYYSGSTYYN PSLK SRVTISVDTSKNQFSLKLSSVTAADTAVYY CAR GSPRYMQDWGQGTLVTVSSASTKGPSVFP LAPC SRSTSESTAALGCLVKDYFPEPVTVSWNSG ALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT ı43 KT YTCNVDHKPSNTKVDKRVESKYGPPCPPC PAPE FLGGPSVFLFPPKPKDTLMISRTPEVTCVVV DV SQEDPEVQFNWYVDGVEVHNAKTKPREE QFNST YRVVSVLTVLHQDWLNGKEYKCKVSNKG LPSSI EKTISKAKGQPREPQVYTLPPSQEEMTKNQ VSL TCLVKGFYPSDIAVEWESNGQPENNYKTTP PVL DSDGSFFLYSRLTVDKSRWQEGNVFSCSV MHEA LHNHYTQKSLSLSPGK IGG4 HC 33351 QVQLVESGGGLVKPGGSLRLSCAASGFTFS DYY MSWIRQAPGKGLEWVSYISSSGSTIYYADS VKG RFTISRDNAKNSLYLQMNSLRAEDTAVYY CARH SSLGTHNWFDPWGQGTLVTVSSASTKGPS VFPL APCSRSTSESTAALGCLVKDYFPEPVTVSW NSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LG TKTYTCNVDHKPSNTKVDKRVESKYGPPC PPCP APEFLGGPSVFLFPPKPKDTLMISRTPEVTC VV VDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVS NKGLP SSIEKTISKAKGQPREPQVYTLPPSQEEMTK NQ VSLTCLVKGFYPSDIAVEWESNGQPENNY KTTP PVLDSDGSFFLYSRLTVDKSRWQEGNVFSC SVM HEALHNHYTQKSLSLSPGK IGG4 HC 33357 QVQLQESGPGLVKPSETLSLTCAVSGYSISS GY YWGWIRQPPGKGLEWIGSIYHSGSTYYNPS LKS RVTISVDTSKNQFSLKLSSVTAADTAVYYC ARE GALSYSWLAAFDIWGQGTMVTVSSASTKG PSVF PLAPCSRSTSESTAALGCLVKDYFPEPVTVS WN SGALTSGVHTFPAVLQSSGLYSLSSVVTVP SSS LGTKTYTCNVDHKPSNTKVDKRVESKYGP PCPP CPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TC VVVDVSQEDPEVQFNWYVDGVEVHNAKT KPREE QFNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKG LPSSIEKTISKAKGQPREPQVYTLPPSQEEM TK NQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKT ı45 TPPVLDSDGSFFLYSRLTVDKSRWQEGNVF SCS VMHEALHNHYTQKLSLS PGK LC 33343 EIVLTQSPGTLSLSPGERATLSCRASQSVSS SY LAWYQQKPGQAPRLLIYGASSRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQAVHSP YTF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 37268 EIVLTQSPGTLSLSPGERATLSCRASQSVSS SY LAWYQQKPGQAPRLLIYGASSRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQAVHSP YTF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 37269 EIVLTQSPGTLSLSPGERATLSCRASQSVSS SY LAWYQQKPGQAPRLLIYGASSRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQAVHSP YTF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 37271 EIVLTQSPGTLSLSPGERATLSCRASQSVSS SY LAWYQQKPGQAPRLLIYGASSRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQAVHSP YTF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 37272 EIVLTQSPGTLSLSPGERATLSCRASQSVSS SY LAWYQQKPGQAPRLLIYGASSRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQAVHSP YTF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 37277 EIVLTQSPGTLSLSPGERATLSCGASQSVSS DY LAWYQQKPGQAPRLLIYGAYSLATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQWAVHSP YTF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 38373 EIVLTQSPGTLSLSPGERATLSCQASQAVSS NY LAWYQQKPGQAPRLLIYGASSRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQVVHSP YTF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 38375 EIVLTQSPGTLSLSPGERATLSCGASQSVSS AF LAWYQQKPGQAPRLLIYGASARATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQVVHSP YTF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 38379 EIVLTQSPGTLSLSPGERATLSCRASQSVSS TY LAWYQQKPGQAPRLLIYGASSREAGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQTVHSP YTF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 38381 EIVLTQSPGTLSLSPGERATLSCQASQAVSS NY LAWYQQKPGQAPRLLIYGASNRAAGIPDR FSGS GSGTDFTLTISRLEPEDFAVYYCQQAIHSPY TF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 38383 EIVLTQSPGTLSLSPGERATLSCQASQSVSS SY LAWYQQKPGQAPRLLIYGASNRAAGIPDR FSGS GSGTDFTLTISRLEPEDFAVYYCQQVVHSP YTF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 38386 EIVLTQSPGTLSLSPGERATLSCKASQAVSS SY LAWYQQKPGQAPRLLIYGASSRQDGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQVVHSP YTF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 37273 EIVLTQSPGTLSLSPGERATLSCRASQSVSS SY LAWYQQKPGQAPRLLIYGASSRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQAVHSP YTF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 33361 EIVLTQSPGTLSLSPGERATLSCRASQSVSS SY LAWYQQKPGQAPRLLIYGASSRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQHSSYPP TF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 35624 EIVLTQSPGTLSLSPGERATLSCRASQSVSS SY LAWYQQKPGQAPRLLIYGASSRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQHSSYPP TF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 38410 EIVLTQSPGTLSLSPGERATLSCEASQSVSSS Y LAWYQQKPGQAPRLLIYGASNRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQHSLYPP TF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 38418 EIVLTQSPGTLSLSPGERATLSCEASQSVSA SY LAWYQQKPGQAPRLLIYDASSRASGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQFSSYPP TF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 38420 EIVLTQSPGTLSLSPGERATLSCEASQSVSS AY LAWYQQKPGQAPRLLIYDASTRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQVSSYPP TF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 38421 EIVLTQSPGTLSLSPGERAALSCRVSQSVSD AY LAWYQQKPGQAPRLLIYDASSRASGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQVSSYPP TF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 38422 EIVLTQSPGTLSLSPGERATLSCEVSQSVSA SY LAWYQQKPGQAPRLLIYGASSRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQHSLYPP TF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 38424 EIVLTQSPGTLSLSPGERATLSCRASQSVSS AY LAWYQQKPGQAPRLLIYGASDRANGIPDR FSGS GSGTDFTLTISRLEPEDFAVYYCQQHSLYPP TF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 38425 EIVLTQSPGTLSLSPGERATLSCRASNAVSS SY LAWYQQKPGQAPRLLIYGASDRANGIPDR FSGS GSGTDFTLTISRLEPEDFAVYYCQQHSIYPP TF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 38426 EIVLTQSPGTLSLSPGERATLSCRASNAVSS SY LAWYQQKPGQAPRLLIYGASYRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQHSLYPP TF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 37323 DIQMTQSPSTLSASVGDRVTITCRASQSINS WL AWYQQKPGKAPKLLISDASSLESGVPSRFS GSG SGTEFTLTISSLQPDDFATYYCQQYDSHITF GG GTKVEIKRTVAAPSVFIFPPSDEQLKSGTAS W CLLNNFYPREAKVQWKVDNALQSGNSQES VTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEV THQ GLSSPVTKSFNRGEC LC 38389 DIQMTQSPSSVSASVGDRVTITCRASQGISS DL AWYQQKPGKAPKLLIYSASSTQSGVPSRFS GSG SGTDFTLTISSLQPEDFATYYCQQAYLYPIT FG GGTKVEIKRTVAAPSVFIFPPSDEQLKSGTA SV VCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACE VTH QGLSSPVTKSFNRGEC LC 38358 GVQMTQSPSSLSASVGDRVTITCRASQDIS TYL NWYQQKPGKAPKLLIYDAFNLETGVPSRFS GSG SGTDFTFTISSLQPEDIATYYCQQLPFLPITF ı55 G GGTKVEIKRTVAAPSVFIFPPSDEQLKSGTA SV VCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACE VTH QGLSSPVTKSFNRGEC LC 33303 DIVMTQSPLSLPVTPGEPASISCRSSQSLLHS N GYNYLDWYLQKPGQSPQLLIYLGSNRASG VPDR FSGSGSGTDFTLKISRVEAEDVGVYYCMQ ALGG PWTFGGGTKVEIKRTVAAPSVFIFPPSDEQL KS GTASWCLLNNFYPREAKVQWKVDNALQS GNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHK VYA CEVTHQGLSSPVTKSFNRGEC LC 33342 EIVLTQSPGTLSLSPGERATLSCRASQSVSS SY LAWYQQKPGQAPRLLIYGASRRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQYVSDPI TF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS WCLLNNFYPREAKVQWKVDNALQSGNSQ ESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 33299 EIVLTQSPGTLSLSPGERATLSCRASQSVSS SY LAWYQQKPGQAPRLLIYGASRRATGIPDRF SGS GSGTDFTLTISRLEPEDFAVYYCQQVGSSPI TF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS WCLLNNFYPREAKVQWKVDNALQSGNSQ ESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC LC 33351 DIQMTQSPSSLSASVGDRVTITCRASQSISS YL NWYQQKPGKAPKLLIYAASSLQSGVPSRFS GSG SGTDFTLTISSLQPEDFATYYCQQSHLVPRT FG GGTKVEIKRTVAAPSVFIFPPSDEQLKSGTA SV VCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACE VTH QGLSSPVTKSFNRGEC LC 33357 EIVMTQSPATLSVSPGERATLSCRASQSVSS NL AWYQQKPGQAPRLLIYGASTRATGIPARFS GSG SGTEFTLTISSLQSEDFAVYYCQQANHHPPF TF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNS QESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVT HQGLSSPVTKSFNRGEC Fc for ASTKGPSVFPLAPSSKSTSGGTAALGCLVK IGG1 DYF PEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLS SVVTVPSSSLGTQTYICNVNHKPSNTKVDK KVE PKSCDKTHTCPPCPAPEAAGAPSVFLFPPKP KD TLMISRTPEVTCVVVDVSHEDPEVKFNWY VDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLN GKEYKCKVSNKALPAPIEKTISKAKGQPRE PQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEW ESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDK SRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK Fc region ASTKGPSVFPLAPCSRSTSESTAALGCLVK for IGG4 DYF PEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLS SVVTVPSSSLGTKTYTCNVDHKPSNTKVD KRVE SKYGPPCPPCPAPEFLGGPSVFLFPPKPKDT LM ISRTPEVTCVVVDVSQEDPEVQFNWYVDG VEVH NAKTKPREEQFNSTYRVVSVLTVLHQDWL NGKE YKCKVSNKGLPSSIEKTISKAKGQPREPQV YTL PPSQEEMTKNQVSLTCLVKGFYPSDIAVEW ESN GQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRW QEGNVFSCSVMHEALHNHYTQKSLSLSPG K Kappa RTVAAPSVFIFPPSDEQLKSGTASVVCLLN region for NFY LC PREAKVQWKVDNALQSGNSQESVTEQDSK DSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSS PVT KSFNRGEC hHLA-G1 MWMAPRTLFLLLSGALTLTETWAGSHSMR YFS AAVSRPGRGEPRFIAMGYVDDTQFVRFDS DSAC PRMEPRAPWVEQEGPEYWEEETRNTKAHA QTDR MNLQTLRGYYNQSEASSHTLQWMIGCDLG SDGR LLRGYEQYAYDGKDYLALNEDLRSWTAA DTAAQ ISKRKCEAANVAEQRRAYLEGTCVEWLHR YLEN GKEMLQRADPPKTHVTHHPVFDYEATLRC WALG FYPAEIILTWQRDGEDQTQDVELVETRPAG DGT FQKWAAVVVPSGEEQRYTCHVQHEGLPEP LMLR WKQSSLPTIPIMGIVAGLVVLAAVVTGAAV AAV LWRKKSSD hHLA-G5 MWMAPRTLFLLLSGALTLTETWAGSHSMR YFS AAVSRPGRGEPRFIAMGYVDDTQFVRFDS DSAC PRMEPRAPWVEQEGPEYWEEETRNTKAHA QTDR MNLQTLRGYYNQSEASSHTLQWMIGCDLG SDGR LLRGYEQYAYDGKDYLALNEDLRSWTAA DTAAQ ISKRKCEAANVAEQRRAYLEGTCVEWLHR YLEN GKEMLQRADPPKTHVTHHPVFDYEATLRC WALG FYPAEIILTWQRDGEDQTQDVELVETRPAG DGT FQKWAAVVVPSGEEQRYTCHVQHEGLPEP LMLR WSKEGDGGIMSVRESRSLSEDL Cyno HLA-AG MAVMAPRTLLLVLSGVLALTQPRAGSHSM RYFY TAVSRPGRGQPRFIAVGYVDDTQFVRFDSD AES PRMEPRAPWVEQEGPEYWDRETQNMKTA TQTYQ ANLRTLLRYYNQSEAGSHTFQKMYGCDLG PDGR LLRGYEQFAYDGRDYIILNEDLRSWTAAD MAAQ NTQRKWEAAGAAEQHRTYLEGECLEWLR RYLEN GKETLQRADPPKTNVTHHPVSDYEATLRC WALG FYPAEITLTWQRDGEEQTEDTELVETRPTG DGT FQKWAAVVVPSGEEQRYTCHVQHEGLPKP LTLR WEPSSQSTILIVGIIAGLVLLGTVVTGAVVA AV MWRRKS Rhesus HLA- MAVMAPRTLLLVLSGVLALTQTRAGSHSM AG RYFY TSMSRPGRGQPRFIAVGYVDDTQFVRFDSD AES PRMEPRAPWVEQEGPEYWDRETQNMKTA TQTYR ENLRTLLRYYNQSEAGSHTIQKMYGCDLG PDGR LLRGYEQFAYDGRDYIALNEDLRSWTAAD MAAQ FTQRKWEAAGAAEQHRTYLEGECLEWLR RYLEN GKETLQRADPPKTNVTHHPVSDYEATLRC WALG FYPAEITLTWQRDGEEQTEDTELVETRPTG DGT FQKWAAVVVPSGEEQRYTCHVQHEGLPEP LTLR WEPSSQSTILIVGIIAGLVLLGTVVTGAVVA AV MWRRKSSDR hHLA-G ECD MWMAPRTLFLLLSGALTLTETWAGSHSMR with signal YFS peptide AAVSRPGRGEPRFIAMGYVDDTQFVRFDS DSAC PRMEPRAPWVEQEGPEYWEEETRNTKAHA QTDR MNLQTLRGYYNQSEASSHTLQWMIGCDLG SDGR LLRGYEQYAYDGKDYLALNEDLRSWTAA DTAAQ ISKRKCEAANVAEQRRAYLEGTCVEWLHR YLEN GKEMLQRADPPKTHVTHHPVFDYEATLRC WALG FYPAEIILTWQRDGEDQTQDVELVETRPAG DGT FQKWAAVVVPSGEEQRYTCHVQHEGLPEP LMLR W hHLA-G ECD GSHSMRYFSAAVSRPGRGEPRFIAMGYVD without signal DTQF peptide VRFDSDSACPRMEPRAPWVEQEGPEYWEE ETRN TKAHAQTDRMNLQTLRGYYNQSEASSHTL QWMI GCDLGSDGRLLRGYEQYAYDGKDYLALN EDLRS WTAADTAAQISKRKCEAANVAEQRRAYLE GTCV EWLHRYLENGKEMLQRADPPKTHVTHHP VFDYE ATLRCWALGFYPAEIILTWQRDGEDQTQD VELV ETRPAGDGTFQKWAAVVVPSGEEQRYTCH VQHE GLPEPLMLRW Equivalents [0270] The disclosure set forth above may encompass multiple distinct inventions with independent utility. Although each of these inventions has been disclosed in its preferred form(s), the specific embodiments thereof as disclosed and illustrated herein are not to be considered in a limiting sense, because numerous variations are possible. The subject matter of the inventions includes all novel and nonobvious combinations and subcombinations of the various elements, features, functions, and/or properties disclosed herein. The following claims particularly point out certain combinations and subcombinations regarded as novel and nonobvious. Inventions embodied in other combinations and subcombinations of features, functions, elements, and/or properties may be claimed in this application, in applications claiming priority from this application, or in related applications. Such claims, whether directed to a different invention or to the same invention, and whether broader, narrower, equal, or different in scope in comparison to the original claims, also are regarded as included within the subject matter of the inventions of the present disclosure.

Claims

WHAT IS CLAIMED IS: 1. A conjugate comprising: (i) an antibody that binds specifically to a human HLA-G (hHLA-G), and (ii) a molecule coupled to the antibody. 2. The conjugate of claim 1, wherein the antibody has 1,
2,
3,
4,
5,
6, or 7 of the following characteristics: a) is a monoclonal antibody; b) is a human antibody, a humanized antibody, or a chimeric antibody; c) is a bispecific antibody, a multi-specific antibody, a diabody, or a multivalent antibody; d) is of the IgA, IgGl, IgG2, IgG3, IgG4, or IgM type; e) is an antigen-binding antibody fragment; f) is a Fab fragment, a Fab' fragment, a F(ab')2 fragment, or an Fv fragment; and/or g) is a single chain antibody, a single domain antibody, or a nanobody. 3. The conjugate of claim 1, wherein the molecule coupled to the antibody comprises one selected from the group consisting of a detectable label, a drug, a toxin, a cytokine, a radionuclide, an enzyme, and combinations thereof. 4. The conjugate of claim 1, wherein the molecule coupled to the antibody comprises a DNA- alkylating cytotoxic molecule or an antineoplastic agent. 5. The conjugate of claim 1, wherein the molecule coupled to the antibody comprises one selected from the group consisting of Formulas I-VIII:
Figure imgf000166_0001
Formula I: DGN549-C
in) nd 6. The conjugate of claim 1, wherein the antibody binds to a human HLA-G polypeptide or a variant thereof with a KD of less than about 20 nM.
7. The conjugate of claim 1, wherein the antibody comprises a human heavy chain constant region or fragment or a variant thereof and/or a light chain constant region or fragment or variant thereof, wherein the constant region or fragment of variant thereof comprises up to 20 conservatively modified amino acid substitutions from any sequence set forth SEQ ID NOS: 170-200 and/or SEQ ID NOS: 204-228.
8. A pharmaceutical composition comprising an effective amount of the conjugate of any of claims 1-7; and a pharmaceutically acceptable diluent, carrier or excipient.
9. The pharmaceutical composition of claim 8 further comprising an effective amount of at least one of the following: a) an anti-ILT2 antibody; b) an anti-ILT3 antibody; c) an anti-ILT4 antibody; d) an anti-KIR2DL4 antibody; e) an anti-HLA-E antibody; f) an anti-NKG2A antibody; g) an anti-HLA-F antibody; h) an anti-HLA-J antibody; i) an anti-PD-L1 antibody; j) an anti-PD-1 antibody; k) an anti-CD38 antibody; l) an anti-CD39 antibody; m) an anti-CD73 antibody; n) an anti-A2A receptor antibody; o) an anti-A2B receptor antibody; p) an anti-A2A/A2B dual receptor antibody or a combination thereof; q) an anti-CD47 antibody; r) a small molecule inhibitor; s) a bi-specific T cell engager and/or CAR-T therapy and or CAR-NK therapy, CAR-Macrophage therapy t) an oncolytic virus; u) a chemotherapy; v) ADCC capable therapies using an effector competent antibody selected from the group consisting of anti-CDl9, anti-CD20, anti-EGFR, anti-Her2, anti-SLAMF7, anti-CD52, anti-BCMA, anti-GD2, anti-CCR4, anti-CTLA4, and mixtures thereof.
10. The pharmaceutical composition of claim 8 or claim 9, further comprising at least one of a) an antibody to an immune inhibitory receptor or ligand and/or b) an antibody to an immune stimulatory receptor or ligand.
11. A conjugate comprising: (i) an isolated antibody molecule capable of binding to human HLA-G (hHLA- G), comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH and/or VL comprising 1, 2, 3, 4, 5, or 6 of: a) a VHCDR1 having the sequence set forth in SEQ ID NOS: 1 -14 or SEQ ID NOS: 18-34, b) a VHCDR2 having the sequence set forth in SEQ ID NOS: 38-50 or SEQ ID NOS: 54-71 , c) a VHCDR3 having the sequence set forth in SEQ ID NOS: 76-101, d) a VLCDR1 having the sequence set forth in SEQ ID NOS: 105-124, e) a VLCDR2 having the sequence set forth in SEQ ID NOS: 128-145, and f) a VLCDR3 having the sequence set forth in SEQ ID NOS: 149-166; and (ii) a molecule coupled to the antibody.
12. A conjugate comprising: (i) an isolated antibody molecule capable of binding to human HLA-G (hHLA- G), comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising: a) a VHCDR1 having a sequence set forth in SEQ ID NOS: 1-14 or SEQ ID NOS: 18- 34, b) a VHCDR2 having a sequence set forth in SEQ ID NOS: 38-50 or SEQ ID NOS: 54-71 , and c) a VHCDR3 having a sequence set forth in SEQ ID NOS: 76-101; and the VL comprising: a) a VLCDR1 having a sequence set forth in SEQ ID NO: 105-124, b) a VLCDR2 having a sequence set forth in SEQ ID NO: 128-145, and c) a VLCDR3 having a sequence set forth in SEQ ID NO: 149-166; and (ii) a molecule coupled to the antibody.
13. A conjugate comprising: (i) an isolated antibody molecule capable of binding to human HLA-G (hHLA- G), and comprising a heavy chain variable region (VH) and/or a light chain variable region (VL), the VH comprising at least one sequence set forth in any of SEQ ID NOS: 170-200 and the VL comprising at least one sequence set forth in any of SEQ ID NOS: 204-228; and (ii) a molecule coupled to the antibody.
14. A conjugate comprising: (i) an isolated antibody molecule capable of binding to human HLA-G (hHLA- G), the isolated antibody molecule comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising 1, 2, or 3 of: a) a VHCDR1 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOS: 1-14 or 18-34, b) a VHCDR2 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOS: 54-71, and c) a VHCDR3 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOS: 76-101; and the VL comprising 1, 2, or 3 of: a) a VLCDR1 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOS: 105-124, b) a VLCDR2 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOS: 128-145, and c) a VLCDR3 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOs 149-166; and (ii) a molecule coupled to the antibody.
15. A conjugate comprising: (i) an isolated antibody molecule capable of binding to human HLA-G (hHLA- G), the isolated antibody molecule comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising 1, 2, or 3 of: a) a VHCDR1 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 1-14 or SEQ ID NOS: 18-34, b) a VHCDR2 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 38-50 or SEQ ID NOS: 54-71, and c) a VHCDR3 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 76-101; and the VL comprising 1, 2, or 3 of: a) a VLCDR1 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 105-124, b) a VLCDR2 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 128-145, and c) a VLCDR3 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOS: 149-166; and (ii) a molecule coupled to the isolated antibody molecule.
16. A conjugate comprising: (i) an isolated antibody molecule capable of binding to human HLA-G (hHLA- G), the isolated antibody molecule comprising a heavy chain and a light chain, the heavy chain comprising one or more molecules having a sequence consisting of one of SEQ ID NOS: 232-262 or SEQ ID NOS: 266-296, and the light chain comprising one or more molecules having a sequence consisting of one of SEQ ID NOS: 300-330; and (ii) a molecule coupled to the isolated antibody molecule.
17. A conjugate comprising: (i) an isolated antibody molecule capable of binding to human HLA-G (HLA-G), the isolated antibody molecule comprising a heavy chain and a light chain and being selected from the group consisting of: a) the heavy chain comprising one or more molecules each having a sequence consisting of SEQ ID NO: 232 and the light chain comprising one or more molecules each having a sequence consisting of SEQ ID NO: 300; b) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 233 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 301 ; c) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 234 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 302; d) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 235 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 303; e) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 236 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 304; f) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 237 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 305; g) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 238 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 306; h) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 239 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 307; i) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 240 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 308; j) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 241 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 309; k) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 242 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 310; l) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 243 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 311 ; m) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 244 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 312; n) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 245 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 313; o) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 246 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 314; p) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 247 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 315; q) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 248 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 316; r) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 249 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 317; s) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 250 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 318; t) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 251 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 319; u) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 252 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 320; v) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 253 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 321 ; w) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 254 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 322; x) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 255 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 323; y) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 256 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 324; z) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 257 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 325; aa) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 258 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 326; ab) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 259 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 327; ac) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 260 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 328; ad) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 261 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 329; ae) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 262 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 330; af) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 266 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 300; ag) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 267 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 301; ah) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 268 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 302; ai) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 269 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 303; aj) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 270 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 304; ak) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 271 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 305; al) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 272 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 306; am) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 273 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 307; an) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 274 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 308; ao) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 275 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 309; ap) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 276 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 310; aq) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 277 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 311; ar) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 278 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 312; as) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 279 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 313; at) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 280 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 314; au) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 281 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 315; av) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 282 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 316; aw)the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 283 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 317; ax) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 284 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 318; ay) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 285 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 319; az) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 286 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 320; ba) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 287 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 321; bb) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 288 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 322; be) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 289 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 323; bd) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 290 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 324; be) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 291 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 325; bf) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 292 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 326; bg) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 293 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 327; bh) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 294 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 328; bi) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 295 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 329; and bj) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 296 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 330; and (ii) a molecule coupled to the isolated antibody molecule.
18. A conjugate comprising: (i) an isolated antibody molecule capable of binding to human HLA-G (hHLA- G), the isolated antibody molecule comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH and/or VL comprising 1, 2, 3, 4, 5, or 6 of: a) a VHCDR1 sequence comprising: (i) Kabat CDR-H1 sequence defined by the consensus sequence S-S-Δ3-Δ4-Y-W- Δ7 (SEQ ID NOS: 18-21 , 23, and 34), where Δ3 is D or S; Δ4 is T or Y; and Δ7 is A, G, or S; (ii) a Kabat CDR-H1 sequence defined by the consensus sequence S-G-θ3-Y- W- θ6 (SEQ ID NOS: 24-29), where θ3 is F, H, or Y; and θ6 is F, G, I, L, or T; (iii) a Chothia CDR-H1 sequence defined by the consensus sequence G-G-S- -S-S-Ω7- Ω8- Ω9 (SEQ ID NOS: 1-4 and 13-14), where Ω 7 is S or A; Ω8 is D, S, or N; and Ω9 is T, N, Y, or is absent; or (iv) a Chothia CDR-H1 sequence defined by the consensus sequence G-F-T-F-κ5-κ6- κ7 (SEQ ID NOS: 10-12), where κ5 is D or s; κ6 is D, N, or S; and κ7 is S or Y, b) a VHCDR2 sequence comprising: (i) a Kabat CDR-H2 sequence defined by the consensus sequence β1-I-β3- β4-β5-β6-β7- T-β9-Y-N-P-S-L-K-S (SEQ ID NOS: 54-65 and 69-70) where β1 is A, E, G, or S; β3 is A, H, S, or Y; β4 is H, S, or Y; β5 is N or S; β6 is A or G; β7 is A, L, or S; and β9 is A, N, L, V, or Y; (ii) a Chothia CDR-H2 sequence defined by the consensus sequence U-ε2- S-ε4-S (SEQ ID NOS: 38 and 44-45), where ε2 is H or Y and ε4 is A or G; (iii) a Chothia CDR-H2 sequence defined by the consensus sequence α1-α2-S-G-S (SEQ ID NOS: 39, 41-42, and 49), where α1 is A, H, or S; and α2 is S or Y; or (iv) a Chothia CDR-H2 sequence defined by the consensus sequence β1- β2- S-G- β5- β6 (SEQ ID NOS: 56-60), where β1 is A or S; β2 is G or S; β5 is I or S; and β6 is T or c) a
Figure imgf000175_0001
P-F-Y9- Y10 (SEQ ID NOS: 76-84), where Y2 is I, P, Q, T, or V; Y3 is A, F, K, or R; Y9 is A, D, Q, or V; Y10 is D, R, or Y; or (ii) a CDR-H3 sequence defined by the consensus sequence G-G-Φ3-Φ4-Φ5-Y-S-R-G- P-Φ11-D-V (SEQ ID NOS: 85-93), where Φ3 is E, G, Q, or T; Φ4 is A, H, P, Q, or V; Φ5 is K or T; and Φ11 is F, L, or M, d) a VLCDR1 sequence comprising: (i) a CDR-L1 sequence defined by the consensus sequence Φ1-A-S-Q-Φ5- V-S-S-Φ9- Φ10-L-A (SEQ ID NOS: 105-112 and 117), where Φ1 is E, G, K, Q, or R; Φ5 is A or S; Φ9 is A, D, N, S, or T; and Φ10 is F or Y; S-σ9-L- W, or
Figure imgf000176_0001
(iii) a Γ9- Y-L-A and Γ
Figure imgf000176_0002
9 is A e) a VLCDR2 sequence comprising: (i) a CDR-L2 sequence defined by the consensus sequence ψ1-A-S-ψ4-R-A-ψ7 (SEQ ID NOS: 128, 130, 132, 134-138, 143, and 145), where ψ1 is D or G; ψ4 is A, D, N, R, S, T, or Y; and ψ7 is A, N, S, or T, and f) a VLCDR3 sequence comprising: (i) a CDR-L3 sequence defined by the consensus sequence Q-π2-π3-π4-H-S-P-Y-T (SEQ ID NOS: 149-153), where π2 is Q or W; π3 is A, T, or V; and π4 is I or V; (ii) a CDR-L3 sequence defined by the consensus (SEQ ID NOS: 154-158), where λ3 is F, H, or V; and λ5 is (iii) a CDR-L3 sequence defined by the consensus T (SEQ ID NOS: 160-161 and 163-164), where ω3 is A, L, Y; ω5 is S, L, or F; and ω6 is D, L, S, or Y; and (ii) a molecule coupled to the isolated antibody molecule.
Figure imgf000176_0003
19. The conjugate of any of claims 11-18, wherein the molecule coupled to the antibody comprises one selected from the group consisting of a detectable label, a drug, a toxin, a cytokine, a radionuclide, an enzyme, and combinations thereof.
20. The conjugate of any of claims 11-18, wherein the molecule coupled to the antibody comprises a DNA-alkylating cytotoxic molecule or an antineoplastic agent.
21. The conjugate of any of claims 11-18, wherein the molecule coupled to the antibody comprises one selected from the group consisting of Formulas I-VIII: C in) nd
22. A method for treatment of a subject suffering from cancer, a chronic infection, and/or from an inflammatory disease, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of the conjugate of any of claims 1-7 and 11-21 or the pharmaceutical composition of any of claims 8-10.
23. The method of claim 22, wherein the cancer is a solid cancer or a hematological cancer.
24. The method of claim 22, wherein the subject is a human subject.
25. The method of claim 22, wherein the method further comprises one or more of the following: a) administering chemotherapy; b) administering radiation therapy; and/or c) administering one or more additional therapeutic agents.
26. The method of claim 25, wherein the one or more additional therapeutic agents comprise one or more immunostimulatory agents.
27. The method of claim 26, wherein the one or more immunostimulatory agents comprise an antagonist to an inhibitory receptor of an immune cell.
28. The method of claim 27, wherein the inhibitory receptor is selected from the group consisting of ILT2, ILT3, ILT4, KIR2DL4, CTLA-4, PD-l , CD39, CD73, PD-L1 , PD-L2, LAG-3, Tim3, TIGIT, B7-H3, B7-H4, neuritin, BTLA, CECAM-l , CECAM-5, VISTA, LAIR1 , CD160, 2B4,TGF-B (including traps and GARP), NKG2A, a Killer-cell immunoglobulin-like receptor (KIR), and combinations thereof.
29. The method of claim 26, wherein the one or more immunostimulatory agents comprise an agonist of a co-stimulatory receptor of an immune cell.
30. The method of claim 29, wherein the co-stimulatory receptor is at least one of OX40, CD2, CD27, ICAM-l, LFA-l , ICOS (CD278), 4-1BB (CD 137), GITR, CD28, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp30, NKp46, NKp80, CD160, and/or a CD83 ligand.
31. The method of claim 26, wherein the one or more immunostimulatory agents comprise or consist of an ADCC competent antibody selected from the group consisting of an anti-CD19, anti-CD20, anti-EGFR, anti-Her2, anti-SLAMF7, anti-CD52, anti-BCMA, anti-GD2, anti- CD38, anti-CCR4, anti-CTLA4 antibody, and combinations thereof.
32. The method of claim 26, wherein the one or more immunostimulatory agents comprise a cytokine.
33. The method of claim 32, wherein the cytokine is selected from the group consisting of IL- l, IL-2, IL-5, IL-7, IL-10, IL-l2, IL-l5, IL-18, IL-21, IL-27, and combinations thereof.
34. The method of claim 26, wherein the one or more immunostimulatory agents comprise an oncolytic virus.
35. The method of claim 34, wherein the oncolytic virus is selected from the group consisting of a Herpes simplex virus, a Vesicular stomatitis virus, an adenovirus, a Newcastle disease virus, a vaccinia virus, and a maraba virus.
36. The method of claim 26, wherein the one or more immunostimulatory agents comprise a chimeric antigen engineered T cell.
37. The method of claim 26, wherein the one or more immunostimulatory agents comprise a bi- or multi-specific T cell directed antibody.
38. A method for modulating immune system function in a subject in need thereof, the method comprising contacting a population of immune cells of the subject with a pharmaceutical composition comprising an effective amount of the conjugate of claim 1, under conditions such that the immune system is modulated.
39. A method for producing the conjugate of claim 1, the method comprising conjugating the molecule to the antibody using an amino or sulfhydryl specific linker attached to the molecule that react with lysines or cysteines on the antibody surface.
40. The method of claim 39, wherein the conjugating comprising treating the antibody to create a conjugation site on the antibody surface and reacting the conjugation site with the amino or sulfhydryl specific linker attached to the molecule.
PCT/US2024/045367 2023-09-05 2024-09-05 Hla-g antibodies in antibody-drug conjugates Pending WO2025054312A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363536635P 2023-09-05 2023-09-05
US63/536,635 2023-09-05

Publications (1)

Publication Number Publication Date
WO2025054312A1 true WO2025054312A1 (en) 2025-03-13

Family

ID=92883199

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/045367 Pending WO2025054312A1 (en) 2023-09-05 2024-09-05 Hla-g antibodies in antibody-drug conjugates

Country Status (1)

Country Link
WO (1) WO2025054312A1 (en)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009036379A2 (en) 2007-09-14 2009-03-19 Adimab, Inc. Rationally designed, synthetic antibody libraries and uses therefor
WO2010105256A1 (en) 2009-03-13 2010-09-16 Adimab, Inc. Rationally designed, synthetic antibody libraries and uses therefor
WO2012009568A2 (en) 2010-07-16 2012-01-19 Adimab, Llc Antibody libraries
WO2014179363A1 (en) 2013-04-29 2014-11-06 Adimab, Llc Polyspecificity reagents, methods for their preparation and use
US20190112359A1 (en) * 2017-09-22 2019-04-18 Immunogen, Inc. Separation of Triple-Light Chain Antibodies Using Cation Exchange Chromatography
US20200102389A1 (en) * 2016-11-18 2020-04-02 Hoffmann-La Roche Inc. Anti-hla-g antibodies and use thereof
US20210147553A1 (en) * 2018-04-18 2021-05-20 Hoffmann-La Roche Inc. Anti-hla-g antibodies and use thereof
WO2023021187A1 (en) * 2021-08-19 2023-02-23 UCB Biopharma SRL Anti-hla-g antibodies

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009036379A2 (en) 2007-09-14 2009-03-19 Adimab, Inc. Rationally designed, synthetic antibody libraries and uses therefor
WO2010105256A1 (en) 2009-03-13 2010-09-16 Adimab, Inc. Rationally designed, synthetic antibody libraries and uses therefor
WO2012009568A2 (en) 2010-07-16 2012-01-19 Adimab, Llc Antibody libraries
WO2014179363A1 (en) 2013-04-29 2014-11-06 Adimab, Llc Polyspecificity reagents, methods for their preparation and use
US20200102389A1 (en) * 2016-11-18 2020-04-02 Hoffmann-La Roche Inc. Anti-hla-g antibodies and use thereof
US20190112359A1 (en) * 2017-09-22 2019-04-18 Immunogen, Inc. Separation of Triple-Light Chain Antibodies Using Cation Exchange Chromatography
US20210147553A1 (en) * 2018-04-18 2021-05-20 Hoffmann-La Roche Inc. Anti-hla-g antibodies and use thereof
WO2023021187A1 (en) * 2021-08-19 2023-02-23 UCB Biopharma SRL Anti-hla-g antibodies

Non-Patent Citations (17)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical Excipients,", 2009, THE PHARMACEUTICAL PRESS
AL-LAZIKANI ET AL., J. MOL. BIOL., vol. 273, 1997, pages 927 - 948
CREIGHTON: "Proteins: Structures and Molecular Properties", 1993, W. H. FREEMAN & CO.
HONEGGEPLUCKTHUN, J. MOL. BIOL., vol. 309, 2001, pages 657 - 70
JONES ET AL., NATURE, vol. 321, 1986, pages 522 - 525
LEFRANC ET AL., DEV. COMP. IMMUNOL.., vol. 27, 2003, pages 55 - 77
MACCALLUM ET AL., J. MOL. BIOL., vol. 262, 1996, pages 732 - 745
MATSUDA Y, J. ADC., 5 January 2023 (2023-01-05)
MCCOMBS ET AL., AAPS J., vol. 17, no. 2, March 2015 (2015-03-01), pages 339 - 351
MICHITA, RAFAEL TOMOYAET, HUMAN IMMUNOLOGY., vol. 77, no. 10, 2016, pages 892 - 897
MORANDI FABIO ET AL: "HLA-G and Other Immune Checkpoint Molecules as Targets for Novel Combined Immunotherapies", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 23, no. 6, 8 March 2022 (2022-03-08), Basel, CH, pages 2925, XP093111479, ISSN: 1422-0067, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8948858/pdf/ijms-23-02925.pdf> DOI: 10.3390/ijms23062925 *
PLÜCKTHUN A.: "The Pharmacology of MonoclonalAntibodies", vol. 113, 1994, SPRINGER-VERLAG, article "Antibodies from Escherichia coli.", pages: 269 - 315
PRESTA, CURR. OP. STRUCT. BIOL., vol. 2, 1992, pages 593 - 596
RIECHMANN ET AL., NATURE, vol. 332, 1988, pages 323 - 329
SHARLENE ADAMS ET AL: "IMGN632: AN ANTIBODY-DRUG CONJUGATE (ADC) OF A CD123-TARGETING ANTIBODY WITH A NOVEL DNA-ALKYLATING PAYLOAD IS HIGHLY ACTIVE AND PROLONGS SURVIVAL IN AML XENOGRAFT MODELS BACKGROUND", 3 December 2016 (2016-12-03), ASH San Diego, XP055489392, Retrieved from the Internet <URL:https://www.immunogen.com/wp-content/uploads/2018/05/ASH_2016_IMGN632_ab_2832.pdf> [retrieved on 20180702] *
SIEGEL ET AL., J. IMMUNOL. METH., vol. 286, 2004, pages 141 - 153
XU ET AL., PROTEIN ENG. DES. SEL., vol. 26, 2013, pages 663 - 670

Similar Documents

Publication Publication Date Title
JP6759508B2 (en) Disease treatment by inducing an immune response against Trop-2 expressing cells
JP6767029B2 (en) Combination therapy to induce an immune response to the disease
US20250353913A1 (en) Anti-hla-g antibodies, compositions comprising anti-hla-g antibodies and methods of using anti-hla-g antibodies
ES2784131T3 (en) PDGF receptor beta-binding polypeptides
CN112424229B (en) Antibody molecules that bind CD137 and OX40
US20210403593A1 (en) Anti-cd39 antibodies, compositions comprising anti-cd39 antibodies and methods of using anti-cd39 antibodies
ES3005783T3 (en) Multi-specific binding proteins for activation of natural killer cells and therapeutic uses thereof to treat cancer
JP7724866B2 (en) Antibody-drug conjugates and uses thereof
ES2800674T3 (en) Bispecific antigen-binding polypeptides
CN113454116A (en) RANK antagonists and uses thereof
JP7104153B2 (en) Combination therapy of anti-progastrin antibody and immunotherapy to treat cancer
JP2024512478A (en) B lymphocyte-specific amatoxin antibody conjugate
JP2023548522A (en) Composition for use in cancer treatment comprising a combination of an immune checkpoint inhibitor and an antibody-amatoxin conjugate
JP2025503229A (en) Anti-HER2/TROP2 antibodies and uses thereof
WO2025054312A1 (en) Hla-g antibodies in antibody-drug conjugates
WO2023235933A1 (en) Combination therapy
WO2022232488A1 (en) Combination therapies using an anti-bcma antibody drug conjugate (adc) in combination with a gamma secretase inhibitor (gsi)
WO2025165879A1 (en) Methods of using anti-hla-g antibodies
WO2025113644A1 (en) Combination of pd-l1 binding molecule and protein-drug conjugate, and use thereof
JP2019505516A (en) Method of treating acne using an interleukin-17 (IL-17) antagonist
JP2025183203A (en) Antibody-drug conjugates and uses thereof
HK40018067A (en) Anti-tigit antigen-binding proteins and methods of use thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24776094

Country of ref document: EP

Kind code of ref document: A1