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WO2025151607A1 - Methods and compositions for treating autoimmune, allergic and inflammatory diseases - Google Patents

Methods and compositions for treating autoimmune, allergic and inflammatory diseases

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Publication number
WO2025151607A1
WO2025151607A1 PCT/US2025/010901 US2025010901W WO2025151607A1 WO 2025151607 A1 WO2025151607 A1 WO 2025151607A1 US 2025010901 W US2025010901 W US 2025010901W WO 2025151607 A1 WO2025151607 A1 WO 2025151607A1
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WIPO (PCT)
Prior art keywords
seq
amino acid
acid sequence
region
sequence
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PCT/US2025/010901
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French (fr)
Inventor
Peter Emtage
Nancy EMTAGE
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Santa Ana Bio Inc
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Santa Ana Bio Inc
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Publication of WO2025151607A1 publication Critical patent/WO2025151607A1/en
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/524—CH2 domain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/526—CH3 domain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/72—Increased effector function due to an Fc-modification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/734—Complement-dependent cytotoxicity [CDC]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • antibodies or antigen-binding fragments thereof that are capable of binding to PD-1, wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable (VH) region comprising: heavy chain complementarity- determining region 1 (HCDR1) having the amino acid sequence of SEQ ID NO: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 98, and HCDR3 having the amino acid sequence of SEQ ID NO: 4.
  • VH heavy chain variable
  • HCDR1 heavy chain complementarity- determining region 1
  • HCDR2 having the amino acid sequence of SEQ ID NO: 98
  • HCDR3 having the amino acid sequence of SEQ ID NO: 4.
  • the antibody or antigen binding fragment further comprises a light chain variable (VL) region comprising: Page 1 of 99 IPTS/128817054.1 Attorney Docket No.
  • LCDR1 light chain complementarity-determining region 1
  • LCDR2 having the amino acid sequence of SEQ ID NO: 7, and LCDR3 having the amino acid sequence of SEQ ID NO: 8
  • LCDR1 having the amino acid sequence of SEQ ID NO: 6, LCDR2 having the amino acid sequence of SEQ ID NO: 103, and LCDR3 having the amino acid sequence of SEQ ID NO: 104
  • LCDR1 having the amino acid sequence of SEQ ID NO: 6, LCDR2 having the amino acid sequence of SEQ ID NO: 7, and LCDR3 having the amino acid sequence of SEQ ID NO: 109.
  • antibodies or antigen-binding fragments thereof that are capable of binding to PD-1, wherein the antibody or antigen binding fragment thereof comprises a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from SEQ ID NOs: 12-19, 97, and 100; and/or a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NOs: 23-26, 102, 106, and 108.
  • the antibody or antigen binding fragment comprises: a VH region comprising an amino acid sequence selected from SEQ ID NOs: 12-19, 97, and 100; and a VL region comprising an amino acid sequence selected from SEQ ID NOs: 23-26, 102, 106, and 108.
  • antibodies or antigen-binding fragments thereof that are capable of binding to PD-1, wherein the antibody or antigen binding fragment comprises: (a) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 9, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 26; or (b) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 18, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 21; or (c) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO:
  • SANA-007WO (d) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 19, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 26; or (e) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 15, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 24; or (f) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 15, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of S
  • the antibody or antigen binding fragment comprises: (a) a VH region comprising an amino acid sequence of SEQ ID NO: 9, and a VL region comprising an amino acid sequence of SEQ ID NO: 26; or (b) a VH region comprising an amino acid sequence of SEQ ID NO: 18, and a VL region comprising an amino acid sequence of SEQ ID NO: 21; or (c) a VH region comprising an amino acid sequence of SEQ ID NO: 18, and a VL region comprising an amino acid sequence of SEQ ID NO: 26; or (d) a VH region comprising an amino acid sequence of SEQ ID NO: 19, and a VL region comprising an amino acid sequence of SEQ ID NO: 26; or (e) a VH region comprising an amino acid sequence of SEQ ID NO: 15, and a VL region comprising an amino acid sequence of SEQ ID NO: 24; or (f) a VH region comprising an amino acid sequence of SEQ ID NO: 15, and a VL region comprising an amino acid sequence of S
  • the antibody heavy chain constant region is a human IgG1 heavy chain constant region comprising one of the following mutation(s): (a) G236D or G236A; (b) S239D; (c) H268D or H268F; (d) L328Y; (e) S324T; (f) I332E; (g) E345K, E345Y, E345Q, or E345R; (h) E430G, E430S, E430F, or E430T; (i) S440Y; (j) S239D and H268D; or a combination thereof, wherein the numbering of the constant region is as per the EU index.
  • the antibody heavy chain constant region is a human IgG1 heavy chain constant region comprising the following mutations: E430G or E345K, wherein the numbering of the constant region is as per the EU index.
  • the antibody heavy chain constant region comprises an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 125.
  • the antibody heavy chain constant region has the amino acid sequence of SEQ ID NO: 125.
  • antibodies or antigen-binding fragments thereof that are capable of binding to PD-1, wherein the antibody or antigen binding fragment thereof comprises a human IgG1 heavy chain constant region comprising a mutation selected from E345K, E345Y, E345Q, E345R, E430G, E430S, E430F, E430T, S440Y, wherein the numbering of the constant region is as per the EU index; and the antibody or antigen binding fragment thereof comprises (a) (i) a heavy chain variable (VH) region comprising: heavy chain complementarity-determining region 1 (HCDR1) having the amino acid sequence of SEQ ID NO: 2, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 3, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 4, or a sequence differing in 1 or 2 amino acids therefrom; and Page 7 of 99 IPTS/12
  • SANA-007WO HCDR3 having the amino acid sequence of SEQ ID NO: 4, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 6, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 103, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 104, or a sequence differing in 1 or 2 amino acids therefrom; (n) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 2, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 98, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 4, or a sequence differing in 1 or 2 amino acids therefrom
  • SANA-007WO LCDR2 having the amino acid sequence of SEQ ID NO: 7, or a sequence differing in 1 or 2 amino acids therefrom
  • LCDR3 having the amino acid sequence of SEQ ID NO: 109, or a sequence differing in 1 or 2 amino acids therefrom.
  • the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise amino acid sequences that collectively differ by no more than two amino acid residues from the sequences of: (a) SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively; (b) SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 33, and SEQ ID NO: 34, respectively; (c) SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42, respectively; (d) SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 49, and SEQ ID NO: 50, respectively; (e) SEQ ID NO: 52, SEQ ID NO: 53
  • the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise amino acid sequences of: (a) SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively; (b) SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 33, and SEQ ID NO: 34, respectively; (c) SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42, respectively; (d) SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 49, and SEQ ID NO: 50, respectively; (e) SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 56, SEQ
  • a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 59 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 63;
  • a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 67, 128, 69, or 60 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:
  • the IgG1 heavy chain constant region comprises E430G or E345K, wherein the numbering of the constant region is as per the EU index.
  • the IgG1 heavy chain constant region further comprises one of the following mutation(s): (a) E233D; (b) G236D or G236A; (c) G237D; (d) P238D; (e) S239D; (f) S267E; (g) H268D or H268F; (h) P271G; (i) S324T; (j) L328Y, L328F, or L328E; (k) A330R; (l) I332E; (m) G236D and H268D; (n) S239D and H268D; (o) S239D, H268D, L328Y, and I332E; (p) P238D and L328E; (q) G237D, P
  • the IgG1 heavy chain constant region comprises the following mutations: S239D and H268D, wherein the numbering of the constant region is as per the EU index. In some embodiments, the IgG1 heavy chain constant region comprises the following mutations: E233D, G237D, H268D, P271G, and A330R, wherein the numbering of the constant region is as per the EU index. In some embodiments, the IgG1 heavy chain constant region comprises comprises the following mutations: S267E and L328F, wherein the numbering of the constant region is as per the EU index.
  • the IgG1 heavy chain constant region comprises an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to Page 19 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO the amino acid sequence of SEQ ID NO: 125. In some embodiments, the IgG1 heavy chain constant region has the amino acid sequence of SEQ ID NO: 125.
  • an antibody or antigen binding fragment thereof described above is a PD-1 agonist. In some embodiments, the antibody or antigen binding fragment thereof is capable binding to human PD-1. In some embodiments, the antibody or antigen binding fragment thereof is capable of binding to cynomonguls PD-1.
  • the antibody or antigen-binding fragment is capable of blocking PD-1/PD-L1 interaction.
  • an antibody or antigen binding fragment thereof described above has enhanced binding to an Fc receptor.
  • the Fc receptor is an inhibitory Fc receptor (e.g., Fc ⁇ RII).
  • the Fc receptor is an activating Fc receptor (e.g., Fc ⁇ RI or Fc ⁇ RIII).
  • an antibody or antigen binding fragment thereof described above has enhanced effector function.
  • the effector function is antibody- dependent cellular cytotoxicity (ADCC).
  • the effector function is antibody-dependent cellular phagocytosis (ADCP).
  • the immune cell is an antigen-activated T cell or B cell.
  • an antibody or antigen binding fragment thereof described above is at least about 60%, about 75%, or about 90% non-fucosylated.
  • the antibody or antigen binding fragment thereof is produced in a cell line (a) having an alpha-1,6-fucosyltransferase (Fut8) knockout; or (b) line overexpressing ⁇ 1,4-N-acetylglucosaminyltransferase III (GnT-III) and optionally overexpressing Golgi ⁇ - mannosidase II (ManII).
  • an antibody or antigen binding fragment thereof described above is capable of inhibiting T cell activation.
  • an antibody or antigen binding fragment thereof described above is capable of inhibiting T cell proliferation.
  • Page 20 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO
  • an antibody or antigen binding fragment thereof described above is capable of inhibiting IFN ⁇ secretion.
  • an antibody or antigen binding fragment thereof described above is conjugated to an agent.
  • the agent is a cytotoxic agent or label.
  • the agent is a therapeutic agent.
  • compositions comprising an antibody or antigen binding fragment thereof described herein.
  • the antibody or antigen- binding fragment comprises an Fc region and N-glycoside-linked carbohydrate chains linked to the Fc region, optionally wherein less than 50% of the N-glycoside-linked carbohydrate chains contain a fucose residue. In some embodiments, substantially none of the N-glycoside- linked carbohydrate chains contain a fucose residue.
  • polynucleotides encoding an antibody or antigen 5 binding fragment thereof described herein.
  • expression vectors comprising a polynucleotide described herein.
  • FIGs.3A and 3B show the complement-dependent cytotoxicity of PD-1 antibodies with wild-type IgG1 Fc or modified Fc containing mutations that increase binding to Fc ⁇ RII and optionally mutation that induces antibody hexamer formation in Raji cells (FIG.3A) and CHO-K1 cells (FIG.3B).
  • FIGs.4A and 4B shows the depletion of CD8 T cells expressing high (FIG.4A) and intermediate (FIG.4B) levels of cell surcase PD-1 by PD-1 antibodies with wild-type IgG1 Fc or modified Fc containing mutations that increase binding to Fc ⁇ RII and optionally mutation that induces antibody hexamer formation.
  • FIG.5 depicts the binding of humanized PD-1 antibodies to PD-1 on cell surface.
  • FIG.6 depicts the cross-reactivity of PD-1 antibody to human and cynomolgus PD- 1.
  • FIGs.7A-7C show that PD-1 antibodies activate siganling through Fc ⁇ receptrs CD16a (FIG.7A), CD32a (FIG.7B), and CD64 (FIG.7C).
  • FIG.8 depicts the inhibition of the activation of Jurkat reporter T cells incubated with Raji-APC cells modified to express Fc ⁇ RIIb by PD-1 antibodies with modified Fc containing mutations that increase binding to Fc ⁇ RII and induce antibody hexamer formation.
  • FIG.9 depicts the antibody dependent cellular phagocytosis of PD-1 positive target cells induced by PD-1 antibodies.
  • antibody refers to a polypeptide whose amino acid sequence includes immunoglobulins and fragments thereof which specifically bind to a designated antigen, or fragments thereof.
  • Antibodies in accordance with the present invention may be of any type (e.g., IgA, IgD, IgE, IgG, or IgM) or subtype (e.g., IgA1, IgA2, IgG1, IgG2, IgG3, or IgG4).
  • a characteristic sequence or portion of an antibody may include amino acids found in one or more regions of an antibody (e.g., variable region, hypervariable region, constant region, heavy chain, light chain, and combinations thereof).
  • antibody mimetic refers to any molecule that is capable of mimicking an antibody’s ability to bind an antigen, but which are not limited to antibody structures.
  • antibody mimetics include, but are not limited to, Affibodies, Affilins, Affimers, Afftins, Alphabodies, Anticalins, avimers, Centyrins, DARPins, Fynomers, monobodies, nanobody, and nanoCLAMPs.
  • an “antigen-binding fragment” of an antibody comprises a portion of an intact antibody, which portion is still capable of antigen binding.
  • papain digestion of antibodies produce two identical antigen-binding fragments, called “Fab” fragments, and a residual “Fc” fragment, a designation reflecting the ability to crystallize readily.
  • the Fab fragment consists of an entire light chain along with the variable region domain of the heavy chain (V H ), and the first constant domain of one heavy chain (C H 1).
  • Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding Page 23 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO site.
  • the term “antigen-binding site” refers to any molecule or any part of a molecule that is capable of antigen binding.
  • the antigen-binding site is formed by amino acid residues of the N-terminal variable (“V”) regions of the heavy (“H”) and light (“L”) chains.
  • V N-terminal variable
  • L light
  • Three highly divergent stretches within the V regions of the heavy and light chains are referred to as “hypervariable regions” which are interposed between more conserved flanking stretches known as “framework regions,” or “FR.”
  • FR refers to amino acid sequences which are naturally found between and adjacent to hypervariable regions in immunoglobulins.
  • the three hypervariable regions of a light chain and the three hypervariable regions of a heavy chain are disposed relative to each other in three dimensional space to form an antigen-binding surface.
  • the antigen-binding surface is complementary to the three-dimensional surface of a bound antigen, and the three hypervariable regions of each of the heavy and light chains are referred to as “complementarity-determining regions,” or “CDRs.”
  • CDRs complementarity-determining regions
  • the antigen-binding site may by formed by a single antibody chain providing a “single domain antibody.”
  • An antigen-binding site can also be or exist in an antibody mimetic.
  • the CDRs can be determined by the methods described in Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of protein of immunological interest. (1991), Chothia et al., J. Mol. Biol. 196:901-917 (1987), and MacCallum et al., J. Mol. Biol. 262:732-745 (1996).
  • the CDRs determined under these definitions typically include overlapping or subsets of amino acid residues when compared against each other.
  • the term “CDR” is a CDR as defined by MacCallum et al., J. Mol.
  • CDR is a CDR as defined by Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of protein Page 24 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO of immunological interest. (1991).
  • heavy chain CDRs and light chain CDRs of an antibody are defined using different conventions.
  • the heavy chain CDRs are defined according to MacCallum (supra), and the light CDRs are defined according to Kabat (supra).
  • CDRH1, CDRH2 and CDRH3 denote the heavy chain CDRs
  • CDRL1, CDRL2 and CDRL3 denote the light chain CDRs.
  • binding affinity of a molecule of the disclosure (e.g., an antigent- binding site) to a given targets (e.g., PD-1, PD-L1, or PD-L2) can be determined by a multitude of methods known to those skilled in the art.
  • bispecific refers to a molecule is able to specifically bind to at least two distinct targets.
  • a bispecific molecule comprises two antigen-binding sites, each of which is specific for a different target.
  • a bispecific molecule is capable of binding two targets simultaneously.
  • “detectable affinity” refers to the ability to bind to a given target with an affinity constant, typically measured by K D or EC 50 , of at most about 10 -5 M or lower (a lower K D or EC 50 value reflects better binding ability). Lower affinities that are no longer measurable with common methods such as ELISA (enzyme-linked immunosorbent assay) are of secondary importance.
  • the term “epitope” is an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule, known as the paratope, and which is comprised of the six complementary-determining regions of the antibody. A single antigen may have more than one epitope.
  • Epitopes may be conformational or linear.
  • a conformational epitope is comprised of spatially juxtaposed amino acids from different segments of a linear polypeptide chain.
  • a linear epitope is comprised of adjacent amino acid residues in a polypeptide chain.
  • An “Fc” fragment comprises the carboxy-terminal portions of both heavy chains held together by disulfides. The effector functions of antibodies are determined by sequences in the Fc region, the region which is also recognized by Fc receptors (FcR) found on certain types of cells.
  • FcR Fc receptors
  • a “fragment” with respect to an antigen refers to N- terminally and/or C- terminally truncated or protein domains of the antigen.
  • a fragment of the antigen retains the capability of the full-length antigen to be recognized and/or bound by an antigen-binding site of the disclosure.
  • Page 25 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO
  • “fucosylation” or “fucosylated” refers to the presence of fucose residues within the oligosaccharides attached to the peptide backbone of an antibody.
  • an antibody with reduced fucose or lacking fucose has improved ADCC function.
  • the “degree of fucosylation” is the percentage of fucosylated oligosaccharides relative to all oligosaccharides, which may be identified by methods known in the art, e.g., in an N-glycosidase F treated antibody composition assessed by matrix-assisted laser desorption- ionization time-of-flight mass spectrometry (MALDI-TOF MS).
  • MALDI-TOF MS matrix-assisted laser desorption- ionization time-of-flight mass spectrometry
  • a composition of a fully fucosylated antibody has a degree of fucosylation of at least about 90%. In contrast, in a composition of a “fully non-fucosylated antibody,” essentially none of the oligosaccharides are fucosylated. In some embodiments, a composition of a fully non-fucosylated antibody has a degree of fucosylation of less than about 10%. In a composition of a “partially fucosylated antibody,” only part of the oligosaccharides comprise fucose.
  • An individual antibody in such a composition may comprise fucose residues in none, one or both of the N-linked oligosaccharides in the Fc region, provided that the composition does not comprise essentially all individual antibodies that lack fucose residues in the N-linked oligosaccharides in the Fc region, nor essentially all individual antibodies that contain fucose residues in both of the N-linked oligosaccharides in the Fc region.
  • a composition of a partially fucosylated antibody has a degree of fucosylation of about 10% to about 80% (e.g., about 50% to about 80%, about 60% to about 80%, or about 70% to about 80%).
  • the term “monoclonal antibody” refers to an antibody obtained from a population of substantially homogeneous antibodies, e.g., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed Page 26 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO against a single antigenic site.
  • each monoclonal antibody is directed against a single determinant on the antigen.
  • the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • monoclonal antibodies may be made by a hybridoma method, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567).
  • “Monoclonal antibodies” may also be isolated from phage antibody libraries.
  • the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • pharmaceutically acceptable salt refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound described in the present application which, upon administration to a subject, is capable of providing a compound described in this application or an active metabolite or residue thereof.
  • salts of the compounds described in the present application may be derived from inorganic or organic acids and bases.
  • Exemplary acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p- sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like.
  • Exemplary bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and compounds of formula NW4 + , wherein W is C1-4 alkyl, and the like.
  • salts of the compounds described in the present application are contemplated as being pharmaceutically acceptable.
  • salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
  • antigen-binding sites disclosed herein bind PD-1 presented on the surface of a membrane (e.g., plasma membrane of a cell). [0110] In some embodiments, antigen-binding sites disclosed herein bind cynomolgus PD- 1. In some embodiments, antigen-binding sites disclosed herein bind cynomolgus PD-1 at a comparable affinity to that of binding human PD-1. [0111] In some embodiments, antigen-binding sites disclosed herein does not significantly bind other PD-1 family members. In some embodiments, antigen-binding sites disclosed herein does not significantly bind ICOS, CD28, or CTLA-4.
  • the antibody has reduced or no ability to bind an Fc receptor.
  • it is an isotype or subtype, fragment or other mutant, which does not support binding to an Fc receptor, e.g., it has a mutagenized or deleted Fc receptor binding region.
  • the constant region comprises one or more mutation(s) that enhance effector function.
  • the constant region comprises one or more mutation(s) that enhance binding to Fc ⁇ RII (CD32).
  • the constant region comprises a heavy chain constant region of IgG1, comprising one or more of the following mutations, numbering based on EU index, (a) E233D or G236A; (b) G236D; (c) G237D; (d) P238D; (e) S239D; (f) S267E; (g) H268D; (h) P271G; (i) S324T; (j) L328Y, L328F, or L328E; (k) A330R; (l) I332E; (m) E345K, E345Y, E345Q, or E345R; (n) E430G, E430S, E430F, or E430T; (o) S440Y; (p) G236D and H268D; (q) S239D and H268D; (r) S239D, H268D, L328Y, and I332E; (s) P238
  • the constant region comprises a heavy chain constant region of IgG1, comprising one or more of the following mutations, numbering based on EU index, (a) G236D or G236A; (b) S239D; (c) H268D or H268F; (d) L328Y; (e) S324T; (f) I332E; (g) E345K, E345Y, E345Q, or E345R; (h) E430G, E430S, E430F, or E430T; (i) S440Y, or a combination thereof.
  • the constant region comprises a heavy chain constant region of IgG1, comprising one or more of the following mutations, numbering based on EU index, (a) G236D or G236A; (b) S239D; (c) H268D or H268F; (d) S324T; (e) L328Y; (f) I332E; (g) E345K, E345Y, E345Q, or E345R; (h) E430G, E430S, E430F, or E430T; (i) S440Y, or a combination thereof.
  • the constant region comprises a heavy chain constant region of IgG1 comprising the mutations of S239D and H268D, numbering based on EU index. In certain embodiments, the constant region comprises a heavy chain constant region of IgG1 comprising the mutations of S239D, H268D, and E430G, numbering based on EU index. In certain embodiments, the constant region comprises a heavy chain constant region of IgG1 comprising the mutations of S239D, H268D, and E345K, numbering based on EU index.
  • the constant region comprises a heavy chain constant region of IgG1 comprising the mutations of E233D, G237D, H268D, P271G, and A330R, numbering based on EU index. In certain embodiments, the constant region comprises a heavy chain constant region of IgG1 comprising the mutation of E430G or E345K, numbering based on EU index. In certain Page 40 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO embodiments, the constant region comprises a heavy chain constant region of IgG1 comprising the mutations of S267E and L328F, numbering based on EU index.
  • the constant region comprises a heavy chain constant region of IgG1, comprising one or more of the following mutations, numbering based on EU index, F243L, R292P, Y300L, V305I, and/or P396L; (b) S239D and/or I332E; (c) S239D, I332E, and/or A330L; (d) S298A, E333A, and/or K334A; (e) G236A, S239D, and/or I332E; (f) K326W and/or E333S; (g) S267E, H268F, and/or S324T; or (h) E345R, E430G, and/or S440Y.
  • the constant region comprises one or more mutation(s) that reduce effector function.
  • the constant region comprises a heavy chain constant region of IgG1, comprising one or more of the following mutations, numbering based on EU index, (a) L234A and/or L235A; (b) A327G, A330S, and/or P331S; (c) E233P, L234V, L235A, and/or G236del; (d) E233P, L234V, and/or L235A; (e) E233P, L234V, L235A, G236del, A327G, A330S, and/or P331S; (f) E233P, L234V, L235A, A327G, A330S, and/or P331S; (g) N297A; (h) N297G; (i) N297Q; (j) L242C, N297C,
  • the constant region comprises a heavy chain constant region of IgG2, comprising one or more of the following mutations, numbering based on EU index, (a) A330S and/or P331S; (b) V234A, G237A, P238S, H268A, V309L, A330S, and/or P331S; or (c) V234A, G237A, H268Q, V309L, A330S, P331S, C232S, C233S, S267E, L328F, M252Y, S254T, and/or T256E.
  • the constant region comprises a heavy chain constant region of IgG4, comprising one or more of the following mutations, numbering based on EU index, (a) E233P, F234V, L235A, and/or G236del; (b) E233P, F234V, and/or L235A; (c) S228P and/or L235E; or (d) S228P and/or L235A.
  • the antigen-binding site is linked to the antibody constant region or fragment or variant thereof.
  • the antigen-binding site is linked to an IgG constant region including hinge, CH2 and CH3 domains with or without a CH1 domain.
  • molecules containing disclosed antigen-binding sites further comprises a Fc region that is non-fucosylated.
  • the Fc region is non- fucosylated IgG1 Fc region.
  • the bispecific molecule may be a fusion protein containing one or more antibody mimetics.
  • the bispecific molecule may be a fusion Page 41 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO protein containing one or more antibody mimetics and one or more antibodies or antigen- binding fragments thereof.
  • Amino acid sequence modifications [0130] Amino acid sequence modification(s) of the antigen-binding sites and molecules containing antigen-binding sites (e.g., antibodies or antigen-binding fragments thereof) disclosed herein are contemplated. For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibodies or antigen-binding fragments.
  • Amino acid sequence variants can be prepared, e.g., by introducing appropriate nucleotide changes into a nucleic acid sequence encoding the antigen-binding site or molecule containing antigen-binding site, or by peptide synthesis. Such modifications can include, for example, deletions from, and/or insertions into and/or substitutions of, residues within the amino acid sequences.
  • amino acid changes are introduced to alter post-translational processes, such as changing the number or position of glycosylation sites.
  • a useful method for identification of certain residues or regions that are preferred locations for mutagenesis is called “alanine scanning mutagenesis.”
  • a residue or group of target residues are identified (e.g., charged residues such as Arg, Asp, His, Lys, and Glu) and replaced by a neutral or negatively charged amino acid (most preferably alanine or polyalanine) to affect the interaction of the amino acids with antigen.
  • Those amino acid locations demonstrating functional sensitivity to the substitutions then are refined by introducing further or other variants at, or for, the sites of substitution.
  • the site for introducing an amino acid sequence variation is predetermined, the nature of the mutation per se need not be predetermined. For example, to analyze the performance of a mutation at a given site, ala scanning or random mutagenesis may be conducted at the target codon or region, and the expressed variants may be screened for a desired activity.
  • amino acid sequence insertions include, but are not limited to, amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues.
  • An example of a terminal insertion includes, but are not limited to, N-terminal methionyl residues. Page 42 of 99 IPTS/128817054.1 Attorney Docket No.
  • the antigen-binding site or molecule containing antigen- binding site is fused at one terminus to another polypeptide, e.g., a cytotoxic polypeptide, an enzyme, or a polypeptide which increases the serum half-life of the antibody or antigen-binding fragment.
  • another polypeptide e.g., a cytotoxic polypeptide, an enzyme, or a polypeptide which increases the serum half-life of the antibody or antigen-binding fragment.
  • Another type of variant is an amino acid substitution variant. These variants have at least one amino acid residue in the amino acid sequence of the molecule replaced by a different residue. Sites of greatest interest for substitutional mutagenesis are typically the hypervariable regions, but framework region alterations are also contemplated.
  • SANA-007WO (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain.
  • Naturally occurring residues are typically divided into groups based on common side-chain properties: (1) hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic: Cys, Ser, Thr; (3) acidic: Asp, Glu; (4) basic: Asn, Gln, His, Lys, Arg; (5) residues that influence chain orientation: Gly, Pro; and (6) aromatic: Trp, Tyr, Phe.
  • Non-conservative substitutions can entail exchanging a member of one of these classes for another class.
  • cysteine residues not involved in maintaining the proper conformation of the antibody or antigen-binding fragment may be substituted, generally with serine, to improve the oxidative stability of the molecule and prevent aberrant crosslinking.
  • cysteine bond(s) may be added to the antibody to improve its stability (particularly where the antibody is an antibody fragment such as an Fv fragment).
  • a substitutional variant comprises a substitution within one or more hypervariable region residues of a parent antibody (e.g., a human antibody).
  • a method for generating such substitutional variants involves affinity maturation using phage display.
  • several hypervariable region sites e.g., 6-7 sites
  • Antibody variants thus generated are displayed in a monovalent fashion, e.g., from filamentous phage particles as fusions to the gene III product of M13 packaged within each particle.
  • the phage- displayed variants are then screened for their biological activity (e.g., binding affinity).
  • alanine scanning mutagenesis can be performed to identify hypervariable region residues contributing significantly to antigen binding.
  • Such contact residues and neighboring residues are candidates for substitution according to the techniques elaborated herein.
  • the original glycosylation pattern of a parent antibody is altered. Such alteration(s) may comprise deleting one or more carbohydrate moieties found in the antibody, and/or adding one or more glycosylation sites that are not present in the antibody.
  • Glycosylation of antibodies is typically either N-linked or O-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue.
  • the tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are recognition sequences for enzymatic attachment of the carbohydrate moiety to an asparagine side chain.
  • glycosylation sites refers to the attachment of one of the sugars N-aceylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used.
  • Addition of glycosylation sites to the antibody may be accomplished by altering the antibody or antigen-bindng fragment’s amino acid sequence such that it contains one or more of the above-described tripeptide sequences (for N-linked glycosylation sites).
  • Nucleic acid molecules encoding amino acid sequence variants of antibodies or antigen-binding fragments may be prepared by a variety of methods known in the art. These methods include, but are not limited to, isolation from a natural source (in the case of naturally occurring amino acid sequence variants) or preparation by oligonucleotide-mediated (or site- directed) mutagenesis, PCR mutagenesis, and cassette mutagenesis of an earlier prepared variant or a non-variant version of the antibody or antigen-binding fragment thereof.
  • a modification that increases the serum half-life is used.
  • a salvage receptor binding epitope can be incorporated into a molecule containing disclosed antigen-binding site as described, e.g., in U.S. Pat. No. 5,739,277.
  • the term “salvage receptor binding epitope” refers to an epitope of the Fc region of an IgG molecule (e.g., IgG1, IgG2, IgG3, or IgG4) that is responsible for increasing the in vivo serum half-life of the IgG molecule.
  • Page 45 of 99 IPTS/128817054.1 Attorney Docket No.
  • nucleic acid sequences encoding a protein containing the disclosed antigen-binding site can be cloned into one or more expression vectors; the expression vectors can be stably transfected into host cells capable of expressing the gene(s). After transfection, single clones can be isolated for cell bank generation using methods known in the art, such as limited dilution, ELISA, FACS, microscopy, or Clonepix.
  • Clones can be cultured under conditions suitable for bio-reactor scale-up and maintained expression of a protein comprising an antigen-binding site disclosed herein.
  • the protein can be isolated and purified using methods known in the art, such as centrifugation, depth filtration, cell lysis, homogenization, freeze-thawing, affinity purification, gel filtration, ion exchange chromatography, hydrophobic interaction exchange chromatography, and mixed-mode chromatography.
  • isolated nucleic acids encoding antigen- binding sites and molecules (e.g., proteins) containing antigen-binding sites, vectors and host cells comprising the nucleic acid, and recombinant techniques for the production.
  • one or more isolated nucleic acids comprising sequences encoding an immunoglobulin heavy chain and/or immunoglobulin light chain variable region of any antibody disclosed herein, and one or more expression vectors that express the immunoglobulin heavy chain and/or immunoglobulin light chain variable region of any antibody disclosed herein.
  • host cells comprising one or more of the foregoing expression vectors and/or isolated nucleic acids.
  • antigen-binding sites and molecules e.g., proteins
  • containing antigen-binding sites of the present disclosure may be fused to another agent, e.g., another therapeutic agent. Construction of fusion proteins is within ordinary skill in the art.
  • hybridoma cells thus prepared are seeded and grown in a suitable culture medium which medium preferably contains one or more substances that inhibit the growth or survival of the unfused, parental myeloma cells (also referred to as fusion partner).
  • the selective culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (HAT medium), which substances prevent the growth of HGPRT-deficient cells.
  • HGPRT hypoxanthine guanine phosphoribosyl transferase
  • suitable fusion partner include, but are not limited to, myeloma cells are those that fuse efficiently, support stable high-level production of antibody by the selected antibody-producing cells, and are sensitive to a selective medium that selects against the unfused parental cells.
  • myeloma cell lines include, but are not limited to, are murine myeloma lines, such as those derived from MOPC-21 and MPC-11 mouse tumors available from the Salk Institute Cell Distribution Center, San Diego, Calif. USA, and SP-2 and derivatives e.g., X63-Ag8-653 cells available from the American Type Culture Collection, Rockville, Md. USA.
  • Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies.
  • culture medium in which hybridoma cells are growing is then assayed for production of monoclonal antibodies directed against the antigen.
  • DNA encoding the monoclonal antibodies can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies).
  • Hybridoma cells can serve as a preferred source of such DNA.
  • the DNA may be placed into expression vectors, which are then transfected into host cells such as E. coli cells, simian COS cells, Chinese Hamster Ovary (CHO) cells, or myeloma cells that do not otherwise produce antibody protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells.
  • monoclonal antibodies or antibody fragments are isolated from antibody phage libraries.
  • Human antibodies can be generated by methods known in the art, including methods described herein. For example, it is possible to produce transgenic animals (e.g., mice) that are capable, upon immunization, of producing a full repertoire of human antibodies in the absence of endogenous immunoglobulin production. For example, it has been described that the homozygous deletion of the antibody heavy-chain joining region (JH) gene in chimeric and germ-line mutant mice results in complete inhibition of endogenous antibody production.
  • JH antibody heavy-chain joining region
  • phage display technology can be used to produce human antibodies and antibody fragments in vitro, from immunoglobulin variable (V) domain gene repertoires from Page 48 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO unimmunized donors.
  • V-gene segments can be used for phage display, e.g., from random combinatorial librarues of V genes such as libraries derived from the spleens of immunized mice.
  • a repertoire of V genes from unimmunized human donors can be constructed and antibodies to a diverse array of antigens (including self-antigens) can be isolated essentially following methods described in the art. See, e.g., U.S. Pat. Nos.5,565,332 and 5,573,905.
  • Human antibodies may also be generated by in vitro activated B cells (see, e.g., U.S. Pat. Nos.5,567,610 and 5,229,275).
  • Competition assays for determining whether an antibody binds to the same epitope as, or competes for binding with a disclosed antibody are known in the art.
  • Exemplary competition assays include immunoassays (e.g., ELISA assays, RIA assays), surface plasmon resonance (e.g., BIAcore analysis), bio-layer interferometry, and flow cytometry.
  • a competition assay involves the use of an antigen bound to a solid surface or expressed on a cell surface, a test antibody, and a reference antibody. The reference antibody is labeled and the test antibody is unlabeled.
  • test antibody competes with the reference antibody for specific binding to the antigen if an excess of one antibody (e.g., 1x, 5x, 10x, 20x or 100x) inhibits binding of the Page 49 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO other antibody, e.g., by at least 50%, 75%, 90%, 95% or 99% as measured in a competitive binding assay.
  • an excess of one antibody e.g., 1x, 5x, 10x, 20x or 100x
  • SANA-007WO other antibody e.g., by at least 50%, 75%, 90%, 95% or 99% as measured in a competitive binding assay.
  • Two antibodies may be determined to bind to the same epitope if essentially all amino acid mutations in the antigen that reduce or eliminate binding of one antibody reduce or eliminate binding of the other. Two antibodies may be determined to bind to overlapping epitopes if only a subset of the amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other.
  • the antibodies disclosed herein may be further optimized (e.g., affinity-matured) to improve biochemical characteristics including affinity and/or specificity, improve biophysical properties including aggregation, stability, precipitation and/or non-specific interactions, and/or to reduce immunogenicity. Affinity-maturation procedures are within ordinary skill in the art.
  • compositions [0173] In certain embodiments, provided molecules containing disclosed antigen-binding sites are incorporated together with one or more pharmaceutically acceptable carriers into a pharmaceutical composition suitable for administration to a subject.
  • pharmaceutically acceptable carrier refers to any of a variety of solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Examples of pharmaceutically acceptable carriers include, but are not limited to, water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof.
  • pharmaceutical compositions comprise one or more tonicity agents or stabilizers.
  • Non-limiting examples of such tonicity agents or stabilizers include sugars (e.g., sucrose), polyalcohols (e.g., mannitol or sorbitol), and sodium chloride.
  • sugars e.g., sucrose
  • polyalcohols e.g., mannitol or sorbitol
  • sodium chloride e.g., sodium chloride.
  • compositions comprise one or more auxiliary substances such as wetting or emulsifying agents, preservatives (e.g., benzyl alcohol) or buffers, which may enhance the shelf life and/or effectiveness of immunoconjugates disclosed herein.
  • auxiliary substances such as wetting or emulsifying agents, preservatives (e.g., benzyl alcohol) or buffers, which may enhance the shelf life and/or effectiveness of immunoconjugates disclosed herein.
  • Pharmaceutical compositions may be provided in any of a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. Suitability of certain forms may depend on the intended mode of administration and therapeutic application.
  • compositions are in the form of injectable or infusible solutions.
  • Pharmaceutical compositions are typically sterile and stable under conditions of manufacture, transport, and storage.
  • Pharmaceutical compositions may be formulated as, for example, a solution, microemulsion, dispersion, liposome, or other ordered structure.
  • a pharmaceutical composition is formulated as a structure particularly suitable for high drug concentration.
  • sterile injectable solutions can be prepared by incorporating a therapeutic agent (e.g., immunoconjugate) in a desired amount in an appropriate solvent with one or a combination of ingredients enumerated herein, optionally followed by sterilization (e.g., filter sterilization).
  • Therapeutically effective amounts may be administered via a single dose or via multiple doses (e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten doses).
  • any of a variety of suitable therapeutic regimens may be used, including administration at regular intervals (e.g., once every other day, once every three days, once every four days, once every five days, thrice weekly, twice weekly, once a week, once every two weeks, once every three weeks, etc.).
  • the dosage regimen (e.g., amounts of each therapeutic, relative timing of therapies, etc.) that is effective in methods of treatment may depend on the severity of the disease or condition and the weight and general state of the subject.
  • the therapeutically effective amount of a particular composition comprising a therapeutic agent applied to mammals can be determined by the ordinarily-skilled artisan with consideration of individual differences in age, weight, and the condition of the mammal.
  • Therapeutically effective and/or optimal amounts can also be determined empirically by those of skill in the art.
  • Page 53 of 99 IPTS/128817054.1 Attorney Docket No.
  • the molecule containing antigen-binding site or pharmaceutical composition thereof may be administered by any of a variety of suitable routes, including, but not limited to, systemic routes such as parenteral (e.g., intravenous or subcutaneous) or enteral routes.
  • systemic routes such as parenteral (e.g., intravenous or subcutaneous) or enteral routes.
  • administering therapeutic agents containing antigen-binding sites or pharmaceutical compositions thereof in accordance with provided methods results in depletion of cells involved in the disease to be treated.
  • the cell expresses an antigen to which the antigen-binding sites comprised in the therapeutic agents bind.
  • Raji-APC cells modified to express the Fc ⁇ RII receptor were incubated for 30 minutes at 37 o C, 5% CO2 with isotype controls or PD-1 antibodies.
  • Tested antibodies comprise wild- type IgG1 Fc, IgG1 Fc carrying X3 mutations, or IgG1 Fc carrying X3 mutations and a E430G or E345K mutation that induces antibody hexamer formation (“HexaBody” mutation).
  • Jurkat-Lucia TCR-hPD-1 cells were added to the culture, and the plate was incubated for an additional 5.5 hours at 37 o C, 5% CO 2 .
  • PD-1 positive positive Raji cells were incubated with PD- 1 antibodies 3H4, 3H4 with X3 mutations (“3H4 X3”), and 3H4 with X3 and HexaBody mutations (“3H4 X3 Hex”) for 30 minutes at 37 o C in a 96 well clear bottom white walled plate.
  • 3H4 X3 3H4 with X3 mutations
  • 3H4 X3 Hex 3H4 with X3 and HexaBody mutations
  • Luminescence was measured on a plate reader (PerkinElmer). Percent cytotoxicity was calculated by subtracting background RLU from all samples and then applying the formula 100% ⁇ (1 – RLU of the sample) / (RLU of the no antibody control).
  • CHO-K1 cell-based assay PD-1 positive CHO-K1 cells were incubated with serially diluted PD-1 antibody 3H4 X3 HexaBody for 30 minutes at room temperature in a clear bottom white walled plate. Following incubation, normal human serum complement was added, and the plate incubated at 37 o C, 5% CO2 for 4 hours.
  • Example 4 Depletion of CD8 T cells induced by PD-1 antibodies
  • the ability of exemplary PD-1 antibodies to deplete CD8 T cells was assessed.
  • Fresh whole blood was collected into heparin vacutainer tubes.
  • PD-1 antibodies or isotype control antibodies (100nM) were incubated with whole blood in polypropylene tubes for 24 hours at 37 o C, 5% CO2. Following incubation, cells were stained with fluorescently labeled antibodies for PD-1, CD3, CD4, CD8, and CD45 for 30 minutes at room temperature. Cells were lysed by the addition of lysis buffer for 15 minutes at room temperature, centrifuged at 400 ⁇ g for 4 min and washed twice with cell staining buffer.
  • PD-1 antibodies 3H4 X3 and 3H4 X3 Hex showed mediated the depletion of CD8 T cells with both high and intermediate levels of PD-1 cell surface expression.
  • Example 5 Binding of antibodies toward PD-1 [0201] Binding of humanized PD-1 antibodies to human PD-1 was assessed by biolayer interferometry (BLI). [0202] Binding experiments were performed on an Octet BLI instrument. Testing antibodies were loaded onto Anti-Human IgG Fc Capture (AHC) sensors, and the sensors were dipped into serial dilutions of His-tagged PD-1. A baseline after loading and before each association was performed. Data were single referenced for analysis. Kinetic constants were calculated using monovalent (1:1) curve fit model.
  • SPR surface plasmon resonance
  • PD-1 anibody AHF29879_R was capable of binding to both human and cynomolgus PD-1.
  • Table 4 Cross-reactivity of PD-1 antibodies Antiboby KD (nM) [0 09] e cross-reac v y o - an bodes oward uman - and cynomongus PD-1 was also analyzed using an ELISA-based assay.
  • His-tagged extracellular domains of human PD-1 and cynomolgus PD-1 were immobilized on 96 well ELISA plates (Nunc Maxisorp, ThermoFisher) and blocked for 1 hour with 1% BSA in PBS. Following washing with PBST (phosphate buffered saline + 0.05% Tween 20), serially diluted test PD-1 antibodies were added to the coated plate and incubated for 2 hours at room temperature. Plates were washed and incubated with HRP-conjugated goat anti-human IgG secondary antibody (Jackson Immunoresearch) for 1 hour at room temperature.
  • PBST phosphate buffered saline + 0.05% Tween 20
  • a commercially available assay comprising an antigen- presenting cell line (APC) and a human Jurkat reporter T cell line expressing a specific T cell receptor (TCR) and the Lucia luciferase reporter gene. In this assay, activation of the Jurkat cells leads to NFAT-mediated luminescence.
  • APC antigen-presenting cell line
  • TCR T cell receptor
  • Target cells expressing PD-1 in a multi-well plate were incubated with humanized PD-1 antibodies with effector enhanced IgG1 Fc or isotype controls and Jurkat-Lucia reporter cell lines modified to express Fc ⁇ receptor CD16a (Fc ⁇ RIIIa), CD32a (Fc ⁇ RIIa), or CD64 (Fc ⁇ RI) at 37 o C, 5%CO 2 for 6 hours.
  • the effoctor enhanced IgG1 Fc contains mutations S239D/H268D (“X3” mutations), as well as a E430G mutation that induces antibody hexamer formation (together, “X3 Hex” mutations).
  • Jurkat-Lucia TCR-hPD-1 cells (Invivogen) were added to the culture, and the plate was incubated for an additional 5.5 hours at 37 o C, 5% CO2. The cells were centrifuged at 400 x g for 5 minutes and 20mL of supernatant was transferred into a 96-well white plate. Activation of the Jurkat cells is measured via a bioluminescent signal produced by Lucia luciferase. 50mL of QUANTI-Luc 4 Reagent (Invivogen) was added to the plate and luminescence (RLU) was read immediately using a plate reader (PerkinElmer). Data were analyzed using GraphPad Prism.
  • CD4 T cells and autologous NK cells were isolated from PBMCs using StemCell Technologies isolation kits. T cells were treated with anti-CD3, anti-CD28 to activate them, which activation resulted in increased expression of PD-1 on the surface of the cells. NK cells were incubated with human IL-15 overnight, and their purity was checked by flow cytometry. Activated T cells were incubated with increasing concentrations of test PD-1 antibodies or an isotype control in a 96-well plate for 40 minutes at 37 o C, 5% CO 2 . NK cells were added to the culture, and the plate was incubated overnight (18-24 hours) at 37 o C, 5% CO 2 .
  • Triton X was added to control wells for 15 minutes to induce total cell lysis.
  • the plate was centrifuged at 250 x g for 10 minutes. 100 mL of supernatant from each well was transferred to an optically clear, 96-well, flat bottom plate. 100 mL freshly prepared LDH reaction mixture was added to each well and the plate incubated for up to 30 minutes for color development. Absorbance was measured at 492 nm using a plate reader (PerkinElmer), and 650 nm was used as a reference. Data were analyzed using GraphPad Prism. The values obtained from the reference wavelength were subtracted Page 60 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO from values at 492 nM.
  • IFN- ⁇ levels in the culture supernatants were measured using a commercial IFN- ⁇ ELISA kit (R&D Systems).
  • IFN- ⁇ capture antibody was immobilized on 96-well ELISA plates. Plates were washed with PBST (phosphate buffered saline + 0.05% Tween 20) and blocked for 1 hour with 1% BSA in PBS. Following washing with PBST, supernatants and an IFN- ⁇ standard curve were added to the coated plates and incubated for 2 hours at room temperature. Plates were washed and incubated with HRP-conjugated detection antibody for 2 hours at room temperature.
  • PBST phosphate buffered saline + 0.05% Tween 20
  • Page 71 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO EQUIVALENTS/ OTHER EMBODIMENTS [0228] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. Such equivalents are intended to be encompassed by the following claims. Page 72 of 99 IPTS/128817054.1

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Abstract

Disclosed herein are compositions and methods for treating autoimmune, allergic, and/or inflammatory diseases in a subject in need thereof.

Description

Attorney Docket No. SANA-007WO METHODS AND COMPOSITIONS FOR TREATING AUTOIMMUNE, ALLERGIC AND INFLAMMATORY DISEASES RELATED APPLICATIONS [0001] The present application claims priority to U.S. Provisional Patent Application No. 63/619,442, filed January 10, 2024, the entire contents of which are hereby incorporated by reference for all purposes. BACKGROUND [0002] The immune system is tightly controlled by various immune cells and co-stimulatory and co-inhibitory ligands and receptors. Inflammation is a normal physiological defense against pathogen infection and tissue damage and quickly ends under normal circumstances. However, in many chronic conditions, the inflammatory response continues and may lead to significant tissue and organ damage. Abnormal inflammatory response is shown to be associated with many chronic diseases, especially autoimmune diseases, in which immune cells act against self-protein. Allergy also results from dysregulation of the immune system, recognizing innocuous non-self-antigens. Mast cells and IgE antibodies take center stage in the allergic response, while rogue T or B cells are the primary actors in autoimmunity. [0003] There remains a need for therapeutic agents and methods of treatment that fine-tune the activity of immune cells and the immune system that can be used alone or in combination for autoimmune, allergic, and inflammatory diseases. SUMMARY [0004] The present application provides methods and compositions for treating autoimmune, allergic, and inflammatory diseases. [0005] In one aspect, provided are antibodies or antigen-binding fragments thereof that are capable of binding to PD-1, wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable (VH) region comprising: heavy chain complementarity- determining region 1 (HCDR1) having the amino acid sequence of SEQ ID NO: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 98, and HCDR3 having the amino acid sequence of SEQ ID NO: 4. [0006] In some embodiments, the antibody or antigen binding fragment further comprises a light chain variable (VL) region comprising: Page 1 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO (a) light chain complementarity-determining region 1 (LCDR1) having the amino acid sequence of SEQ ID NO: 6, LCDR2 having the amino acid sequence of SEQ ID NO: 7, and LCDR3 having the amino acid sequence of SEQ ID NO: 8; or (b) LCDR1 having the amino acid sequence of SEQ ID NO: 6, LCDR2 having the amino acid sequence of SEQ ID NO: 103, and LCDR3 having the amino acid sequence of SEQ ID NO: 104; or (c) LCDR1 having the amino acid sequence of SEQ ID NO: 6, LCDR2 having the amino acid sequence of SEQ ID NO: 7, and LCDR3 having the amino acid sequence of SEQ ID NO: 109. [0007] In another aspect, provided are antibodies or antigen-binding fragments thereof that are capable of binding to PD-1, wherein the antibody or antigen binding fragment thereof comprises a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from SEQ ID NOs: 12-19, 97, and 100; and/or a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NOs: 23-26, 102, 106, and 108. [0008] In some embodiments, the antibody or antigen binding fragment comprises: a VH region comprising an amino acid sequence selected from SEQ ID NOs: 12-19, 97, and 100; and a VL region comprising an amino acid sequence selected from SEQ ID NOs: 23-26, 102, 106, and 108. [0009] In another aspect, provided are antibodies or antigen-binding fragments thereof that are capable of binding to PD-1, wherein the antibody or antigen binding fragment comprises: (a) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 9, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 26; or (b) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 18, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 21; or (c) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 18, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 26; or Page 2 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO (d) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 19, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 26; or (e) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 15, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 24; or (f) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 15, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 25; or (g) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 16, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 24; or (h) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 16, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 25; or (i) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 17, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 24; or (j) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 17, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 25; (k) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 97, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 102; or (l) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 100, Page 3 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 106; or (m) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 97, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 108. [0010] In some embodiments, the antibody or antigen binding fragment comprises: (a) a VH region comprising an amino acid sequence of SEQ ID NO: 9, and a VL region comprising an amino acid sequence of SEQ ID NO: 26; or (b) a VH region comprising an amino acid sequence of SEQ ID NO: 18, and a VL region comprising an amino acid sequence of SEQ ID NO: 21; or (c) a VH region comprising an amino acid sequence of SEQ ID NO: 18, and a VL region comprising an amino acid sequence of SEQ ID NO: 26; or (d) a VH region comprising an amino acid sequence of SEQ ID NO: 19, and a VL region comprising an amino acid sequence of SEQ ID NO: 26; or (e) a VH region comprising an amino acid sequence of SEQ ID NO: 15, and a VL region comprising an amino acid sequence of SEQ ID NO: 24; or (f) a VH region comprising an amino acid sequence of SEQ ID NO: 15, and a VL region comprising an amino acid sequence of SEQ ID NO: 25; or (g) a VH region comprising an amino acid sequence of SEQ ID NO: 16, and a VL region comprising an amino acid sequence of SEQ ID NO: 24; or (h) a VH region comprising an amino acid sequence of SEQ ID NO: 16, and a VL region comprising an amino acid sequence of SEQ ID NO: 25; or (i) a VH region comprising an amino acid sequence of SEQ ID NO: 17, and a VL region comprising an amino acid sequence of SEQ ID NO: 24; or (j) a VH region comprising an amino acid sequence of SEQ ID NO: 17, and a VL region comprising an amino acid sequence of SEQ ID NO: 25; (k) a VH region comprising an amino acid sequence of SEQ ID NO: 97, and a VL region comprising an amino acid sequence of SEQ ID NO: 102; or (l) a VH region comprising an amino acid sequence of SEQ ID NO: 100, and a VL region comprising an amino acid sequence of SEQ ID NO: 106; or (m) a VH region comprising an amino acid sequence of SEQ ID NO: 97, and a VL region comprising an amino acid sequence of SEQ ID NO: 108. Page 4 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO [0011] In some embodiments, the antibody or antigen binding fragment comprises: a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 16, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 24. In some embodiments, the antibody or antigen binding fragment comprises: a VH region comprising an amino acid sequence of SEQ ID NO: 16, and a VL region comprising an amino acid sequence of SEQ ID NO: 24. [0012] In some embodiments, the antibody or antigen binding fragment comprises: a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 17, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 25. In some embodiments, the antibody or antigen binding fragment comprises: a VH region comprising an amino acid sequence of SEQ ID NO: 17, and a VL region comprising an amino acid sequence of SEQ ID NO: 25. [0013] some embodiments, the antibody or antigen binding fragment comprises: a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 97, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 102. In some embodiments, the antibody or antigen binding fragment comprises: a VH region comprising an amino acid sequence of SEQ ID NO: 97, and a VL region comprising an amino acid sequence of SEQ ID NO: 102. [0014] some embodiments, the antibody or antigen binding fragment comprises: a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 100, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 106. In some embodiments, the antibody or antigen binding fragment comprises: a VH region comprising an amino acid sequence of SEQ ID NO: 100, and a VL region comprising an amino acid sequence of SEQ ID NO: 106. [0015] some embodiments, the antibody or antigen binding fragment comprises: a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 97, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 108. In some embodiments, the antibody or antigen binding fragment Page 5 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO comprises: a VH region comprising an amino acid sequence of SEQ ID NO: 97, and a VL region comprising an amino acid sequence of SEQ ID NO: 108. [0016] In some embodiments, the antibody is a humanized antibody. In some embodiments, the antigen binding fragment is a Fab, a Fab’, a Fab2, a F(ab’)2, Fv, a single-chain Fv (scFv), or a diabody. In some embodiments, the antigen binding fragment is an scFv. [0017] In some embodiments, the antibody or antigen binding fragment thereof comprises an antibody heavy chain constant region. [0018] In some embodiments, the antibody heavy chain constant region is a human IgG heavy chain constant region. In some embodiments, the antibody heavy chain constant region is a human IgG1 heavy chain constant region. In some embodiments, the antibody heavy chain constant region comprises an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 111. In some embodiments, the antibody heavy chain constant region has the amino acid sequence of SEQ ID NO: 111. [0019] In some embodiments, the antibody heavy chain constant region comprises one or more mutations that enhance effector function. In some embodiments, the antibody heavy chain constant region comprises one or more mutations that enhances binding to an inhibitory Fc receptor (e.g., FcγRII). [0020] In some embodiments, the antibody heavy chain constant region is a human IgG1 heavy chain constant region comprising one of the following mutation(s): (a) E233D; (b) G236D or G236A; (c) G237D; (d) P238D; (e) S239D; (f) S267E; (g) H268D or H268F; (h) P271G; (i) S324T; (j) L328Y, L328F, or L328E; (k) A330R; (l) I332E; (m) E345K, E345Y, E345Q, or E345R; (n) E430G, E430S, E430F, or E430T; (o) S440Y; (p) G236D and H268D; (q) S239D and H268D; (r) S239D, H268D, L328Y, and I332E; (s) P238D and L328E; (t) G237D, P271G, and A330R; (u) G237D, H268D, P271G, and A330R; (v) S267E and L328F; (w) S239D and S267E; (x) G236D and S276E; (y) E233D, G237D, H268D, P271G, and A330R; (z) S239D, H268D, and E430G; or (aa) S239D, H268D, and E345K, or a combination thereof, wherein the numbering of the constant region is as per the EU index. In some embodiments, the antibody heavy chain constant region is a human IgG1 heavy chain constant region comprising one of the following mutation(s): (a) G236D or G236A; (b) S239D; (c) H268D or H268F; (d) L328Y; (e) S324T; (f) I332E; (g) E345K, E345Y, E345Q, or E345R; (h) E430G, E430S, E430F, or E430T; (i) S440Y; (j) S239D and H268D; or a combination thereof, wherein the numbering of the constant region is as per the EU index. In some embodiments, the antibody heavy chain constant region is a human IgG1 heavy chain constant Page 6 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO region comprising the following mutations: S239D and H268D, and optionally E430G or E345K, wherein the numbering of the constant region is as per the EU index. In some embodiments, the antibody heavy chain constant region is a human IgG1 heavy chain constant region comprising the following mutations: S239D, H268D, and E430G, wherein the numbering of the constant region is as per the EU index. In some embodiments, the antibody heavy chain constant region is a human IgG1 heavy chain constant region comprising the following mutations: S239D, H268D, and E345K, wherein the numbering of the constant region is as per the EU index. In some embodiments, the antibody heavy chain constant region is a human IgG1 heavy chain constant region comprising the following mutations: E233D, G237D, H268D, P271G, and A330R, wherein the numbering of the constant region is as per the EU index. In some embodiments, the antibody heavy chain constant region is a human IgG1 heavy chain constant region comprising the following mutations: S267E and L328F, wherein the numbering of the constant region is as per the EU index. In some embodiments, the antibody heavy chain constant region is a human IgG1 heavy chain constant region comprising the following mutations: E430G or E345K, wherein the numbering of the constant region is as per the EU index. In some embodiments, the antibody heavy chain constant region comprises an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 125. In some embodiments, the antibody heavy chain constant region has the amino acid sequence of SEQ ID NO: 125. [0021] In another aspect, provided are antibodies or antigen-binding fragments thereof that are capable of binding to PD-1, wherein the antibody or antigen binding fragment thereof comprises a human IgG1 heavy chain constant region comprising a mutation selected from E345K, E345Y, E345Q, E345R, E430G, E430S, E430F, E430T, S440Y, wherein the numbering of the constant region is as per the EU index; and the antibody or antigen binding fragment thereof comprises (a) (i) a heavy chain variable (VH) region comprising: heavy chain complementarity-determining region 1 (HCDR1) having the amino acid sequence of SEQ ID NO: 2, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 3, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 4, or a sequence differing in 1 or 2 amino acids therefrom; and Page 7 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO (ii) a lighat chain variable (VL) region comprising: light chain complementarity-determining region 1 (LCDR1) having the amino acid sequence of SEQ ID NO: 6, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 7, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 8, or a sequence differing in 1 or 2 amino acids therefrom; (b) (i) a heavy chain variable (VH) region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 28, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 29, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 30, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a lighat chain variable (VL) region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 32, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 33, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 34, or a sequence differing in 1 or 2 amino acids therefrom; (c) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 36, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 37, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 38, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 40, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 41, or a sequence differing in 1 or 2 amino acids therefrom, and Page 8 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO LCDR3 having the amino acid sequence of SEQ ID NO: 42, or a sequence differing in 1 or 2 amino acids therefrom; (d) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 44, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 45, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 46, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 48, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 49, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 50, or a sequence differing in 1 or 2 amino acids therefrom; (e) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 52, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 53, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 54, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 56, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 57, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 58, or a sequence differing in 1 or 2 amino acids therefrom; (f) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 2, or a sequence differing in 1 or 2 amino acids therefrom, Page 9 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO HCDR2 having the amino acid sequence of SEQ ID NO: 10, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 4, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 6, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 7, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 8, or a sequence differing in 1 or 2 amino acids therefrom; (g) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 60, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 61, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 62, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 64, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 65, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 66, or a sequence differing in 1 or 2 amino acids therefrom; (h) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 60, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 68, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 62, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: Page 10 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO LCDR1 having the amino acid sequence of SEQ ID NO: 64, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 65, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 66, or a sequence differing in 1 or 2 amino acids therefrom; (i) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 73, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 74, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 75, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 77, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 78, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 79, or a sequence differing in 1 or 2 amino acids therefrom; (j) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 73, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 81, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 75, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 77, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 78, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 79, or a sequence differing in 1 or 2 amino acids therefrom; Page 11 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO (k) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 85, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 86, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 87, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 89, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 90, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 91, or a sequence differing in 1 or 2 amino acids therefrom; (l) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 85, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 93, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 87, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 89, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 90, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 91, or a sequence differing in 1 or 2 amino acids therefrom; (m) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 2, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 98, or a sequence differing in 1 or 2 amino acids therefrom, and Page 12 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO HCDR3 having the amino acid sequence of SEQ ID NO: 4, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 6, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 103, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 104, or a sequence differing in 1 or 2 amino acids therefrom; (n) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 2, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 98, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 4, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 6, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 7, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 8, or a sequence differing in 1 or 2 amino acids therefrom; or (o) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 2, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 98, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 4, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 6, or a sequence differing in 1 or 2 amino acids therefrom, Page 13 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO LCDR2 having the amino acid sequence of SEQ ID NO: 7, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 109, or a sequence differing in 1 or 2 amino acids therefrom. [0022] In some embodiments, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise amino acid sequences that collectively differ by no more than two amino acid residues from the sequences of: (a) SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively; (b) SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 33, and SEQ ID NO: 34, respectively; (c) SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42, respectively; (d) SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 49, and SEQ ID NO: 50, respectively; (e) SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 57, and SEQ ID NO: 58, respectively; (f) SEQ ID NO: 2, SEQ ID NO: 10, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively; (g) SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 66, respectively; (h) SEQ ID NO: 60, SEQ ID NO: 68, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 66, respectively; (i) SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 77, SEQ ID NO: 78, and SEQ ID NO: 79, respectively; (j) SEQ ID NO: 73, SEQ ID NO: 81, SEQ ID NO: 75, SEQ ID NO: 77, SEQ ID NO: 78, and SEQ ID NO: 79, respectively; (k) SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 90, and SEQ ID NO: 91, respectively; (l) SEQ ID NO: 85, SEQ ID NO: 93, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 90, and SEQ ID NO: 91, respectively; (m) SEQ ID NO: 2, SEQ ID NO: 98, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 103, and SEQ ID NO: 104, respectively; Page 14 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO (n) SEQ ID NO: 2, SEQ ID NO: 98, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively; or (o) SEQ ID NO: 2, SEQ ID NO: 98, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 109, respectively. [0023] In some embodiments, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise amino acid sequences of: (a) SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively; (b) SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 33, and SEQ ID NO: 34, respectively; (c) SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42, respectively; (d) SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 49, and SEQ ID NO: 50, respectively; (e) SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 57, and SEQ ID NO: 58, respectively; (f) SEQ ID NO: 2, SEQ ID NO: 10, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively; (g) SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 66, respectively; (h) SEQ ID NO: 60, SEQ ID NO: 68, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 66, respectively; (i) SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 77, SEQ ID NO: 78, and SEQ ID NO: 79, respectively; (j) SEQ ID NO: 73, SEQ ID NO: 81, SEQ ID NO: 75, SEQ ID NO: 77, SEQ ID NO: 78, and SEQ ID NO: 79, respectively; (k) SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 90, and SEQ ID NO: 91, respectively; (l) SEQ ID NO: 85, SEQ ID NO: 93, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 90, and SEQ ID NO: 91, respectively; (m) SEQ ID NO: 2, SEQ ID NO: 98, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 103, and SEQ ID NO: 104, respectively; Page 15 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO (n) SEQ ID NO: 2, SEQ ID NO: 98, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively; or (o) SEQ ID NO: 2, SEQ ID NO: 98, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 109, respectively. [0024] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 1 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 5; (b) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 27 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 31; (c) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 35 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 39; (d) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 43 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 47; (e) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 51 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 55; (f) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 9 or 11 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, Page 16 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 20 or 21; (g) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 59 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 63; (h) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 67, 128, 69, or 60 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 71; (i) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 72 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 76; (j) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 80 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 82 or 83; (k) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 84 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 88; (l) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 92 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 94 or 95; (m) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: Page 17 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO 97 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 102 or 108; or (n) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 100 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 106. [0025] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a VH region having the amino acid sequence of SEQ ID NO: 1 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 27; (b) a VH region having the amino acid sequence of SEQ ID NO: 1 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 31; (c) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 35 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 39; (d) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 43 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 47; (e) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 51 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 55; (f) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 9 or 11 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 20 or 21; (g) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 59 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 63; (h) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 67, 128, 69, or 60 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 71; (i) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 72 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 76; Page 18 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO (j) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 80 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 82 or 83; (k) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 84 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 88; (l) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 92 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 94 or 95; (m) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 97 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 102 or 108; or (m) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 100 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 106. [0026] In some embodiments, the IgG1 heavy chain constant region comprises E430G or E345K, wherein the numbering of the constant region is as per the EU index. [0027] In some embodiments, the IgG1 heavy chain constant region further comprises one of the following mutation(s): (a) E233D; (b) G236D or G236A; (c) G237D; (d) P238D; (e) S239D; (f) S267E; (g) H268D or H268F; (h) P271G; (i) S324T; (j) L328Y, L328F, or L328E; (k) A330R; (l) I332E; (m) G236D and H268D; (n) S239D and H268D; (o) S239D, H268D, L328Y, and I332E; (p) P238D and L328E; (q) G237D, P271G, and A330R; (r) G237D, H268D, P271G, and A330R; (s) S267E and L328F; (t) S239D and S267E; (u) G236D and S276E; or (v) E233D, G237D, H268D, P271G, and A330R, or a combination thereof, wherein the numbering of the constant region is as per the EU index. In some embodiments, the IgG1 heavy chain constant region comprises the following mutations: S239D and H268D, wherein the numbering of the constant region is as per the EU index. In some embodiments, the IgG1 heavy chain constant region comprises the following mutations: E233D, G237D, H268D, P271G, and A330R, wherein the numbering of the constant region is as per the EU index. In some embodiments, the IgG1 heavy chain constant region comprises comprises the following mutations: S267E and L328F, wherein the numbering of the constant region is as per the EU index. In some embodiments, the IgG1 heavy chain constant region comprises an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to Page 19 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO the amino acid sequence of SEQ ID NO: 125. In some embodiments, the IgG1 heavy chain constant region has the amino acid sequence of SEQ ID NO: 125. [0028] In some embodiments, an antibody or antigen binding fragment thereof described above is a PD-1 agonist. In some embodiments, the antibody or antigen binding fragment thereof is capable binding to human PD-1. In some embodiments, the antibody or antigen binding fragment thereof is capable of binding to cynomonguls PD-1. In some embodiments, the antibody or antigen-binding fragment is capable of blocking PD-1/PD-L1 interaction. [0029] In some embodiments, an antibody or antigen binding fragment thereof described above has enhanced binding to an Fc receptor. In some embodiments, the Fc receptor is an inhibitory Fc receptor (e.g., FcγRII). In some embodiments, the Fc receptor is an activating Fc receptor (e.g., FcγRI or FcγRIII). [0030] In some embodiments, an antibody or antigen binding fragment thereof described above has enhanced effector function. In some embodiments, the effector function is antibody- dependent cellular cytotoxicity (ADCC). In some embodiments, the effector function is antibody-dependent cellular phagocytosis (ADCP). In some embodiments, the effector function is complement dependent cytotoxicity (CDC). [0031] In some embodiments, an antibody or antigen binding fragment thereof described above is capable of depleting a cell. In some embodiments, the cell is a PD-1 expressing cell. In some embodiments, the cell is an immune cell. In some embodiments, the immune cell is a T cell, a B cell, a macrophage, a natural killer (NK) cell, a dendritic cell (DC), a monocyte, a neutrophil, a fibroblast, or an epithelial cell. In some embodiments, the immune cell is a T cell or a B cell. In some embodiments, the immune cell is activated. In some embodiments, the immune cell is an antigen-activated T cell or B cell. [0032] In some embodiments, an antibody or antigen binding fragment thereof described above is at least about 60%, about 75%, or about 90% non-fucosylated. In some embodiments, the antibody or antigen binding fragment thereof is produced in a cell line (a) having an alpha-1,6-fucosyltransferase (Fut8) knockout; or (b) line overexpressing β1,4-N-acetylglucosaminyltransferase III (GnT-III) and optionally overexpressing Golgi μ- mannosidase II (ManII). [0033] In some embodiments, an antibody or antigen binding fragment thereof described above is capable of inhibiting T cell activation. [0034] In some embodiments, an antibody or antigen binding fragment thereof described above is capable of inhibiting T cell proliferation. Page 20 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO [0035] In some embodiments, an antibody or antigen binding fragment thereof described above is capable of inhibiting IFN‐γ secretion. [0036] In some embodiments, an antibody or antigen binding fragment thereof described above is conjugated to an agent. In some embodiments, the agent is a cytotoxic agent or label. In some embodiments, the agent is a therapeutic agent. [0037] In another aspects, provided are compositions comprising an antibody or antigen binding fragment thereof described herein. In some embodiments, the antibody or antigen- binding fragment comprises an Fc region and N-glycoside-linked carbohydrate chains linked to the Fc region, optionally wherein less than 50% of the N-glycoside-linked carbohydrate chains contain a fucose residue. In some embodiments, substantially none of the N-glycoside- linked carbohydrate chains contain a fucose residue. [0038] In another aspect, provided are polynucleotides encoding an antibody or antigen 5 binding fragment thereof described herein. [0039] In another aspect, provided are expression vectors comprising a polynucleotide described herein. [0040] In another aspect, provided are host cell comprising a polynucleotide or an expression vector described herein. In some embodiments, the host cell is a mammalian or insect cell. In some embodiments, the host cell (a) comprises a Fut8 knockout; and/or (b) overexpresses GnT- III and optionally ManII. [0041] In another aspect, provided are pharmaceutical compositions comprising an antibody or antigen binding fragment thereof described herein and a pharmaceutically acceptable carrier. [0042] In another aspect, provided are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof described herein. In some embodiments, the disease or disorder is an autoimmune disease. In some embodiments, the disease or disorder is an allergy. In some embodiments, the disease or disorder is an inflammatory disease. BRIEF DESCRIPTION OF THE DRAWINGS [0043] FIG.1 depicts the activation of Fc-gamma receptor FcγRIIIA by disclosed PD-1 antibodies. [0044] FIG.2 depicts the inhibition of the activation of Jurkat reporter T cells incubated with Raji-APC cells modified to express the FcγRII receptor by PD-1 antibodies with wild- type IgG1 Fc or modified Fc containing mutations that increase binding to FcγRII and optionally mutation that induces antibody hexamer formation. Page 21 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO [0045] FIGs.3A and 3B show the complement-dependent cytotoxicity of PD-1 antibodies with wild-type IgG1 Fc or modified Fc containing mutations that increase binding to FcγRII and optionally mutation that induces antibody hexamer formation in Raji cells (FIG.3A) and CHO-K1 cells (FIG.3B). [0046] FIGs.4A and 4B shows the depletion of CD8 T cells expressing high (FIG.4A) and intermediate (FIG.4B) levels of cell surcase PD-1 by PD-1 antibodies with wild-type IgG1 Fc or modified Fc containing mutations that increase binding to FcγRII and optionally mutation that induces antibody hexamer formation. [0047] FIG.5 depicts the binding of humanized PD-1 antibodies to PD-1 on cell surface. [0048] FIG.6 depicts the cross-reactivity of PD-1 antibody to human and cynomolgus PD- 1. [0049] FIGs.7A-7C show that PD-1 antibodies activate siganling through Fcγ receptrs CD16a (FIG.7A), CD32a (FIG.7B), and CD64 (FIG.7C). [0050] FIG.8 depicts the inhibition of the activation of Jurkat reporter T cells incubated with Raji-APC cells modified to express FcγRIIb by PD-1 antibodies with modified Fc containing mutations that increase binding to FcγRII and induce antibody hexamer formation. [0051] FIG.9 depicts the antibody dependent cellular phagocytosis of PD-1 positive target cells induced by PD-1 antibodies. [0052] FIG.10 depicts the natural killer cell-mediated antibody-dependent cellular cytotoxicity of PD-1 positive target cells induced by PD-1 antibodies. [0053] FIG.11 shows that PD-1 antibodies inhibited IFN-γ secretion from PBMC following tetanus toxoid antigen re-exposure. DETAILED DESCRIPTION Definitions [0054] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate. [0055] As used herein, the terms “about,” “approximately,” and “comparable to,” when used herein in reference to a value, refer to a value that is similar to the referenced value in the context of that referenced value. In general, those skilled in the art, familiar with the context, will appreciate the relevant degree of variance encompassed by “about,” “approximately,” and “comparable to” in that context. For example, in some embodiments, the terms “about,” “approximately,” and “comparable to” may encompass a range of values that within 25%, 20%, Page 22 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value. [0056] As used herein, “agonist” or “agonistisc,” when used in reference to an antigen- binding site or a molecule containing an antigen-binding site, refers to that binding of the antigen-binding site or molecule to its target results in stimulation or activation of the target, or enhancement, increase, promotion, induction, or prolong of one or more functions or biological activity of the target. [0057] As used herein, the term “antagonist,” “antagonistic,” “neutralizing,” or “blocking,” when used in reference to an antigen-binding site or a molecule containing an antigen-binding site, refers to that binding of the antigen-binding site or molecule to its target results in inhibition of at least some of the biological activity of the target. [0058] As used herein, “antibody” refers to a polypeptide whose amino acid sequence includes immunoglobulins and fragments thereof which specifically bind to a designated antigen, or fragments thereof. Antibodies in accordance with the present invention may be of any type (e.g., IgA, IgD, IgE, IgG, or IgM) or subtype (e.g., IgA1, IgA2, IgG1, IgG2, IgG3, or IgG4). Those of ordinary skill in the art will appreciate that a characteristic sequence or portion of an antibody may include amino acids found in one or more regions of an antibody (e.g., variable region, hypervariable region, constant region, heavy chain, light chain, and combinations thereof). Moreover, those of ordinary skill in the art will appreciate that a characteristic sequence or portion of an antibody may include one or more polypeptide chains, and may include sequence elements found in the same polypeptide chain or in different polypeptide chains. [0059] As used herein, “antibody mimetic” refers to any molecule that is capable of mimicking an antibody’s ability to bind an antigen, but which are not limited to antibody structures. Examples of antibody mimetics include, but are not limited to, Affibodies, Affilins, Affimers, Afftins, Alphabodies, Anticalins, avimers, Centyrins, DARPins, Fynomers, monobodies, nanobody, and nanoCLAMPs. [0060] An “antigen-binding fragment” of an antibody comprises a portion of an intact antibody, which portion is still capable of antigen binding. In certain embodiments, papain digestion of antibodies produce two identical antigen-binding fragments, called “Fab” fragments, and a residual “Fc” fragment, a designation reflecting the ability to crystallize readily. The Fab fragment consists of an entire light chain along with the variable region domain of the heavy chain (VH), and the first constant domain of one heavy chain (CH1). Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding Page 23 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO site. In certain embodiments, pepsin treatment of an antibody yields a single large F(ab')2 fragment which roughly corresponds to two disulfide linked Fab fragments having different antigen-binding activity and that is still capable of cross-linking antigen. Fab' fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of the CH1 domain, including one or more cysteines from the antibody hinge region. Fab'-SH designates an Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab')2 antibody fragments originally were produced as pairs of Fab' fragments having hinge cysteines between them. Other chemical couplings of antibody fragments are also known. [0061] As used herein, the term “antigen-binding site” refers to any molecule or any part of a molecule that is capable of antigen binding. In human antibodies, the antigen-binding site is formed by amino acid residues of the N-terminal variable (“V”) regions of the heavy (“H”) and light (“L”) chains. Three highly divergent stretches within the V regions of the heavy and light chains are referred to as “hypervariable regions” which are interposed between more conserved flanking stretches known as “framework regions,” or “FR.” Thus, the term “FR” refers to amino acid sequences which are naturally found between and adjacent to hypervariable regions in immunoglobulins. In a human antibodies, the three hypervariable regions of a light chain and the three hypervariable regions of a heavy chain are disposed relative to each other in three dimensional space to form an antigen-binding surface. The antigen-binding surface is complementary to the three-dimensional surface of a bound antigen, and the three hypervariable regions of each of the heavy and light chains are referred to as “complementarity-determining regions,” or “CDRs.” In certain animals, such as camels and cartilaginous fish, the antigen-binding site may by formed by a single antibody chain providing a “single domain antibody.” An antigen-binding site can also be or exist in an antibody mimetic. [0062] The CDRs can be determined by the methods described in Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of protein of immunological interest. (1991), Chothia et al., J. Mol. Biol. 196:901-917 (1987), and MacCallum et al., J. Mol. Biol. 262:732-745 (1996). The CDRs determined under these definitions typically include overlapping or subsets of amino acid residues when compared against each other. In certain embodiments, the term “CDR” is a CDR as defined by MacCallum et al., J. Mol. Biol.262:732- 745 (1996) and Martin A., Protein Sequence and Structure Analysis of Antibody Variable Domains, in Antibody Engineering, Kontermann and Dubel, eds., Chapter 31, pp. 422-439, Springer-Verlag, Berlin (2001). In certain embodiments, the term “CDR” is a CDR as defined by Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of protein Page 24 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO of immunological interest. (1991). In certain embodiments, heavy chain CDRs and light chain CDRs of an antibody are defined using different conventions. For example, in certain embodiments, the heavy chain CDRs are defined according to MacCallum (supra), and the light CDRs are defined according to Kabat (supra). CDRH1, CDRH2 and CDRH3 denote the heavy chain CDRs, and CDRL1, CDRL2 and CDRL3 denote the light chain CDRs. [0063] As used herein, “binding affinity” of a molecule of the disclosure (e.g., an antigent- binding site) to a given targets (e.g., PD-1, PD-L1, or PD-L2) can be determined by a multitude of methods known to those skilled in the art. Such methods include, but are not limited to, fluorescence titration, ELISA (enzyme-linked immunosorbent assay), calorimetric methods such as isothermal titration calorimetry (ITC), and surface plasmon resonance (SPR). [0064] As used herein, “bispecific” refers to a molecule is able to specifically bind to at least two distinct targets. Typically, a bispecific molecule comprises two antigen-binding sites, each of which is specific for a different target. In some embodiments, a bispecific molecule is capable of binding two targets simultaneously. [0065] As used herein, “detectable affinity” refers to the ability to bind to a given target with an affinity constant, typically measured by KD or EC50, of at most about 10-5 M or lower (a lower KD or EC50 value reflects better binding ability). Lower affinities that are no longer measurable with common methods such as ELISA (enzyme-linked immunosorbent assay) are of secondary importance. [0066] As used herein, the term “epitope” is an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule, known as the paratope, and which is comprised of the six complementary-determining regions of the antibody. A single antigen may have more than one epitope. Epitopes may be conformational or linear. A conformational epitope is comprised of spatially juxtaposed amino acids from different segments of a linear polypeptide chain. A linear epitope is comprised of adjacent amino acid residues in a polypeptide chain. [0067] An “Fc” fragment comprises the carboxy-terminal portions of both heavy chains held together by disulfides. The effector functions of antibodies are determined by sequences in the Fc region, the region which is also recognized by Fc receptors (FcR) found on certain types of cells. [0068] A “fragment” with respect to an antigen (e.g., PD-1, PD-L1, or PD-L2) refers to N- terminally and/or C- terminally truncated or protein domains of the antigen. In some embodiments, a fragment of the antigen retains the capability of the full-length antigen to be recognized and/or bound by an antigen-binding site of the disclosure. Page 25 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO [0069] As used herein, “fucosylation” or “fucosylated” refers to the presence of fucose residues within the oligosaccharides attached to the peptide backbone of an antibody. Specifically, a fucosylated antibody comprises α(l,6)-linked fucose at the innermost N- acetylglucosamine (GlcNAc) residue in one or both of the N-linked oligosaccharides attached to the antibody Fc region. “Non-fucosylated,” “afucosylated,” or “fucose-deficient” antibody refers to a glycosylation antibody variant comprising an Fc region wherein a carbohydrate structure attached to the Fc region has reduced fucose or lacks fucose. In some embodiments, non-fucosylated or fucose-deficient antibodies have reduced fucose relative to the amount of fucose on the same antibody produced in a cell line. In some embodiments, an antibody with reduced fucose or lacking fucose has improved ADCC function. [0070] The “degree of fucosylation” is the percentage of fucosylated oligosaccharides relative to all oligosaccharides, which may be identified by methods known in the art, e.g., in an N-glycosidase F treated antibody composition assessed by matrix-assisted laser desorption- ionization time-of-flight mass spectrometry (MALDI-TOF MS). In a composition of a “fully fucosylated antibody,” essentially all oligosaccharides comprise fucose residues, i.e., are fucosylated. In some embodiments, a composition of a fully fucosylated antibody has a degree of fucosylation of at least about 90%. In contrast, in a composition of a “fully non-fucosylated antibody,” essentially none of the oligosaccharides are fucosylated. In some embodiments, a composition of a fully non-fucosylated antibody has a degree of fucosylation of less than about 10%. In a composition of a “partially fucosylated antibody,” only part of the oligosaccharides comprise fucose. An individual antibody in such a composition may comprise fucose residues in none, one or both of the N-linked oligosaccharides in the Fc region, provided that the composition does not comprise essentially all individual antibodies that lack fucose residues in the N-linked oligosaccharides in the Fc region, nor essentially all individual antibodies that contain fucose residues in both of the N-linked oligosaccharides in the Fc region. In one embodiment, a composition of a partially fucosylated antibody has a degree of fucosylation of about 10% to about 80% (e.g., about 50% to about 80%, about 60% to about 80%, or about 70% to about 80%). Assays for measuring degree of fucosylation, as well as methods and cell lines for producing antibodies with altered, reduced, or eliminated fucosylation, are known in the art (see, e.g., WO 2023/044390 A1). [0071] As used herein, the term “monoclonal antibody” refers to an antibody obtained from a population of substantially homogeneous antibodies, e.g., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed Page 26 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO against a single antigenic site. Furthermore, in contrast to conventional (polyclonal) antibody preparations which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies may be made by a hybridoma method, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). “Monoclonal antibodies” may also be isolated from phage antibody libraries. [0072] As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo. [0073] As used herein, the term “pharmaceutically acceptable salt” refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound described in the present application which, upon administration to a subject, is capable of providing a compound described in this application or an active metabolite or residue thereof. As is known to those of skill in the art, “salts” of the compounds described in the present application may be derived from inorganic or organic acids and bases. [0074] Exemplary acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p- sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds described in the present application and their pharmaceutically acceptable acid addition salts. [0075] Exemplary bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and compounds of formula NW4+, wherein W is C1-4 alkyl, and the like. [0076] Exemplary salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, Page 27 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds described in the present application compounded with a suitable cation such as Na+, NH4 +, and NW4 + (wherein W is a C1-4 alkyl group), and the like. [0077] For therapeutic use, salts of the compounds described in the present application are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. [0078] As used herein, the phrase “reference level” generally refers to a level considered “normal” for comparison purposes, e.g., a level of an appropriate control. For example, in the context of antibody effector function enhancement, a “reference level” may refer to the level of effector function of an antibody comprising an wild-type constant (Fc) region. As another example, in the context of target binding, a “reference level” may refer to the level of binding affinity (e.g., defined by a KD or EC50 value) of a natural ligand of the target. A reference level may be determined contemporaneously or may be predetermined, e.g., known or deduced from past observations. [0079] As used herein, the terms “subject” and “patient” refer to an organism to be treated by the methods and compositions described herein. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and more preferably include humans. [0080] As used herein, the phrases “therapeutically effective amount” and “effective amount” are used interchangeably and refer to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount may vary according to factors such as the type of disease (e.g., cancer), disease state, age, sex, and/or weight of the individual, and the ability of an immunoconjugate (or pharmaceutical composition thereof) to elicit a desired response in the individual. An effective amount may also be an amount for which any toxic or detrimental effects of the immunoconjugate or pharmaceutical composition thereof are outweighed by therapeutically beneficial effects. [0081] As used herein, to “treat” a condition or “treatment” of the condition (e.g., the conditions described herein such as cancer) is an approach for obtaining beneficial or desired results, such as clinical results. Beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilized (i.e., not worsening) state of disease, disorder, or condition; preventing spread of disease, disorder, or condition (e.g., of a primary cancer and/or Page 28 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO of a secondary metastases); delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable. Antigen-binding sites [0082] In one aspect, the present application provides an antigen-binding site that is capable of binding to a given antigen, e.g., an antigen on a cell involved in an immune disease. In some embodiments, the antigen-binding site capable of binding to an epitope within the antigen. [0083] In some embodiments, the antigen-binding site is capable of binding to an antigen on a cell involved in an autoimmune, allergic, or inflammatory disease. In some embodiments, the cell is an immune cell, e.g., a T cell, a B cell, a mast cell, a macrophage, a natural killer (NK) cell, a dendritic cell (DC), a monocyte, a neutrophil, a fibroblast, or an epithelial cell. In some embodiments, the cell is an activated cell, e.g., an antigen-activated T cell or B cell. Examples of such antigens include, but are not limited to, PD-1, PD-L1, PD-L2, CTLA-4, a C- type lectin (CLEC), a Siglec, a tumor necrosis factor (TNF) receptor superfamily member, 4- 1BB ligand (4-1BBL), OX40 ligand (OX40L), CD40 ligand (CD40L), CD30 ligand (CD30L), CD70 ligand (CD70L), CD27 ligand (CD27L), TIM-3, LAG-3, BTLA, KLRG1, 2B4, CD244, CD19, CD20, CD22, CD28, CD38, CD39, CD72, CD73, CD79A, CD79B, glycoprotein 130 (gp130), BCMA, BAFF receptor (BAFF-R), TACI, integrin alpha 4, integrin beta 7, FCGR2B, ICOS ligand, CD138, SLAMF7, a LILR family member, fibroblast activated protein alpha (FAP), DLK-1, CD26, TE-7, CD29, PDGRF alpha, TGF beta receptor, MAS516, CD13, or a combination thereof. In some embodiments, the antigen is PD-1, PD-L1, or PD-L2. In some embodiments, the antigen is PD-1. [0084] In some embodiments, a provided antigen-binding sites is present as an antibody mimetic, e.g., an Affibody, an Affilin, an Affimer, an afftin, an Alphabody, an Anticalin, an avimer, a Centyrin, a DARPin, a Fynomer, a monobody, nanobody, or a nanoCLAMP. [0085] In some embodiments, a provided antigen-binding sites comprises a heavy chain variable domain and/or a light chain variable domain. In some embodiments, the antigen- binding sites comprise a heavy chain variable domain comprising CDR-H1, CDR-H2, and CDR-H3, and/or a light chain variable domain compriseing CDR-L1, CDR-L2, and CDR-L3. In some embodiments, the antigen-binding site is present as a single-chain fragment variable (scFv). [0086] In some embodiments, provided antigen-binding sites are capable of binding PD-1. In some embodiments, the antigen-binding site is present as an antibody. In some Page 29 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO embodiments, provided are antigen-binding sites that are variants of an antigen-binding site capable of binding PD-1 and present as an antibody described herein, in that such antigen- binding sites comprise an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence comprised in said antigen- binding site capable of binding PD-1 and present as an antibody described herein. [0087] In some embodiments, provided antigen-binding sites capable of binding PD-1 comprise a heavy chain variable domain (VH) comprising a CDR-H1, CDR-H2, and CDR-H3, and/or a light chain variable domain (VL) comprising a CDR-L1, CDR-L2, and CDR-L3. [0088] In some embodiments, provided antigen-binding sites capable of binding PD-1 comprise a VH and a VL, wherein the VH comprises a CDR-H1, CDR-H2, and CDR-H3, and the VL comprises a CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1, CDR-H2, CDR- H3, CDR-L1, CDR-L2, and CDR-L3 are each independently selected from those of a VH or VL described in Table 5. CDRs are determined under Kabat, AbM, Chothia, or any other CDR determination method known in the art, of the VH and VL. In certain embodiments, the antigen-binding site comprises the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 each independently selected from those described in Table 5. [0089] In some embodiments, provided are antigen-binding sites that are variants of the antigen-binding sites capable of binding PD-1 described herein, in that such antigen-binding sites have CDR sequences that differ by no more than two amino acid residues (e.g., two or one amino acid residue(s)) per CDR from a CDR sequence described in Table 5. In some embodiments, provided are an antigen-binding sites that are variants of the antigen-binding sites capable of binding PD-1 described herein, in that such antigen-binding sites have a set of six CDRs whose sequences collectively differ by no more than two amino acid residues (e.g., two or one amino acid residues) from a set of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR- L2, and CDR-L3 selected from Table 5. In some embodiments, provided are an antigen- binding sites that are variants of the antigen-binding sites capable of binding PD-1 described herein, in that such antigen-binding sites have a set of six CDRs whose sequences collectively differ by no more than two amino acid residues (e.g., two or one amino acid residues) from those of an anti-PD-1 having a set of VH and VL selected from Table 5. [0090] In some embodiments, provided antigen-binding sites capable of binding PD-1 comprise a VH sequence as described in Table 5 and a VL sequence as described in Table 5. In some embodiments, provided are antigen-binding sites that are variants of the antigen- binding site capable of binding PD-1 described herein, such as an anti-PD-1 having a set of VH Page 30 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO and VL selected from Table 5, in that such antigen-binding site have (1) a VH comprising an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of a VH described in Table 5; and (2) a light chain domain comprising an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of a VL described in Table 5. [0091] In certain embodiments, an antigen-binding site described in the present application is derived from murine 3H4. For example, in certain embodiments, an antigen-binding site described in the present application comprises a VH that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 1, and a VL that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 5. In certain embodiments, the antigen- binding site comprises the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, determined under Kabat, AbM, Chothia, or any other CDR determination method known in the art, of the VH and VL sequences of SEQ ID NOs: 1 and 5, respectively. In certain embodiments, the VH comprises CDR-H1, CDR-H2, and CDR-H3, comprising the amino acid sequences of SEQ ID NOs: 2, 3, and 4, respectively. In certain embodiments, the VL comprises CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 6, 7, and 8, respectively. In certain embodiments, the antigen-binding site comprises (a) a VH that comprises CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOs: 2, 3, and 4, respectively; and (b) a VL that comprises CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 6, 7, and 8, respectively. [0092] In certain embodiments, an antigen-binding site described in the present application is derived from humanized 3H4. For example, in certain embodiments, an antigen-binding site described in the present application comprises a VH that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence selected from SEQ ID NOs: 9, 11-19, 97, and 100, and/or a VL that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid Page 31 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO sequence selected from SEQ ID NOs: 20-26, 102, 106, and 108. In certain embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 9. In certain embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 11. In certain embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 12. In certain embodiments, the VH comprises an amino acid sequence of SEQ ID 13. In certain embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 14. In certain embodiments, comprises an amino acid sequence of SEQ ID In certain embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 16. In certain embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 17. In certain embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 18. In certain embodiments, the VH comprises an amino acid sequence of SEQ ID In certain embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 97. In certain embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 100. In certain embodiments, the VL comprises an amino acid sequence of SEQ ID NO: 20. In certain embodiments, the VL comprises an amino acid sequence of SEQ ID NO: 21. In certain embodiments, the VL comprises an amino acid sequence of SEQ ID NO: 22. In certain embodiments, the VL comprises an amino acid sequence of SEQ ID NO: 23. In certain embodiments, the VL comprises an amino acid sequence of SEQ ID In certain embodiments, comprises an amino acid sequence of SEQ ID NO: 25. In certain embodiments, the VL comprises an amino acid sequence of SEQ ID NO: 26. In certain embodiments, the VL comprises an amino acid sequence of SEQ ID NO: 102. In certain embodiments, comprises an amino acid sequence of SEQ ID NO: 106. In certain embodiments, the VL comprises an amino acid sequence of SEQ ID NO: 108. In certain embodiments, the antigen- binding site comprises the CDR-H1, CDR-H2, and CDR-H3, determined under Kabat, AbM, Chothia, or any other CDR determination method known in the art, of the VH sequence selected from SEQ ID NOs: 9, 11-19, 97, and 100; and/or the CDR-L1, CDR-L2, and CDR-L3, determined under Kabat, AbM, Chothia, or any other CDR determination method known in the art, of the VL sequence selected from SEQ ID NOs: 20-26, 102, 106, and 108. [0093] In certain embodiments, an antigen-binding site described in the present application is derived from humanized 3H4-2. For example, in certain embodiments, an antigen-binding site described in the present application comprises a VH that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 9, and a VL that comprises an amino acid sequence at least 90% (e.g., at least Page 32 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 21. [0094] In certain embodiments, an antigen-binding site described in the present application is derived from humanized 3H4-4. For example, in certain embodiments, an antigen-binding site described in the present application comprises a VH that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 11, and a VL that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 21. [0095] In certain embodiments, an antigen-binding site described in the present application is derived from humanized 3H4-5. For example, in certain embodiments, an antigen-binding site described in the present application comprises a VH that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 9, and a VL that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 26. [0096] In certain embodiments, an antigen-binding site described in the present application is derived from humanized 3H4-6. For example, in certain embodiments, an antigen-binding site described in the present application comprises a VH that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 18, and a VL that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 21. [0097] In certain embodiments, an antigen-binding site described in the present application is derived from humanized 3H4-7. For example, in certain embodiments, an antigen-binding site described in the present application comprises a VH that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 18, and a VL that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 26. Page 33 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO [0098] In certain embodiments, an antigen-binding site described in the present application is derived from humanized 3H4-8. For example, in certain embodiments, an antigen-binding site described in the present application comprises a VH that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 19, and a VL that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 26. [0099] In certain embodiments, an antigen-binding site described in the present application is derived from humanized 3H4-V4L3. For example, in certain embodiments, an antigen- binding site described in the present application comprises a VH that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 15, and a VL that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 24. [0100] In certain embodiments, an antigen-binding site described in the present application is derived from humanized 3H4-V4L4. For example, in certain embodiments, an antigen- binding site described in the present application comprises a VH that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 15, and a VL that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 25. [0101] In certain embodiments, an antigen-binding site described in the present application is derived from humanized 3H4-V5L3. For example, in certain embodiments, an antigen- binding site described in the present application comprises a VH that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 16, and a VL that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 24. [0102] In certain embodiments, an antigen-binding site described in the present application is derived from humanized 3H4-V5L4. For example, in certain embodiments, an antigen- Page 34 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO binding site described in the present application comprises a VH that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 16, and a VL that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 25. [0103] In certain embodiments, an antigen-binding site described in the present application is derived from humanized 3H4-V6L3. For example, in certain embodiments, an antigen- binding site described in the present application comprises a VH that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 17, and a VL that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 24. [0104] In certain embodiments, an antigen-binding site described in the present application is derived from humanized 3H4-V6L4. For example, in certain embodiments, an antigen- binding site described in the present application comprises a VH that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 17, and a VL that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 25. [0105] In certain embodiments, an antigen-binding site described in the present application is derived from humanized 3H4-879. For example, in certain embodiments, an antigen-binding site described in the present application comprises a VH that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 97, and a VL that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 102. [0106] In certain embodiments, an antigen-binding site described in the present application is derived from humanized 3H4-892. For example, in certain embodiments, an antigen-binding site described in the present application comprises a VH that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least Page 35 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 100, and a VL that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 106. [0107] In certain embodiments, an antigen-binding site described in the present application is derived from humanized 3H4-887. For example, in certain embodiments, an antigen-binding site described in the present application comprises a VH that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 97, and a VL that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 108. [0108] In each of the foregoing embodiments, it is contemplated herein that the VH and/or VL sequences that bind PD-1 may contain amino acid alterations (e.g., at least 1, 2, 3, 4, 5, or 10 amino acid substitutions, deletions, or additions) in the framework regions of the VH and/or VL without affecting their ability to bind PD-1. For example, it is contemplated herein that VH and VL sequences that bind PD-1 may contain cysteine heterodimerization mutations, facilitating formation of a disulfide bridge between the VH and VL to form an scFv. [0109] In some embodiments, antigen-binding sites disclosed herein bind human PD-1 or the extracellular region thereof. In some embodiments, antigen-binding sites disclosed herein bind PD-1 presented on the surface of a membrane (e.g., plasma membrane of a cell). [0110] In some embodiments, antigen-binding sites disclosed herein bind cynomolgus PD- 1. In some embodiments, antigen-binding sites disclosed herein bind cynomolgus PD-1 at a comparable affinity to that of binding human PD-1. [0111] In some embodiments, antigen-binding sites disclosed herein does not significantly bind other PD-1 family members. In some embodiments, antigen-binding sites disclosed herein does not significantly bind ICOS, CD28, or CTLA-4. [0112] In some embodiments, antigen-binding sites disclosed herein are capable of inhibiting binding of PD-L1 to PD-1. In some embodiments, antigen-binding sites disclosed herein are capable of agonizing PD-1. [0113] In some embodiments, antigen-binding sites disclosed herein are capable of reducing IL-2 secretion. In some embodiments, antigen-binding sites disclosed herein are capable of inhibiting (partially or fully) T cell activation. In some embodiments, antigen-binding sites Page 36 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO disclosed herein are capable of inhibiting (partially or fully) T cell proliferation (e.g., CD4+ and/or CD8+ T cells). [0114] In some embodiments, antigen-binding sites disclosed herein are capable of reducing inflammatory cytokine secretion. In some embodiments, antigen-binding sites disclosed herein are capable of reducing IFN-γ secretion. Molecules containing antigen-binding sites [0115] Also provided herein are molecules containing disclosed antigen-binding sites. Such molecules may be, but are not limited to, antibodies or antigen-binding fragments thereof, antibody fragments, nanobodies, antibody mimetics, etc. In some embodiments, a molecule contatining disclosed antigen-binding sites is a therapeutic agent, i.e., the molecule confers a therapeutic benefit. Accordingly, in some embodiments, provided are therapeutic agents contaitning disclosed antigen-binding sites. In some embodiments, the therapeutic agent is capable of inducing complement dependent cytotoxicity (CDC). In some embodiments, the therapeutic agent is capable of inducing antibody-dependent cell-mediated cytotoxicity (ADCC). In some embodiments, therapeutic agent is capable of inducing antibody-dependent cellular phagocytosis (ADCP). In some embodiments, the therapeutic agent is capable of depleting an immune cell (e.g., a T cell, a B cell, a mast cell, a macrophage, a NK cell, a DC, a monocyte, a neutrophil, a fibroblast, or an epithelial cell). [0116] In some embodiments, the therapeutic agents are antibodies or antigen-binding fragments thereof. In some embodiments, the term “antigen-binding fragment” includes, but not limited to, an Fab, an scFab (single-chain Fab), an F(ab’)2, a Fab’, a single-chain Fv (scFv), an Fv fragment, or a diabody (a dimer of scFv). In some embodiments, the antibodies are monoclonal antibodies. In some embodiments, the antibodies are humanized antbodies. In some embodiments, the antibodies are human antbodies. In some embodiments, the antibodies or antigen-binding fragments thereof are multispecific, e.g., bispecific. In some embodiments, the antibodies are non-fucosylated (afucosylated). In some embodiments, the antibodies are at most about 90%, at most about 80%, at most about 70%, at most about 60%, at most about 50%, at most about 40%, at most about 30%, at most about 25%, at most about 20%, at most about 15%, at most about 10%, at most about 5%, at most about 4%, at most about 3%, at most about 2%, at most about 1% fucosylated. In some embodiments, the antibodies are afucosylated. In some embodiments, the antibodies are at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about Page 37 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% afucosylated. [0117] In some embodiments, the antibodies or antigen-binding fragments thereof are capable of binding PD-1, PD-L1, PD-L2, CTLA-4, a C-type lectin (CLEC), a Siglec, a tumor necrosis factor (TNF) receptor superfamily member, 4-1BB ligand (4-1BBL), OX40 ligand (OX40L), CD40 ligand (CD40L), CD30 ligand (CD30L), CD70 ligand (CD70L), CD27 ligand (CD27L), TIM-3, LAG-3, BTLA, KLRG1, 2B4, CD244, CD19, CD20, CD22, CD28, CD38, CD39, CD72, CD73, CD79A, CD79B, glycoprotein 130 (gp130), BCMA, BAFF receptor (BAFF-R), TACI, integrin alpha 4, integrin beta 7, FCGR2B, ICOS ligand, CD138, SLAMF7, a LILR family member, fibroblast activated protein alpha (FAP), DLK-1, CD26, TE-7, CD29, PDGRF alpha, TGF beta receptor, MAS516, CD13, or a combination thereof. In some embodiments, the antibodies or antigen-binding fragments thereof are caplable of binding PD- 1, PD-L1, or PD-L2. In some embodiments, the antibodies or antigen-binding fragments thereof are caplable of binding PD-1. In some embodiments, the antibodies or antigen-binding fragments thereof are caplable of agonizing PD-1. [0118] In some embodiments, provided are therapeutic agents comprising two or more antigen-binding sites. In some embodiments, the therapeutic agents are bispecific. [0119] Various formats and uses of bispecific molecules are known in the art. Bispecific molecules according to the present invention are not limited to any particular bispecific format or method of producing it. [0120] In some embodiments, the bispecific molecule may be a bispecific antibody or a fragment or derivative thereof including, but not limited to, (i) a single antibody that has two arms, each comprising a different antigen-binding site; (ii) a bispecific scFv, e.g., via two scFvs linked by a peptide linker; (iii) a dual-variable-domain antibody (DVD-Ig), where each light chain and heavy chain contains two variable domains in tandem through a short peptide linkage; (iv) a bispecific (Fab′)2 fragment; (v) a diabody; (vi) a tandem diabody (TandAb), a fusion of two diabodies; and (vii) a “dock-and-lock (DNL)-Fab3, a trivalent bispecific binding protein consisting of two identical Fab fragments linked to a different Fab fragment; (viii) IgG- like molecules with engineered Fc to force heterodimerization; (ix) recombinant IgG-like dual targeting molecules, wherein the two sides of the molecule each contain the Fab fragment or part of the Fab fragment of at least two different antibodies; (x) IgG fusion molecules, wherein full length IgG antibodies are fused to extra Fab fragment or parts of Fab fragment; (xi) Fc fusion molecules; (v) Fab fusion molecules; and (vi) scFv- and diabody-based and heavy chain antibodies (e.g., domain antibodies, nanobodies) wherein different scFvs, diabodies, or heavy- Page 38 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO chain antibodies (e.g., domain antibodies, nanobodies) are fused to each other or to another protein or carrier molecule fused to heavy-chain constant-domains, Fc-regions or parts thereof. [0121] Examples of IgG-like molecules with engineered Fc include, but are not limited, to the triomab, knobs-into-holes (kih) molecules (e.g., kih IgG with common light chain), CrossMAbs, orthoFab IgG molecules electrostatically-matched molecules, the LUZ-Y molecules, DIG-body and PIG-body molecules, the Strand Exchange Engineered Domain body (SEEDbody) molecules, the Biclonics molecules, FcΔAdp molecules, bispecific IgG1 and IgG2 molecules, Azymetric scaffold molecules, and the DuoBody molecules. Examples of recombinant IgG-like dual targeting molecules include, but are not limited, to Dual Targeting (DT)-Ig molecules, two-in-one antibody, mAb2, and Zybody. Examples of IgG fusion molecules include, but are not limited to, DVD-Ig molecules and IgG-scFv. Examples of Fc fusion molecules include, but are not limited to, scFv/Fc fusions, SCORPION molecules, and Fc-DART molecules. Examples of Fab fusion bispecific antibodies include, but are not limited to, F(ab)2 molecules, DNL molecules, and Fab-Fv molecules. Examples of scFv- and diabody- based and domain antibodies include, but are not limited, to bispecific T cell engager (BiTE) molecules, tandem diabody molecules (TandAb), dual-affinity retargeting technology (DART) molecules, single-chain diabody molecules, TCR-like antibodies (AIT, ReceptorLogics), human serum albumin scfv fusion, COMBODY molecules, dual targeting nanobodies, and dual targeting heavy chain only domain antibodies. [0122] In some embodiments, molecules containing disclosed antigen-binding sites further comprise antibody constant regions or fragments or variants thereof. In some embodiments, the antibody constant region may be, e.g., a heavy chain constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE; particularly, chosen from, e.g., the (e.g., human) heavy chain constant regions of IgG1, IgG2, IgG3, and IgG4. In certain embodiments, the antibody constant region or fragment or variant thereof has an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to a heavy chain constant region of, e.g., the heavy chain constant region of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, or IgE, preferably, e.g., the heavy chain constant region of human IgG1, IgG2, IgG3, or IgG4. In certain embodiments, the antibody constant region may be a light chain constant region chosen from, e.g., the (e.g., human) light chain constant regions of kappa or lambda. The constant region can be altered, e.g., mutated, to modify the properties of the antibody (e.g., to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, and/or complement function). In one embodiment, the antibody has effector function and/or can fix complement. Page 39 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO In other embodiments, the antibody does not recruit effector cells or fix complement. In another embodiment, the antibody has reduced or no ability to bind an Fc receptor. For example, it is an isotype or subtype, fragment or other mutant, which does not support binding to an Fc receptor, e.g., it has a mutagenized or deleted Fc receptor binding region. [0123] In some embodiments, the constant region comprises one or more mutation(s) that enhance effector function. [0124] In some embodiments, the constant region comprises one or more mutation(s) that enhance binding to FcγRII (CD32). For example, in certain embodiments, the constant region comprises a heavy chain constant region of IgG1, comprising one or more of the following mutations, numbering based on EU index, (a) E233D or G236A; (b) G236D; (c) G237D; (d) P238D; (e) S239D; (f) S267E; (g) H268D; (h) P271G; (i) S324T; (j) L328Y, L328F, or L328E; (k) A330R; (l) I332E; (m) E345K, E345Y, E345Q, or E345R; (n) E430G, E430S, E430F, or E430T; (o) S440Y; (p) G236D and H268D; (q) S239D and H268D; (r) S239D, H268D, L328Y, and I332E; (s) P238D and L328E; (t) G237D, P271G, and A330R; (u) G237D, H268D, P271G, and A330R; (v) S267E and L328F; (w) S239D and S267E; (x) G236D and S276E; (y) E233D, G237D, H268D, P271G, and A330R, or a combination thereof. In certain embodiments, the constant region comprises a heavy chain constant region of IgG1, comprising one or more of the following mutations, numbering based on EU index, (a) G236D or G236A; (b) S239D; (c) H268D or H268F; (d) L328Y; (e) S324T; (f) I332E; (g) E345K, E345Y, E345Q, or E345R; (h) E430G, E430S, E430F, or E430T; (i) S440Y, or a combination thereof. In certain embodiments, the constant region comprises a heavy chain constant region of IgG1, comprising one or more of the following mutations, numbering based on EU index, (a) G236D or G236A; (b) S239D; (c) H268D or H268F; (d) S324T; (e) L328Y; (f) I332E; (g) E345K, E345Y, E345Q, or E345R; (h) E430G, E430S, E430F, or E430T; (i) S440Y, or a combination thereof. In certain embodiments, the constant region comprises a heavy chain constant region of IgG1 comprising the mutations of S239D and H268D, numbering based on EU index. In certain embodiments, the constant region comprises a heavy chain constant region of IgG1 comprising the mutations of S239D, H268D, and E430G, numbering based on EU index. In certain embodiments, the constant region comprises a heavy chain constant region of IgG1 comprising the mutations of S239D, H268D, and E345K, numbering based on EU index. In certain embodiments, the constant region comprises a heavy chain constant region of IgG1 comprising the mutations of E233D, G237D, H268D, P271G, and A330R, numbering based on EU index. In certain embodiments, the constant region comprises a heavy chain constant region of IgG1 comprising the mutation of E430G or E345K, numbering based on EU index. In certain Page 40 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO embodiments, the constant region comprises a heavy chain constant region of IgG1 comprising the mutations of S267E and L328F, numbering based on EU index. [0125] In certain embodiments, the constant region comprises a heavy chain constant region of IgG1, comprising one or more of the following mutations, numbering based on EU index, F243L, R292P, Y300L, V305I, and/or P396L; (b) S239D and/or I332E; (c) S239D, I332E, and/or A330L; (d) S298A, E333A, and/or K334A; (e) G236A, S239D, and/or I332E; (f) K326W and/or E333S; (g) S267E, H268F, and/or S324T; or (h) E345R, E430G, and/or S440Y. [0126] In some embodiments, the constant region comprises one or more mutation(s) that reduce effector function. For example, in certain embodiments, the constant region comprises a heavy chain constant region of IgG1, comprising one or more of the following mutations, numbering based on EU index, (a) L234A and/or L235A; (b) A327G, A330S, and/or P331S; (c) E233P, L234V, L235A, and/or G236del; (d) E233P, L234V, and/or L235A; (e) E233P, L234V, L235A, G236del, A327G, A330S, and/or P331S; (f) E233P, L234V, L235A, A327G, A330S, and/or P331S; (g) N297A; (h) N297G; (i) N297Q; (j) L242C, N297C, and/or K334C; (k) A287C, N297G, and/or L306C; (l) R292C, N297G, and/or V302C; (m) N297G, V323C, and/or I332C; (n) V259C, N297G, and/or L306C; (o) L234F, L235Q, K322Q, M252Y, S254T, and/or T256E; (p) L234A, L235A, and/or P329G; or (q) L234A, L235Q, and K322Q. In certain embodiments, the constant region comprises a heavy chain constant region of IgG2, comprising one or more of the following mutations, numbering based on EU index, (a) A330S and/or P331S; (b) V234A, G237A, P238S, H268A, V309L, A330S, and/or P331S; or (c) V234A, G237A, H268Q, V309L, A330S, P331S, C232S, C233S, S267E, L328F, M252Y, S254T, and/or T256E. In certain embodiments, the constant region comprises a heavy chain constant region of IgG4, comprising one or more of the following mutations, numbering based on EU index, (a) E233P, F234V, L235A, and/or G236del; (b) E233P, F234V, and/or L235A; (c) S228P and/or L235E; or (d) S228P and/or L235A. [0127] In some embodiments, the antigen-binding site is linked to the antibody constant region or fragment or variant thereof. In certain embodiments, the antigen-binding site is linked to an IgG constant region including hinge, CH2 and CH3 domains with or without a CH1 domain. [0128] In some embodiments, molecules containing disclosed antigen-binding sites further comprises a Fc region that is non-fucosylated. In some embodiments, the Fc region is non- fucosylated IgG1 Fc region. [0129] In some embodiments, the bispecific molecule may be a fusion protein containing one or more antibody mimetics. In some embodiments, the bispecific molecule may be a fusion Page 41 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO protein containing one or more antibody mimetics and one or more antibodies or antigen- binding fragments thereof. Amino acid sequence modifications [0130] Amino acid sequence modification(s) of the antigen-binding sites and molecules containing antigen-binding sites (e.g., antibodies or antigen-binding fragments thereof) disclosed herein are contemplated. For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibodies or antigen-binding fragments. Amino acid sequence variants can be prepared, e.g., by introducing appropriate nucleotide changes into a nucleic acid sequence encoding the antigen-binding site or molecule containing antigen-binding site, or by peptide synthesis. Such modifications can include, for example, deletions from, and/or insertions into and/or substitutions of, residues within the amino acid sequences. Any combination of deletion, insertion, and substitution can be made, provided that the antigen-binding site or molecule containing antigen-binding site retains the desired characteristics and/or functions. In some embodiments, amino acid changes are introduced to alter post-translational processes, such as changing the number or position of glycosylation sites. [0131] A useful method for identification of certain residues or regions that are preferred locations for mutagenesis is called “alanine scanning mutagenesis.” In this method, a residue or group of target residues are identified (e.g., charged residues such as Arg, Asp, His, Lys, and Glu) and replaced by a neutral or negatively charged amino acid (most preferably alanine or polyalanine) to affect the interaction of the amino acids with antigen. Those amino acid locations demonstrating functional sensitivity to the substitutions then are refined by introducing further or other variants at, or for, the sites of substitution. Thus, while the site for introducing an amino acid sequence variation is predetermined, the nature of the mutation per se need not be predetermined. For example, to analyze the performance of a mutation at a given site, ala scanning or random mutagenesis may be conducted at the target codon or region, and the expressed variants may be screened for a desired activity. [0132] Examples of amino acid sequence insertions include, but are not limited to, amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. An example of a terminal insertion includes, but are not limited to, N-terminal methionyl residues. Page 42 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO [0133] In some embodiments, the antigen-binding site or molecule containing antigen- binding site is fused at one terminus to another polypeptide, e.g., a cytotoxic polypeptide, an enzyme, or a polypeptide which increases the serum half-life of the antibody or antigen-binding fragment. [0134] Another type of variant is an amino acid substitution variant. These variants have at least one amino acid residue in the amino acid sequence of the molecule replaced by a different residue. Sites of greatest interest for substitutional mutagenesis are typically the hypervariable regions, but framework region alterations are also contemplated. Examples of conservative substitutions are shown in Table 1 under the heading of “preferred substitutions.” More substantial changes, under the heading “exemplary substitutions” in Table 1, or as further described below in reference to amino acid classes, may be introduced and the resulting antibodies or antigen-binding fragments screened. Table 1. Exemplary Amino acid substitutions Original Residue Exemplary Substitutions Preferred Substitutions Ala (A) Val Leu Ile Val [0135] Substantial modifications in the biological properties of the antibody may be accomplished by selecting substitutions that differ significantly in their effect on maintaining Page 43 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. Naturally occurring residues are typically divided into groups based on common side-chain properties: (1) hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic: Cys, Ser, Thr; (3) acidic: Asp, Glu; (4) basic: Asn, Gln, His, Lys, Arg; (5) residues that influence chain orientation: Gly, Pro; and (6) aromatic: Trp, Tyr, Phe. [0136] Non-conservative substitutions can entail exchanging a member of one of these classes for another class. [0137] Additionally or alternatively, cysteine residues not involved in maintaining the proper conformation of the antibody or antigen-binding fragment may be substituted, generally with serine, to improve the oxidative stability of the molecule and prevent aberrant crosslinking. Conversely, cysteine bond(s) may be added to the antibody to improve its stability (particularly where the antibody is an antibody fragment such as an Fv fragment). [0138] In some embodiments, a substitutional variant comprises a substitution within one or more hypervariable region residues of a parent antibody (e.g., a human antibody). Generally, the resulting variant(s) having improved biological properties relative to the parent antibody from which they are generated are selected for further development. [0139] A method for generating such substitutional variants involves affinity maturation using phage display. In an example of such a method, several hypervariable region sites (e.g., 6-7 sites) are mutated to generate all possible amino substitutions at each site. Antibody variants thus generated are displayed in a monovalent fashion, e.g., from filamentous phage particles as fusions to the gene III product of M13 packaged within each particle. The phage- displayed variants are then screened for their biological activity (e.g., binding affinity). [0140] To identify candidate hypervariable region sites for modification, alanine scanning mutagenesis can be performed to identify hypervariable region residues contributing significantly to antigen binding. Alternatively, or additionally, it may be beneficial to analyze a crystal structure of the antigen-antibody complex to identify contact points between the antibody or antigen-binding fragment and the antigen. Such contact residues and neighboring residues are candidates for substitution according to the techniques elaborated herein. Once Page 44 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO such variants are generated, the panel of variants is subjected to screening, and antibodies with superior properties in one or more relevant assays may be selected for further development. [0141] In some embodiments, the original glycosylation pattern of a parent antibody is altered. Such alteration(s) may comprise deleting one or more carbohydrate moieties found in the antibody, and/or adding one or more glycosylation sites that are not present in the antibody. [0142] Glycosylation of antibodies is typically either N-linked or O-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are recognition sequences for enzymatic attachment of the carbohydrate moiety to an asparagine side chain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N-aceylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used. [0143] Addition of glycosylation sites to the antibody may be accomplished by altering the antibody or antigen-bindng fragment’s amino acid sequence such that it contains one or more of the above-described tripeptide sequences (for N-linked glycosylation sites). The alteration may also be made by the addition of, or substitution by, one or more serine or threonine residues to the sequence of the original antibody (for O-linked glycosylation sites). [0144] Nucleic acid molecules encoding amino acid sequence variants of antibodies or antigen-binding fragments may be prepared by a variety of methods known in the art. These methods include, but are not limited to, isolation from a natural source (in the case of naturally occurring amino acid sequence variants) or preparation by oligonucleotide-mediated (or site- directed) mutagenesis, PCR mutagenesis, and cassette mutagenesis of an earlier prepared variant or a non-variant version of the antibody or antigen-binding fragment thereof. [0145] In some embodiments, a modification that increases the serum half-life is used. For example, a salvage receptor binding epitope can be incorporated into a molecule containing disclosed antigen-binding site as described, e.g., in U.S. Pat. No. 5,739,277. As used herein, the term “salvage receptor binding epitope” refers to an epitope of the Fc region of an IgG molecule (e.g., IgG1, IgG2, IgG3, or IgG4) that is responsible for increasing the in vivo serum half-life of the IgG molecule. Page 45 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO Methods of making antigen-binding sites and molecules containing antigen-binding sites [0146] The proteins herein above can be made using recombinant DNA technology well known to a skilled person in the art. [0147] For example, one or more nucleic acid sequences encoding a protein containing the disclosed antigen-binding site can be cloned into one or more expression vectors; the expression vectors can be stably transfected into host cells capable of expressing the gene(s). After transfection, single clones can be isolated for cell bank generation using methods known in the art, such as limited dilution, ELISA, FACS, microscopy, or Clonepix. Clones can be cultured under conditions suitable for bio-reactor scale-up and maintained expression of a protein comprising an antigen-binding site disclosed herein. The protein can be isolated and purified using methods known in the art, such as centrifugation, depth filtration, cell lysis, homogenization, freeze-thawing, affinity purification, gel filtration, ion exchange chromatography, hydrophobic interaction exchange chromatography, and mixed-mode chromatography. [0148] Accordingly, also provided herein are isolated nucleic acids encoding antigen- binding sites and molecules (e.g., proteins) containing antigen-binding sites, vectors and host cells comprising the nucleic acid, and recombinant techniques for the production. [0149] In certain embodiments, provided are one or more isolated nucleic acids comprising sequences encoding an immunoglobulin heavy chain and/or immunoglobulin light chain variable region of any antibody disclosed herein, and one or more expression vectors that express the immunoglobulin heavy chain and/or immunoglobulin light chain variable region of any antibody disclosed herein. Also provided are host cells comprising one or more of the foregoing expression vectors and/or isolated nucleic acids. [0150] In some embodiments, antigen-binding sites and molecules (e.g., proteins) containing antigen-binding sites of the present disclosure may be fused to another agent, e.g., another therapeutic agent. Construction of fusion proteins is within ordinary skill in the art. Monoclonal Antibodies [0151] Monoclonal antibodies may be made using the hybridoma method first described by, or may be made by recombinant DNA methods (U.S. Pat. No.4,816,567). [0152] In the hybridoma method, a mouse or other appropriate host animal, such as a hamster, is immunized to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the protein used for immunization. Alternatively or additionally, lymphocytes may be immunized in vitro. After immunization, lymphocytes are Page 46 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO isolated and then fused with a myeloma cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell. [0153] The hybridoma cells thus prepared are seeded and grown in a suitable culture medium which medium preferably contains one or more substances that inhibit the growth or survival of the unfused, parental myeloma cells (also referred to as fusion partner). For example, if the parental myeloma cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the selective culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (HAT medium), which substances prevent the growth of HGPRT-deficient cells. [0154] Examples of suitable fusion partner include, but are not limited to, myeloma cells are those that fuse efficiently, support stable high-level production of antibody by the selected antibody-producing cells, and are sensitive to a selective medium that selects against the unfused parental cells. Examples of suitable myeloma cell lines include, but are not limited to, are murine myeloma lines, such as those derived from MOPC-21 and MPC-11 mouse tumors available from the Salk Institute Cell Distribution Center, San Diego, Calif. USA, and SP-2 and derivatives e.g., X63-Ag8-653 cells available from the American Type Culture Collection, Rockville, Md. USA. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies. [0155] According to the hybridoma method, culture medium in which hybridoma cells are growing is then assayed for production of monoclonal antibodies directed against the antigen. For example, the binding specificity of monoclonal antibodies produced by hybridoma cells may be determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). [0156] The binding affinity of the monoclonal antibody can, for example, be determined by a Scatchard analysis. [0157] Once hybridoma cells that produce antibodies of the desired specificity, affinity, and/or activity are identified, clones may be subcloned, e.g., by limiting dilution procedures and grown by standard methods. Suitable culture media for this purpose include, for example, D-MEM or RPMI-1640 medium. In addition, the hybridoma cells may be grown in vivo as ascites tumors in an animal, e.g., by i.p. injection of the cells into mice. [0158] Monoclonal antibodies secreted by the subclones are suitably separated from the culture medium, ascites fluid, or serum by conventional antibody purification procedures such as, for example, affinity chromatography (e.g., using protein A or protein G-Sepharose®) or Page 47 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO ion-exchange chromatography, hydroxylapatite chromatography, gel electrophoresis, dialysis, etc. [0159] DNA encoding the monoclonal antibodies can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies). Hybridoma cells can serve as a preferred source of such DNA. Once isolated, the DNA may be placed into expression vectors, which are then transfected into host cells such as E. coli cells, simian COS cells, Chinese Hamster Ovary (CHO) cells, or myeloma cells that do not otherwise produce antibody protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. [0160] In certain embodiments, monoclonal antibodies or antibody fragments are isolated from antibody phage libraries. High affinity (nM range) human antibodies can be produced, e.g., by chain shuffling. Combinatorial infection and in vivo recombination may provide strategies for constructing very large phage libraries. These techniques are viable alternatives to traditional monoclonal antibody hybridoma techniques for isolation of monoclonal antibodies. [0161] DNA that encodes the antibody may be modified to produce chimeric or fusion antibody polypeptides, for example, by substituting human heavy chain and light chain constant domain (CH and CL) sequences for the homologous murine sequences (see, e.g., U.S. Pat. No. 4,816,567), or by fusing the immunoglobulin coding sequence with all or part of the coding sequence for a non-immunoglobulin polypeptide (heterologous polypeptide). Human Antibodies and Phage Display Methodology [0162] Human antibodies can be generated by methods known in the art, including methods described herein. For example, it is possible to produce transgenic animals (e.g., mice) that are capable, upon immunization, of producing a full repertoire of human antibodies in the absence of endogenous immunoglobulin production. For example, it has been described that the homozygous deletion of the antibody heavy-chain joining region (JH) gene in chimeric and germ-line mutant mice results in complete inhibition of endogenous antibody production. Transfer of the human germ-line immunoglobulin gene array into such germ-line mutant mice will result in the production of human antibodies upon antigen challenge. See, e.g., U.S. Pat. Nos.5,545,806, 5,569,825, 5,591,669; 5,545,807; and WO 97/17852. [0163] Alternatively, phage display technology can be used to produce human antibodies and antibody fragments in vitro, from immunoglobulin variable (V) domain gene repertoires from Page 48 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO unimmunized donors. According to this technique, antibody V domain genes are cloned in- frame into either a major or minor coat protein gene of a filamentous bacteriophage, such as M13 or fd, and displayed as functional antibody fragments on the surface of the phage particle. Because the filamentous particle contains a single-stranded DNA copy of the phage genome, selections based on the functional properties of the antibody also result in selection of the gene encoding the antibody exhibiting those properties. Thus, the phage mimics some of the properties of the B-cell. Phage display can be performed in a variety of formats. Several sources of V-gene segments can be used for phage display, e.g., from random combinatorial librarues of V genes such as libraries derived from the spleens of immunized mice. A repertoire of V genes from unimmunized human donors can be constructed and antibodies to a diverse array of antigens (including self-antigens) can be isolated essentially following methods described in the art. See, e.g., U.S. Pat. Nos.5,565,332 and 5,573,905. [0164] Human antibodies may also be generated by in vitro activated B cells (see, e.g., U.S. Pat. Nos.5,567,610 and 5,229,275). [0165] Competition assays for determining whether an antibody binds to the same epitope as, or competes for binding with a disclosed antibody are known in the art. Exemplary competition assays include immunoassays (e.g., ELISA assays, RIA assays), surface plasmon resonance (e.g., BIAcore analysis), bio-layer interferometry, and flow cytometry. [0166] Typically, a competition assay involves the use of an antigen bound to a solid surface or expressed on a cell surface, a test antibody, and a reference antibody. The reference antibody is labeled and the test antibody is unlabeled. Competitive inhibition is measured by determining the amount of labeled reference antibody bound to the solid surface or cells in the presence of the test antibody. Usually the test antibody is present in excess (e.g., 1x, 5x, 10x, 20x or 100x). Antibodies identified by competition assay (e.g., competing antibodies) include antibodies binding to the same epitope, or similar (e.g., overlapping) epitopes, as the reference antibody, and antibodies binding to an adjacent epitope sufficiently proximal to the epitope bound by the reference antibody for steric hindrance to occur. [0167] A competition assay can be conducted in both directions to ensure that the presence of the label does not interfere or otherwise inhibit binding. For example, in the first direction the reference antibody is labeled and the test antibody is unlabeled, and in the second direction, the test antibody is labeled and the reference antibody is unlabeled. [0168] A test antibody competes with the reference antibody for specific binding to the antigen if an excess of one antibody (e.g., 1x, 5x, 10x, 20x or 100x) inhibits binding of the Page 49 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO other antibody, e.g., by at least 50%, 75%, 90%, 95% or 99% as measured in a competitive binding assay. [0169] Two antibodies may be determined to bind to the same epitope if essentially all amino acid mutations in the antigen that reduce or eliminate binding of one antibody reduce or eliminate binding of the other. Two antibodies may be determined to bind to overlapping epitopes if only a subset of the amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other. [0170] The antibodies disclosed herein may be further optimized (e.g., affinity-matured) to improve biochemical characteristics including affinity and/or specificity, improve biophysical properties including aggregation, stability, precipitation and/or non-specific interactions, and/or to reduce immunogenicity. Affinity-maturation procedures are within ordinary skill in the art. For example, diversity can be introduced into an immunoglobulin heavy chain and/or an immunoglobulin light chain by DNA shuffling, chain shuffling, CDR shuffling, random mutagenesis and/or site-specific mutagenesis. [0171] In certain embodiments, isolated human antibodies contain one or more somatic mutations. In these cases, antibodies can be modified to a human germline sequence to optimize the antibody (e.g., by a process referred to as germlining). [0172] Generally, an optimized antibody has at least the same, or substantially the same, affinity for the antigen as the non-optimized (or parental) antibody from which it was derived. For example, in certain embodiments, an optimized antibody has a higher affinity for the antigen when compared to the parental antibody. Pharmaceutical compositions [0173] In certain embodiments, provided molecules containing disclosed antigen-binding sites are incorporated together with one or more pharmaceutically acceptable carriers into a pharmaceutical composition suitable for administration to a subject. As used herein, “pharmaceutically acceptable carrier” refers to any of a variety of solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Examples of pharmaceutically acceptable carriers include, but are not limited to, water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof. [0174] In some embodiments, pharmaceutical compositions comprise one or more tonicity agents or stabilizers. Non-limiting examples of such tonicity agents or stabilizers include sugars (e.g., sucrose), polyalcohols (e.g., mannitol or sorbitol), and sodium chloride. Page 50 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO [0175] In some embodiments, pharmaceutical compositions comprise one or more bulking agents and/or lyoprotectants (e.g., mannitol or glycine), buffers (e.g., phosphate, acetate, or histidine buffers), surfactants (e.g., polysorbates), antioxidants (e.g., methionine), and/or metal ions or chelating agents (e.g., ethylenediaminetetraacetic acid (EDTA)). [0176] In some embodiments, pharmaceutical compositions comprise one or more auxiliary substances such as wetting or emulsifying agents, preservatives (e.g., benzyl alcohol) or buffers, which may enhance the shelf life and/or effectiveness of immunoconjugates disclosed herein. [0177] Pharmaceutical compositions may be provided in any of a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. Suitability of certain forms may depend on the intended mode of administration and therapeutic application. [0178] In some embodiments, pharmaceutical compositions are in the form of injectable or infusible solutions. [0179] Pharmaceutical compositions are typically sterile and stable under conditions of manufacture, transport, and storage. Pharmaceutical compositions may be formulated as, for example, a solution, microemulsion, dispersion, liposome, or other ordered structure. In some embodiments, a pharmaceutical composition is formulated as a structure particularly suitable for high drug concentration. For example, sterile injectable solutions can be prepared by incorporating a therapeutic agent (e.g., immunoconjugate) in a desired amount in an appropriate solvent with one or a combination of ingredients enumerated herein, optionally followed by sterilization (e.g., filter sterilization). Generally, dispersions may be prepared by incorporating an immunoconjugate into a sterile vehicle that contains a basic dispersion medium and other ingredient(s) such as those additional ingredients mentioned herein. In the case of sterile powders for the preparation of sterile injectable solutions, examples of preparation methods include vacuum drying and freeze-drying to yield a powder of the immunoconjugate and any additional desired ingredient(s), e.g., from a previously sterile- filtered solution thereof. [0180] Proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by maintaining certain particle sizes (e.g., in the case of dispersions), and/or by using surfactants. Prolonged absorption of injectable compositions can be brought about, e.g., by including in the composition an agent that delays absorption (for example, monostearate salts and/or gelatin). Page 51 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO Methods of treatment [0181] The present application provides methods for treating a disease or disorder using a therapeutic agent (e.g., protein, such as antibody or antigen-binding fragment thereof) or pharmaceutical composition described herein. Methods of treatment disclosed herein generally comprise a step of administering a therapeutically effective amount of a disclosed therapeutic agent containing antigen-binding site or a pharmaceutical composition thereof to a subject (e.g., a human subject) in need thereof. [0182] In some embodiments, the disease or disorder is an autoimmune disease. Examples of autoimmune diseases include, not are not limited to, Behcet disease, systemic lupus erythematosus, multiple sclerosis (systemic scleroderma and progressive systemic scleroderma), scleroderma, polymyositis, dermatomyositis, periarteritis nodosa (polyarteritis nodosa and microscopic polyangiitis), aortitis syndrome (Takayasu arteritis), malignant rheumatoid arthritis, rheumatoid arthritis, Wegner’s granulomatosis, mixed connective tissue disease, Sjogren syndrome, adult-onset Still's disease, allergic granulomatous angiitis, hypersensitivity angiitis, Cogan’s syndrome, RS3PE, temporal arteritis, polymyalgia rheumatica, fibromyalgia syndrome, antiphospholipid antibody syndrome, eosinophilic fasciitis, IgG4-related diseases (e.g., primary sclerosing cholangitis and autoimmune pancreatitis), Guillain-Barre syndrome, myasthenia gravis, chronic atrophic gastritis, autoimmune hepatitis, primary biliary cirrhosis, aortitis syndrome, Goodpasture's syndrome, rapidly progressive glomerulonephritis, megaloblastic anemia, autoimmune hemolytic anemia, autoimmune neutropenia, idiopathic thrombocytopenic purpura, Graves’ disease (hyperthyroidism), Hashimoto’s thyroiditis, autoimmune adrenal insufficiency, primary hypothyroidism, idiopathic Addison's disease (chronic adrenal insufficiency), type I diabetes mellitus, chronic discoid lupus erythematosus, localized scleroderma, psoriasis, psoriatic arthritis, pemphigus, pemphigoid, herpes gestationis, linear IgA bullous skin disease, epidermolysis bullosa acquisita, alopecia areata, vitiligo, Harada disease, autoimmune optic neuropathy, idiopathic azoospermia, recurrent fetal loss, and inflammatory bowel diseases (ulcerative colitis and Crohn's disease). The prescription of the present invention can also be applied to prophylaxis or therapy of graft-versus-host disease (GVHD). [0183] In some embodiments, the disease or disorder is an allergy or inflammatory disease. examples of allergies and inflammatory diseases include, not are not limited to, acid reflux/heartburn, acne, acne vulgaris, allergies and sensitivities, Alzheimer’s disease, asthma, atherosclerosis and vascular occlusive disease, optionally atherosclerosis, ischaemic heart Page 52 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO disease, myocardial infarction, stroke, peripheral vascular disease, or vascular stent restenosis, autoimmune diseases, bronchitis, cancer, carditis, cataracts, celiac disease, chronic pain, chronic prostatitis, cirrhosis, colitis, connective tissue diseases, optionally systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis, or Sjogren’s syndrome, corneal disease, crohn's disease, crystal arthropathies, optionally gout, pseudogout, calcium pyrophosphate deposition disease, dementia, dermatitis, diabetes, dry eyes, eczema, edema, emphysema, fibromyalgia, gastroenteritis, gingivitis, glomerulonephritis, heart disease, hepatitis, high blood pressure, hypersensitivities, inflammatory bowel diseases, inflammatory conditions including consequences of trauma or ischaemia, insulin resistance, interstitial cystitis, iridocyclitis, iritis, joint pain, arthritis, rheumatoid arthritis, lyme disease, metabolic syndrome (syndrome x), multiple sclerosis, myositis, nephritis, obesity, ocular diseases including uveitis, osteopenia, osteoporosis, parkinson's disease, pelvic inflammatory disease, periodontal disease, polyarteritis, polychondritis, polymyalgia rheumatica, psoriasis, reperfusion injury, rheumatic arthritis, rheumatic diseases, optionally rheumatoid arthritis, osteoarthritis, or psoriatic arthritis, rheumatoid arthritis, sarcoidosis, scleroderma, sinusitis, sjogren's syndrome, spastic colon, spondyloarthropathies, optionally ankylosing spondylitis, reactive arthritis, or reiter's syndrome, systemic candidiasis, tendonitis, transplant rejection, vaginitis, vascular diseases including atherosclerotic vascular disease, vasculitides, optionally polyarteritis nodosa, Wegener’s granulomatosis, churg-strauss syndrome, or vasculitis. [0184] Therapeutically effective amounts may be administered via a single dose or via multiple doses (e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten doses). When administered via multiple doses, any of a variety of suitable therapeutic regimens may be used, including administration at regular intervals (e.g., once every other day, once every three days, once every four days, once every five days, thrice weekly, twice weekly, once a week, once every two weeks, once every three weeks, etc.). [0185] The dosage regimen (e.g., amounts of each therapeutic, relative timing of therapies, etc.) that is effective in methods of treatment may depend on the severity of the disease or condition and the weight and general state of the subject. For example, the therapeutically effective amount of a particular composition comprising a therapeutic agent applied to mammals (e.g., humans) can be determined by the ordinarily-skilled artisan with consideration of individual differences in age, weight, and the condition of the mammal. Therapeutically effective and/or optimal amounts can also be determined empirically by those of skill in the art. Page 53 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO [0186] The molecule containing antigen-binding site or pharmaceutical composition thereof may be administered by any of a variety of suitable routes, including, but not limited to, systemic routes such as parenteral (e.g., intravenous or subcutaneous) or enteral routes. [0187] In many embodiments, administering therapeutic agents containing antigen-binding sites or pharmaceutical compositions thereof in accordance with provided methods results in depletion of cells involved in the disease to be treated. In some embodiments, the cell expresses an antigen to which the antigen-binding sites comprised in the therapeutic agents bind. In some embodiments, the cell is an immune cell, e.g., a T cell, a B cell, a macrophage, a natural killer (NK) cell, a dendritic cell (DC), a monocyte, a neutrophil, a fibroblast, or an epithelial cell. In some embodiments, the cell is an activated cell, e.g., an antigen-activated T cell or B cell. EXAMPLES Example 1. Activation of FcγRIIIA [0188] The abilities of disclosed PD-1 antibodies to activate Fc-gamma receptors were assessed using an engineered Jurkat reporter T cell line expressing a specific Fc-gamma receptor and Lucia luciferase reporter gene. Activation of the Jurkat cells leads to NFAT- mediated luminescence. [0189] Briefly, PD-1 expressing cells were incubated with Jurkat-Lucia reporter cells expressing FcγRIIIA and PD-1 antibodies having wild-type human IgG1 Fc or IgG1 Fc containing mutations S239D/H268D (“X3” mutations) that increase binding to FcγRIIB at 37oC, 5% CO2 for 6 hours. Jurkat-Lucia TCR-hPD-1 cells were added to the culture, and the plate was incubated for an additional 5.5 hours at 37oC, 5% CO2. Following incubation, 20μL supernatant was transferred into a 96-well white plate. 50 μL of QUANTI-Luc 4 Reagent was added to the plate and luminescence was read immediately using a plate reader (PerkinElmer). Fold change in activation was calculated by comparing the luminescence intensity in RLU (relative light unit) of each sample to the the isotype control. [0190] Exemplary results are shown in FIG.1. Humanized anti-PD-13H4, with or without the X3 mutations, were capable of activating FcγRIIIA, and humanized antibodies 3H4-2, 3H4- 4, 3H4-5, 3H4-7, and 3H4-8 containing the X3 mutations showed the greatest fold increase in activation. Table 2. Antibody Information Antibody SEQ ID NO age 5 o 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO 3H4 1 5 h3H4-1 9 20 1 antibodies [0191] The ability of disclosed PD-1 antibodies in inhibiting T cell activation was assessed using a commercially available assay comprising an antigen-presenting cell line (APC) and a human Jurkat reporter T cell line expressing a specific T cell receptor (TCR) and the Lucia luciferase reporter gene. In this assay, activation of the Jurkat cells leads to NFAT-mediated luminescence.An additional Jurkat reporter cell-based assay was performed as described in Example 4 to assess the abilities of PD-1 antibodies in inhibiting T cell activation. [0192] Raji-APC cells modified to express the FcγRII receptor were incubated for 30 minutes at 37oC, 5% CO2 with isotype controls or PD-1 antibodies. Tested antibodies comprise wild- type IgG1 Fc, IgG1 Fc carrying X3 mutations, or IgG1 Fc carrying X3 mutations and a E430G or E345K mutation that induces antibody hexamer formation (“HexaBody” mutation). Following incubation, Jurkat-Lucia TCR-hPD-1 cells were added to the culture, and the plate was incubated for an additional 5.5 hours at 37oC, 5% CO2. The cells were centrifuged at 400 x g for 5 minutes, and the supernatant was transferred into a 96-well white plate. 50 μL of QUANTI-Luc 4 Reagent was added to the plate and luminescence was read immediately using a plate reader (PerkinElmer). Data were analyzed using GraphPad Prism and relative percent inhibition was calculated compared to the signal obtained from isotype controls. [0193] Exemplary results are shown in FIG. 2. 3H4 and humanized 3H4-2, 3H4-4, 3H4-5, 3H4-6, 3H4-7, and 3H4-8 comprising the X3 mutations significantly inhibited activation of Jurkat cells compared to isotype controls. Additionally, 3H4 comprising the X3 mutations and the HexaBody mutation also inhibited activation of the Jurkat cells. Example 3. Complement-dependent cytotoxicity of PD-1 antibodies [0194] The complement-dependent cytotoxicity (CDC) of exemplary PD-1 antibodies disclosed herein was assessed in Raji cells or in CHO-K1 cells. Page 55 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO [0195] For Raji cell-based assay, PD-1 positive positive Raji cells were incubated with PD- 1 antibodies 3H4, 3H4 with X3 mutations (“3H4 X3”), and 3H4 with X3 and HexaBody mutations (“3H4 X3 Hex”) for 30 minutes at 37oC in a 96 well clear bottom white walled plate. Following incubation, fresh human serum isolated from whole blood was added, and the plate was incubated at 37oC, 5% CO2 for 4 hours. Subsequently, CellTiter-Glo was added to each well, and the plate was incubated for 2 minutes protected from light on a benchtop shaker. Luminescence was measured on a plate reader (PerkinElmer). Percent cytotoxicity was calculated by subtracting background RLU from all samples and then applying the formula 100% × (1 – RLU of the sample) / (RLU of the no antibody control). [0196] For CHO-K1 cell-based assay, PD-1 positive CHO-K1 cells were incubated with serially diluted PD-1 antibody 3H4 X3 HexaBody for 30 minutes at room temperature in a clear bottom white walled plate. Following incubation, normal human serum complement was added, and the plate incubated at 37oC, 5% CO2 for 4 hours. Subsequently, CellCounting-Lite 2.0 Luminescent Cell Viability Assay working solution was added to each well, and the plate was incubated for 10 minutes at room temperature. Luminescence was measured on a plate reader, and data were analyzed using using Microsoft Office Excel 2016 and GraphPad Prism. Concentrations were plotted as a function of relative luminescence and curve fitting was performed using a four-parameter non-linear regression algorithm. Percent cytotoxicity was calculated by subtracting background RLU from all samples and then applying the formula 100% x (1 – RLU of the sample) / (RLU of the no antibody control). [0197] The results are shown in FIG. 3A and FIG. 3B. 3H4 X3 Hex showed significant CDC activity with an EC50 of 4.092nM. Example 4. Depletion of CD8 T cells induced by PD-1 antibodies [0198] The ability of exemplary PD-1 antibodies to deplete CD8 T cells was assessed. [0199] Fresh whole blood was collected into heparin vacutainer tubes. PD-1 antibodies or isotype control antibodies (100nM) were incubated with whole blood in polypropylene tubes for 24 hours at 37oC, 5% CO2. Following incubation, cells were stained with fluorescently labeled antibodies for PD-1, CD3, CD4, CD8, and CD45 for 30 minutes at room temperature. Cells were lysed by the addition of lysis buffer for 15 minutes at room temperature, centrifuged at 400×g for 4 min and washed twice with cell staining buffer. Following washing, cytofluorimetric analysis was conducted using a BD FACS Symphony A3 (BD Biosciences). Cells were sorted by scatter properties and separated for single cell analysis using side scatter width vs side scatter area. Antibody binding to cells was quantitated by measuring fluorescent Page 56 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO emissions of excitation and used to quantify the relative proportion of CD8 T cells with high and intermediated expression of PD-1 compared to the whole CD8 T cell population. Data analysis was performed using FlowJo Software, and the percent of CD8 T cells with high and intermediate levels of PD-1 expression remaining for each condition was normalized by comparison to an isotype control. [0200] The results are shown in FIG. 4A and FIG. 4B. PD-1 antibodies 3H4 X3 and 3H4 X3 Hex showed mediated the depletion of CD8 T cells with both high and intermediate levels of PD-1 cell surface expression. Example 5. Binding of antibodies toward PD-1 [0201] Binding of humanized PD-1 antibodies to human PD-1 was assessed by biolayer interferometry (BLI). [0202] Binding experiments were performed on an Octet BLI instrument. Testing antibodies were loaded onto Anti-Human IgG Fc Capture (AHC) sensors, and the sensors were dipped into serial dilutions of His-tagged PD-1. A baseline after loading and before each association was performed. Data were single referenced for analysis. Kinetic constants were calculated using monovalent (1:1) curve fit model. [0203] Exemplary results are depicted in Table 2. All tested PD-1 anibodies were capable of binding to human PD-1. Table 3. Binding of PD-1 antibodies to human PD-1 Antibody SEQ ID NO KD (nM) h3H4-892 99 and 105 691E-09 [0204] The binding of humanized PD-1 antibodies to human PD-1 was assessed by flow cytometry. PD-1 positive Jurkat cells were suspended in FACS Blocking Buffer (PBS + 10% normal human serum) for 30 minutes. Following washing, cells were incubated with test PD- 1 antibodies in FACS Buffer (PBS + 0.5% bovine serum albumin + 0.09% sodium azide) and incubated at 4°C for 30 minutes, washed and incubated with PE-labeled anti-human secondary antibody (Invitrogen). Cells were incubated at 4°C for 30 minutes in the dark. Following washing, cytofluorimetric analysis was conducted using a BD FACS Symphony A3 (BD Biosciences). Cells were sorted by scatter properties and separated for single cell analysis using side scatter width vs side scatter area. Antibody binding to cells was Page 57 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO quantitated by measuring fluorescent emissions of excitation wavelength of 561 nm using a 586/15 nm filter. Data analysis was performed using FlowJo Software. [0205] Exemplary results are depicted in FIG.5. All tested PD-1 anibodies were capable of binding to cell surface PD-1. Example 6. Cross-reactivity of PD-1 antibodies [0206] An surface plasmon resonance (SPR) binding kinetic assay was employed to assess the cross-reactivity of PD-1 antibodies toward human PD-1 and cynomongus PD-1. [0207] Briefly, testing antibodies were loaded onto AHC sensors, and the sensors were dipped into an eleven-point, three-fold serial dilution of His-tagged PD-1. The kinetic assay was run with an analysis temperature of 25°C using multi-cycle kinetics on a Biacore T200 instrument. Kinetic constants were calculated using monovalent (1:1) curve fit model. [0208] Exemplary results are depicted in Table 3. Tested PD-1 anibody AHF29879_R was capable of binding to both human and cynomolgus PD-1. Table 4. Cross-reactivity of PD-1 antibodies Antiboby KD (nM) [0 09] e cross-reac v y o - an bodes oward uman - and cynomongus PD-1 was also analyzed using an ELISA-based assay. His-tagged extracellular domains of human PD-1 and cynomolgus PD-1 were immobilized on 96 well ELISA plates (Nunc Maxisorp, ThermoFisher) and blocked for 1 hour with 1% BSA in PBS. Following washing with PBST (phosphate buffered saline + 0.05% Tween 20), serially diluted test PD-1 antibodies were added to the coated plate and incubated for 2 hours at room temperature. Plates were washed and incubated with HRP-conjugated goat anti-human IgG secondary antibody (Jackson Immunoresearch) for 1 hour at room temperature. Following washing, antibody binding was detected colorimetrically by adding 3,3’,5,5’-tetramethylbenzidine (TMB) and incubated at room temperature for 10-20 minutes before adding 2.5N sulfuric acid stopping solution. Absorbance at 450 nm was measured on a plate reader (PerkinElmer). Data were analyzed using GraphPad Prism. [0210] Exemplary results are depicted in FIG.6. Tested PD-1 anibody h3H4-879 was capable of binding to both human and cynomolgus PD-1. Page 58 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO Example 7. Signaling of PD-1 antibodies through Fcγ receptors [0211] The ability of effector function modified PD-1 antibodies in inhibiting T cell activation was assessed. A commercially available assay was used, comprising an antigen- presenting cell line (APC) and a human Jurkat reporter T cell line expressing a specific T cell receptor (TCR) and the Lucia luciferase reporter gene. In this assay, activation of the Jurkat cells leads to NFAT-mediated luminescence. [0212] Target cells expressing PD-1 in a multi-well plate were incubated with humanized PD-1 antibodies with effector enhanced IgG1 Fc or isotype controls and Jurkat-Lucia reporter cell lines modified to express Fcγ receptor CD16a (FcγRIIIa), CD32a (FcγRIIa), or CD64 (FcγRI) at 37oC, 5%CO2 for 6 hours. The effoctor enhanced IgG1 Fc contains mutations S239D/H268D (“X3” mutations), as well as a E430G mutation that induces antibody hexamer formation (together, “X3 Hex” mutations). Following incubation, 20 mL of supernatant from each well was transferred into a 96-well white wall plate, and 50 mL of Quanti-Luc4 reagent (Invivogen) was added. Luminescence was measured on a plate reader (PerkinElmer). Fold change in activation was calculated by comparing RLU values from each of the samples to the the isotype control. [0213] Exemplary results are shown in FIGs.7A-7C. All tested PD-1 antibodies with X3 mutations are capable of signaling through Fcγ receptors CD16a, CD32a, and CD64. Example 8. Inhibition of T cell activation by PD-1 antibodies [0214] The ability of effector function modified PD-1 antibodies in inhibiting T cell activation was assessed using a Jurkat reporter assay. [0215] Raji-APC cells (Invivogen) modified to express the FcγRIIb receptor were incubated with test PD-1 antibodies, comprising IgG1 Fc with X3 Hex mutations that increase binding to FcγRIIb, or an isotype control for 30 minutes at 37oC, 5% CO2. Raji-PD- L1 cells were used as a positive control for agonism. Following incubation, Jurkat-Lucia TCR-hPD-1 cells (Invivogen) were added to the culture, and the plate was incubated for an additional 5.5 hours at 37oC, 5% CO2. The cells were centrifuged at 400 x g for 5 minutes and 20mL of supernatant was transferred into a 96-well white plate. Activation of the Jurkat cells is measured via a bioluminescent signal produced by Lucia luciferase. 50mL of QUANTI-Luc 4 Reagent (Invivogen) was added to the plate and luminescence (RLU) was read immediately using a plate reader (PerkinElmer). Data were analyzed using GraphPad Prism. Page 59 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO [0216] Exemplary results are shown in FIG.8. All tested PD-1 antibodies significantly inhibited the activation of Jurkat cells compared to the isotype control. Example 9. Phagocytosis induced by PD-1 antibodies [0217] The ability of PD-1 antibodies in inducing phagocytosis was assessed using a Jurkat reporter assay. [0218] Raji PD-1 positive target cells were labeled with cell tracker deep red and added to the wells of a 96-well plate. Labeled target cells were incubated with increasing concentrations of test PD-1 antibodies or an isotype control for 30 minutes at 37oC. Following incubation, PKH26 stained human monocyte derived macrophages were added to the culture at a 5:1 effector cell to target cell ratio. The plate was incubated for 4 hours, and images were captured using a Cytation 5 cell imaging multimode reader (Agilent). The number of cells undergoing phagocytosis were counted using Gen5 cell counting software. [0219] Exemplary results are shown in FIG.9. All tested PD-1 showed potent antibody dependent cellular phagocytosis of PD-1 positive target cells. Example 10. Cytotoxicity induced by PD-1 antibodies [0220] The killing capacity of PD-1 antibodies was assessed using a natural killer (NK) cell-mediated cytotoxicity assay. [0221] CD4 T cells and autologous NK cells were isolated from PBMCs using StemCell Technologies isolation kits. T cells were treated with anti-CD3, anti-CD28 to activate them, which activation resulted in increased expression of PD-1 on the surface of the cells. NK cells were incubated with human IL-15 overnight, and their purity was checked by flow cytometry. Activated T cells were incubated with increasing concentrations of test PD-1 antibodies or an isotype control in a 96-well plate for 40 minutes at 37oC, 5% CO2. NK cells were added to the culture, and the plate was incubated overnight (18-24 hours) at 37oC, 5% CO2. Following overnight incubation, Triton X was added to control wells for 15 minutes to induce total cell lysis. The plate was centrifuged at 250 x g for 10 minutes. 100 mL of supernatant from each well was transferred to an optically clear, 96-well, flat bottom plate. 100 mL freshly prepared LDH reaction mixture was added to each well and the plate incubated for up to 30 minutes for color development. Absorbance was measured at 492 nm using a plate reader (PerkinElmer), and 650 nm was used as a reference. Data were analyzed using GraphPad Prism. The values obtained from the reference wavelength were subtracted Page 60 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO from values at 492 nM. Percent cytotoxicity was determined by comparing sample OD values to OD values for the triton X wells which represent 100% cytotoxicity. [0222] Exemplary results are shown in FIG.10. All tested PD-1 showed potent antibody- dependent cellular cytotoxicity of PD-1 positive target cells. Example 11. Inhibition of IFN-γ secretion by PD-1 antibodies [0223] The ability of PD-1 antibodies in inhibiting IFN-γ secretion was assessed. [0224] PBMCs from a recently vaccinated tetanus donor were incubated with tetanus toxoid and test PD-1 antibodies or an isotype control for 4 days at 37oC and 5% CO2. IFN-γ levels in the culture supernatants were measured using a commercial IFN-γ ELISA kit (R&D Systems). IFN-γ capture antibody was immobilized on 96-well ELISA plates. Plates were washed with PBST (phosphate buffered saline + 0.05% Tween 20) and blocked for 1 hour with 1% BSA in PBS. Following washing with PBST, supernatants and an IFN-γ standard curve were added to the coated plates and incubated for 2 hours at room temperature. Plates were washed and incubated with HRP-conjugated detection antibody for 2 hours at room temperature. Following washing, antibody binding was detected colorimetrically by adding 3,3’,5,5’-tetramethylbenzidine (TMB) and incubated at room temperature for 10-20 minutes before adding 2.5N sulfuric acid stopping solution. Absorbance at 450 nm was measured on a plate reader (PerkinElmer). Data were analyzed using GraphPad Prism. [0225] Exemplary results are shown in FIG.11. All tested PD-1 significantly inhibited IFN-γ secretion. SEQUENCE ANNEX [0226] In some sequences, variable regions are bolded, and CDRs are underlined. Table 5. Sequences of exemplary antigen-binding sites capable of binding PD-1 SEQ Description Sequence ID NO WI FC LI PY IPTS/128817054.1 Attorney Docket No. SANA-007WO 6 LCDR1 (Kabat) RASQEISGYLS 7 LCDR2 (Kabat) AASTLDS WM YC WI YC WI YC WI FC WI FC WI FC Page 62 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO Humainzed 3H4 heavy chain 7-5 16 Heavy chain variable QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYINWVKQAPGQGLEWI region (VH7-5) GWIYPGSVNTKYNEKFRGKATLTVDTSASTAYMELSSLRSEDTAVYFC WI FC WM YC WI FC WI FC GC SS DV AK TI SN AL WI FC WI FC GC Page 63 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDV FLFPPKPKDTLMISRTPEVTCVVVDVSDEDPEVKFNWYVDGVEVHNAK TI SN AL WI FC LI PY LI PY LI PY LI PY LI PY Page 64 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO Humainzed 3H4 light chain 7-4 25 Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQEISGYLSWLQQKPGKAPKRLI region (VL7-4) YAASTLDSGVPKRFSGSRSGTDYTLTISSLQPEDFATYYCLQYASYPY LI PY LI PY EA VY LI PY LI PY EA VY LI PY LI PY EA VY LI PY Page 65 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO 109 LCDR3 (Kabat) LQIAQYPYT 1-17 27 H v hin vribl QVQLQESGPGVVKPSGTLSLTCAISGGSIGSGGSIRSTRWWSWVRQSP AD TV DS WM YC IY TY WM YC KL IV LE YY Page 66 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO 54 HCDR3 (Kabat) ASDYVWGGYRYMDAFDI 55 Light chain variable QSVLTQPPSASGTPGQRVTISCSGSNSNIGSNSVNWYQQLPGTAPKLL r i n IYGNNQRPSGVPDRFSGSKSGTSASLAISGLQSENEADYYCAAWDDSL WI FC QS QG WM YC WI YC WM YC WI YC Page 67 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO 62 HCDR3 (Kabat) TTGY Humainzed 2.3A9 light chain 2 (h2.3A9-L2) 71 Li ht hin vribl DVVMTQSPLSLPVTLGQPASISCRSSQSLLNSDGKTYLNWLQQRPGQS QG WV YC PP SK WV YC AP SK AP SK WV YC Page 68 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO 86 HCDR2 (Kabat) TITGGGRNTYYPDSVKG 87 HCDR3 (Kabat) QGYDGYTWFAY PP SK WV YC AP SK AP SK Table 6. Other sequences SEQ Description Sequence ID NO TS DK TC VL DE FF TS DK TC VL EE FF Page 69 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO 112 Modified IgG1 CH region ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS – X2 mutations GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK KVEPKSCDKTHTCPPCPAPELLDGPSVFLFPPKPKDTLMISRTPEVTC VL DE FF TS DK TC VL DE FF TS DK TC VL DE FF TS DK TC VL DE FF TS DK TC VL DE FF TS DK TC VL DE FF TS DK TC VL DE FF TS DK TC VL DE Page 70 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 120 Modified IgG1 CH region ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS DK TC VL DE FF TS DK TC VL DE FF TS DK TC VL DE FF TS DK TC VL DE FF TS DK TC VL DE FF TS DK TC VL DE FF LQ SS QS SP CO O O C [0227] Unless stated to the contrary, the entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes. Page 71 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO EQUIVALENTS/ OTHER EMBODIMENTS [0228] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. Such equivalents are intended to be encompassed by the following claims. Page 72 of 99 IPTS/128817054.1

Claims

Attorney Docket No. SANA-007WO WHAT IS CLAIMED IS: 1. An antibody or an antigen-binding fragment thereof that is capable of binding to PD- 1, wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable (VH) region comprising: heavy chain complementarity-determining region 1 (HCDR1) having the amino acid sequence of SEQ ID NO: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 98, and HCDR3 having the amino acid sequence of SEQ ID NO: 4. 2. The antibody or antigen binding fragment thereof of claim 1, wherein the antibody or antigen binding fragment thereof comprises further comprises a light chain variable (VL) region comprising: (a) light chain complementarity-determining region 1 (LCDR1) having the amino acid sequence of SEQ ID NO: 6, LCDR2 having the amino acid sequence of SEQ ID NO: 7, and LCDR3 having the amino acid sequence of SEQ ID NO: 8; or (b) LCDR1 having the amino acid sequence of SEQ ID NO: 6, LCDR2 having the amino acid sequence of SEQ ID NO: 103, and LCDR3 having the amino acid sequence of SEQ ID NO: 104; or (c) LCDR1 having the amino acid sequence of SEQ ID NO: 6, LCDR2 having the amino acid sequence of SEQ ID NO: 7, and LCDR3 having the amino acid sequence of SEQ ID NO: 109. 3. An antibody or an antigen-binding fragment thereof that is capable of binding to PD- 1, wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable (VH) region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from SEQ ID NOs: 12-19, 97, and 100; and/or a light chain variable (VL) region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NOs: 23-26, 102, 106, and 108. 4. The antibody or antigen binding fragment thereof of claim 3, wherein Page 73 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO the VH region comprises an amino acid sequence selected from SEQ ID NOs: 12-19, 97, and 100; and the VL region comprises an amino acid sequence selected from SEQ ID NOs: 23-26, 102, 106, and 108. 5. An antibody or an antigen-binding fragment thereof that is capable of binding to PD- 1, wherein the antibody or antigen binding fragment thereof comprises (a) a heavy chain variable (VH) region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 9, and a light chain variable (VL) region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 26; or (b) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 18, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 21; or (c) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 18, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 26; or (d) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 19, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 26; or (e) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 15, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 24; or (f) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 15, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 25; or (g) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 16, Page 74 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 24; or (h) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 16, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 25; or (i) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 17, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 24; or (j) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 17, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 25; or (k) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 97, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 102; or (l) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 100, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 106; or (m) a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 97, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 108. 6. The antibody or antigen binding fragment thereof of claim 5, wherein (a) the VH region comprises an amino acid sequence of SEQ ID NO: 9, and the VL region comprises an amino acid sequence of SEQ ID NO: 26; or (b) the VH region comprises an amino acid sequence of SEQ ID NO: 18, and the VL region comprises an amino acid sequence of SEQ ID NO: 21; or (c) the VH region comprises an amino acid sequence of SEQ ID NO: 18, and the VL region comprises an amino acid sequence of SEQ ID NO: 26; or Page 75 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO (d) the VH region comprises an amino acid sequence of SEQ ID NO: 19, and the VL region comprises an amino acid sequence of SEQ ID NO: 26; or (e) the VH region comprises an amino acid sequence of SEQ ID NO: 15, and the VL region comprises an amino acid sequence of SEQ ID NO: 24; or (f) the VH region comprises an amino acid sequence of SEQ ID NO: 15, and the VL region comprises an amino acid sequence of SEQ ID NO: 25; or (g) the VH region comprises an amino acid sequence of SEQ ID NO: 16, and the VL region comprises an amino acid sequence of SEQ ID NO: 24; or (h) the VH region comprises an amino acid sequence of SEQ ID NO: 16, and the VL region comprises an amino acid sequence of SEQ ID NO: 25; or (i) the VH region comprises an amino acid sequence of SEQ ID NO: 17, and the VL region comprises an amino acid sequence of SEQ ID NO: 24; or (j) the VH region comprises an amino acid sequence of SEQ ID NO: 17, and the VL region comprises an amino acid sequence of SEQ ID NO: 25; or (k) the VH region comprises an amino acid sequence of SEQ ID NO: 97, and the VL region comprises an amino acid sequence of SEQ ID NO: 102; or (l) the VH region comprises an amino acid sequence of SEQ ID NO: 100, and the VL region comprises an amino acid sequence of SEQ ID NO: 106; or (m) the VH region comprises an amino acid sequence of SEQ ID NO: 97, and the VL region comprises an amino acid sequence of SEQ ID NO: 108. 7. The antibody or antigen binding fragment thereof of claim 3 or 5, wherein the VH region comprises an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 16, and the VL region comprises an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 24. 8. The antibody or antigen binding fragment thereof of claim 7, wherein the VH region comprises an amino acid sequence of SEQ ID NO: 16, and the VL region comprises an amino acid sequence of SEQ ID NO: 24. 9. The antibody or antigen binding fragment thereof of claim 3 or 5, wherein the VH region comprises an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 17, and the VL region Page 76 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO comprises an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 25. 10. The antibody or antigen binding fragment thereof of claim 9, wherein the VH region comprises an amino acid sequence of SEQ ID NO: 17, and the VL region comprises an amino acid sequence of SEQ ID NO: 25. 11. The antibody or antigen binding fragment thereof of claim 1 or 5, wherein the antibody or antigen binding fragment thereof comprises a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 97, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 102. 12. The antibody or antigen binding fragment thereof of claim 11, wherein the VH region comprises an amino acid sequence of SEQ ID NO: 97, and the VL region comprises an amino acid sequence of SEQ ID NO: 102. 13. The antibody or antigen binding fragment thereof of claim 1 or 5, wherein the antibody or antigen binding fragment thereof comprises a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 100, and a VL region comprising an amino acid sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 106. 14. The antibody or antigen binding fragment thereof of claim 13, wherein the VH region comprises an amino acid sequence of SEQ ID NO: 100, and the VL region comprises an amino acid sequence of SEQ ID NO: 106. 15. The antibody or antigen binding fragment thereof of claim 1 or 5, wherein the antibody or antigen binding fragment thereof comprises a VH region comprising an amino acid sequence having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of SEQ ID NO: 97, and a VL region comprising an amino acid Page 77 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO sequence having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 108. 16. The antibody or antigen binding fragment thereof of claim 9, wherein the VH region comprises an amino acid sequence of SEQ ID NO: 97, and the VL region comprises an amino acid sequence of SEQ ID NO: 108. 17. The antibody or antigen binding fragment thereof of any one of claims 1-16, wherein the antibody is a humanized antibody. 18. The antibody or antigen binding fragment thereof of any one of claims 1-17, wherein the antigen binding fragment is a Fab, a Fab’, a Fab2, a F(ab’)2, Fv, a single-chain Fv (scFv), or a diabody. 19. The antibody or antigen binding fragment thereof of claim 18, wherein the antigen binding fragment is an scFv. 20. The antibody or antigen binding fragment thereof of any one of claims 1-19, wherein the antibody or antigen binding fragment thereof comprises an antibody heavy chain constant region. 21. The antibody or antigen binding fragment thereof of claim 20, wherein the antibody heavy chain constant region is a human IgG heavy chain constant region. 22. The antibody or antigen binding fragment thereof of claim 21, wherein the antibody heavy chain constant region is a human IgG1 heavy chain constant region. 23. The antibody or antigen binding fragment thereof of claim 22, wherein the antibody heavy chain constant region comprises an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 111. 24. The antibody or antigen binding fragment thereof of claim 22, wherein the antibody heavy chain constant region has the amino acid sequence of SEQ ID NO: 111. Page 78 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO 25. The antibody or antigen binding fragment thereof of claim 21 or 22, wherein the antibody heavy chain constant region comprises one or more mutations that enhance effector function. 26. The antibody or antigen binding fragment thereof of claim 21 or 22 or 25, wherein the antibody heavy chain constant region comprises one or more mutations that enhances binding to an inhibitory Fc receptor (e.g., FcγRII). 27. The antibody or antigen binding fragment thereof of claim 25 or 26, wherein the antibody heavy chain constant region is a human IgG1 heavy chain constant region comprising one of the following mutation(s), (a) E233D; (b) G236D or G236A; (c) G237D; (d) P238D; (e) S239D; (f) S267E; (g) H268D or H268F; (h) P271G; (i) S324T; (j) L328Y, L328F, or L328E; (k) A330R; (l) I332E; (m) E345K, E345Y, E345Q, or E345R; (n) E430G, E430S, E430F, or E430T; (o) S440Y; (p) G236D and H268D; (q) S239D and H268D; (r) S239D, H268D, L328Y, and I332E; (s) P238D and L328E; (t) G237D, P271G, and A330R; (u) G237D, H268D, P271G, and A330R; (v) S267E and L328F; Page 79 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO (w) S239D and S267E; (x) G236D and S276E; (y) E233D, G237D, H268D, P271G, and A330R; (z) S239D, H268D, and E430G; or (aa) S239D, H268D, and E345K, or a combination thereof, wherein the numbering of the constant region is as per the EU index. 28. The antibody or antigen binding fragment thereof of claim 27, wherein the antibody heavy chain constant region is a human IgG1 heavy chain constant region comprising one of the following mutation(s), (a) G236D or G236A; (b) S239D; (c) H268D or H268F; (d) L328Y; (e) S324T; (f) I332E; (g) E345K, E345Y, E345Q, or E345R; (h) E430G, E430S, E430F, or E430T; (i) S440Y; (j) S239D and H268D; or a combination thereof, wherein the numbering of the constant region is as per the EU index. 29. The antibody or antigen binding fragment thereof of any one of claims 25-28, wherein the antibody heavy chain constant region is a human IgG1 heavy chain constant region comprising the following mutations: S239D and H268D, and optionally E430G or E345K, wherein the numbering of the constant region is as per the EU index. 30. The antibody or antigen binding fragment thereof of claim 29, wherein the antibody heavy chain constant region is a human IgG1 heavy chain constant region comprising the following mutations: S239D, H268D, and E430G, wherein the numbering of the constant region is as per the EU index. Page 80 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO 31. The antibody or antigen binding fragment thereof of any one of claims 25-28, wherein the antibody heavy chain constant region is a human IgG1 heavy chain constant region comprising the following mutations: E233D, G237D, H268D, P271G, and A330R, wherein the numbering of the constant region is as per the EU index. 32. The antibody or antigen binding fragment thereof of any one of claims 25-28, wherein the antibody heavy chain constant region is a human IgG1 heavy chain constant region comprising the following mutations: S267E and L328F, wherein the numbering of the constant region is as per the EU index. 33. The antibody or antigen binding fragment thereof of any one of claims25-32, wherein the antibody heavy chain constant region is a human IgG1 heavy chain constant region comprising the following mutations: E430G or E345K, wherein the numbering of the constant region is as per the EU index. 34. The antibody or antigen binding fragment thereof of claim 25 or 26, wherein the antibody heavy chain constant region comprises an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 125. 35. The antibody or antigen binding fragment thereof of claim 34, wherein the antibody heavy chain constant region has the amino acid sequence of SEQ ID NO: 125. 36. An antibody or antigen-binding fragment thereof that is capable of binding to PD-1, wherein: the antibody or antigen binding fragment thereof comprises a human IgG1 heavy chain constant region comprising a mutation selected from E345K, E345Y, E345Q, E345R, E430G, E430S, E430F, E430T, S440Y, wherein the numbering of the constant region is as per the EU index; and the antibody or antigen binding fragment thereof comprises (a) (i) a heavy chain variable (VH) region comprising: heavy chain complementarity-determining region 1 (HCDR1) having the amino acid sequence of SEQ ID NO: 2, or a sequence differing in 1 or 2 amino acids therefrom, Page 81 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO HCDR2 having the amino acid sequence of SEQ ID NO: 3, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 4, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a lighat chain variable (VL) region comprising: light chain complementarity-determining region 1 (LCDR1) having the amino acid sequence of SEQ ID NO: 6, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 7, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 8, or a sequence differing in 1 or 2 amino acids therefrom; (b) (i) a heavy chain variable (VH) region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 28, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 29, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 30, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a lighat chain variable (VL) region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 32, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 33, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 34, or a sequence differing in 1 or 2 amino acids therefrom; (c) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 36, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 37, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 38, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: Page 82 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO LCDR1 having the amino acid sequence of SEQ ID NO: 40, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 41, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 42, or a sequence differing in 1 or 2 amino acids therefrom; (d) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 44, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 45, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 46, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 48, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 49, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 50, or a sequence differing in 1 or 2 amino acids therefrom; (e) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 52, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 53, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 54, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 56, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 57, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 58, or a sequence differing in 1 or 2 amino acids therefrom; Page 83 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO (f) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 2, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 10, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 4, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 6, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 7, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 8, or a sequence differing in 1 or 2 amino acids therefrom; (g) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 60, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 61, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 62, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 64, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 65, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 66, or a sequence differing in 1 or 2 amino acids therefrom; (h) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 60, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 68, or a sequence differing in 1 or 2 amino acids therefrom, and Page 84 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO HCDR3 having the amino acid sequence of SEQ ID NO: 62, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 64, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 65, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 66, or a sequence differing in 1 or 2 amino acids therefrom; (i) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 73, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 74, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 75, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 77, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 78, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 79, or a sequence differing in 1 or 2 amino acids therefrom; (j) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 73, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 81, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 75, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 77, or a sequence differing in 1 or 2 amino acids therefrom, Page 85 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO LCDR2 having the amino acid sequence of SEQ ID NO: 78, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 79, or a sequence differing in 1 or 2 amino acids therefrom; (k) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 85, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 86, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 87, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 89, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 90, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 91, or a sequence differing in 1 or 2 amino acids therefrom; (l) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 85, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 93, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 87, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 89, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 90, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 91, or a sequence differing in 1 or 2 amino acids therefrom; (m) (i) a VH region comprising: Page 86 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO HCDR1 having the amino acid sequence of SEQ ID NO: 2, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 98, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 4, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 6, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 103, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 104, or a sequence differing in 1 or 2 amino acids therefrom; (n) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 2, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 98, or a sequence differing in 1 or 2 amino acids therefrom, and HCDR3 having the amino acid sequence of SEQ ID NO: 4, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 6, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 7, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 8, or a sequence differing in 1 or 2 amino acids therefrom; or (o) (i) a VH region comprising: HCDR1 having the amino acid sequence of SEQ ID NO: 2, or a sequence differing in 1 or 2 amino acids therefrom, HCDR2 having the amino acid sequence of SEQ ID NO: 98, or a sequence differing in 1 or 2 amino acids therefrom, and Page 87 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO HCDR3 having the amino acid sequence of SEQ ID NO: 4, or a sequence differing in 1 or 2 amino acids therefrom; and (ii) a VL region comprising: LCDR1 having the amino acid sequence of SEQ ID NO: 6, or a sequence differing in 1 or 2 amino acids therefrom, LCDR2 having the amino acid sequence of SEQ ID NO: 7, or a sequence differing in 1 or 2 amino acids therefrom, and LCDR3 having the amino acid sequence of SEQ ID NO: 109, or a sequence differing in 1 or 2 amino acids therefrom. 37. The antibody or antigen-binding fragment thereof of claim 36, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise amino acid sequences that collectively differ by no more than two amino acid residues from the sequences of: (a) SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively; (b) SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 33, and SEQ ID NO: 34, respectively; (c) SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42, respectively; (d) SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 49, and SEQ ID NO: 50, respectively; (e) SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 57, and SEQ ID NO: 58, respectively; (f) SEQ ID NO: 2, SEQ ID NO: 10, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively; (g) SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 66, respectively; (h) SEQ ID NO: 60, SEQ ID NO: 68, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 66, respectively; (i) SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 77, SEQ ID NO: 78, and SEQ ID NO: 79, respectively; (j) SEQ ID NO: 73, SEQ ID NO: 81, SEQ ID NO: 75, SEQ ID NO: 77, SEQ ID NO: 78, and SEQ ID NO: 79, respectively; Page 88 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO (k) SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 90, and SEQ ID NO: 91, respectively; (l) SEQ ID NO: 85, SEQ ID NO: 93, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 90, and SEQ ID NO: 91, respectively; (m) SEQ ID NO: 2, SEQ ID NO: 98, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 103, and SEQ ID NO: 104, respectively; (n) SEQ ID NO: 2, SEQ ID NO: 98, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively; or (o) SEQ ID NO: 2, SEQ ID NO: 98, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 109, respectively. 38. The antibody or antigen-binding fragment thereof of claim 37, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise amino acid sequences of: (a) SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively; (b) SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 33, and SEQ ID NO: 34, respectively; (c) SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42, respectively; (d) SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 49, and SEQ ID NO: 50, respectively; (e) SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 57, and SEQ ID NO: 58, respectively; (f) SEQ ID NO: 2, SEQ ID NO: 10, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively; (g) SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 66, respectively; (h) SEQ ID NO: 60, SEQ ID NO: 68, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 66, respectively; (i) SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 77, SEQ ID NO: 78, and SEQ ID NO: 79, respectively; (j) SEQ ID NO: 73, SEQ ID NO: 81, SEQ ID NO: 75, SEQ ID NO: 77, SEQ ID NO: 78, and SEQ ID NO: 79, respectively; Page 89 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO (k) SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 90, and SEQ ID NO: 91, respectively; (l) SEQ ID NO: 85, SEQ ID NO: 93, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 90, and SEQ ID NO: 91, respectively; (m) SEQ ID NO: 2, SEQ ID NO: 98, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 103, and SEQ ID NO: 104, respectively; (n) SEQ ID NO: 2, SEQ ID NO: 98, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively; or (o) SEQ ID NO: 2, SEQ ID NO: 98, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 109, respectively. 39. The antibody or antigen-binding fragment thereof of any one of claims 36-38, comprising (a) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 1 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 5; (b) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 27 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 31; (c) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 35 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 39; (d) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 43 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 47; Page 90 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO (e) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 51 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 55; (f) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 9 or 11 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 20 or 21; (g) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 59 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 63; (h) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 67, 128, 69, or 60 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 71; (i) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 72 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 76; (j) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 80 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 82 or 83; (k) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 84 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, Page 91 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 88; (l) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 92 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 94 or 95; (m) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 97 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 102 or 108; or (n) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 100 and a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 106. 40. The antibody or antigen-binding fragment thereof of claim 39, comprising: (a) a VH region having the amino acid sequence of SEQ ID NO: 1 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 27; (b) a VH region having the amino acid sequence of SEQ ID NO: 1 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 31; (c) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 35 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 39; (d) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 43 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 47; (e) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 51 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 55; Page 92 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO (f) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 9 or 11 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 20 or 21; (g) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 59 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 63; (h) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 67, 128, 69, or 60 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 71; (i) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 72 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 76; (j) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 80 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 82 or 83; (k) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 84 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 88; (l) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 92 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 94 or 95; (m) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 97 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 102 or 108; or (m) a VH region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 100 and a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 106. 41. The antibody or antigen binding fragment thereof of any one of claims 36-40, wherein the IgG1 heavy chain constant region comprises E430G or E345K, wherein the numbering of the constant region is as per the EU index. Page 93 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO 42. The antibody or antigen binding fragment thereof of any one of claims 36-41, wherein the IgG1 heavy chain constant region further comprises one of the following mutation(s): (a) E233D; (b) G236D or G236A; (c) G237D; (d) P238D; (e) S239D; (f) S267E; (g) H268D or H268F; (h) P271G; (i) S324T; (j) L328Y, L328F, or L328E; (k) A330R; (l) I332E; (m) G236D and H268D; (n) S239D and H268D; (o) S239D, H268D, L328Y, and I332E; (p) P238D and L328E; (q) G237D, P271G, and A330R; (r) G237D, H268D, P271G, and A330R; (s) S267E and L328F; (t) S239D and S267E; (u) G236D and S276E; or (v) E233D, G237D, H268D, P271G, and A330R, or a combination thereof, wherein the numbering of the constant region is as per the EU index. 43. The antibody or antigen binding fragment thereof of claim 42, wherein the IgG1 heavy chain constant region comprises the following mutations: S239D and H268D, wherein the numbering of the constant region is as per the EU index. 44. The antibody or antigen binding fragment thereof of claim 42, wherein the IgG1 heavy chain constant region comprises the following mutations: E233D, G237D, H268D, P271G, and A330R, wherein the numbering of the constant region is as per the EU index. Page 94 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO 45. The antibody or antigen binding fragment thereof of claim 42, wherein the IgG1 heavy chain constant region comprises the following mutations: S267E and L328F, wherein the numbering of the constant region is as per the EU index. 46. The antibody or antigen binding fragment thereof of any one of claims 36-41, wherein the IgG1 heavy chain constant region comprises an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 125. 47. The antibody or antigen binding fragment thereof of claim 46, wherein the IgG1 heavy chain constant region has the amino acid sequence of SEQ ID NO: 125. 48. The antibody or antigen binding fragment thereof of any one of claims 1-47, wherein the antibody or antigen binding fragment thereof is a PD-1 agonist. 49. The antibody or antigen binding fragment thereof of any one of claims 1-48, wherein the antibody or antigen binding fragment thereof has enhanced binding to an Fc receptor. 50. The antibody or antigen binding fragment thereof of claim 49, wherein the Fc receptor is an inhibitory Fc receptor (e.g., FcγRII). 51. The antibody or antigen binding fragment thereof of claim 49, wherein the Fc receptor is an activating Fc receptor (e.g., FcγRI or FcγRIII). 52. The antibody or antigen binding fragment thereof of claims 1-51, wherein the antibody or antigen binding fragment thereof has enhanced effector function. 53. The antibody or antigen binding fragment thereof of claim 52, wherein the effector function is antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and/or complement dependent cytotoxicity (CDC). 54. The antibody or antigen binding fragment thereof of any one of claims 1-53, wherein the antibody or antigen binding fragment thereof is capable of depleting a cell. Page 95 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO 55. The antibody or antigen binding fragment thereof of claim 54, wherein the cell is a PD-1 expressing cell. 56. The antibody or antigen binding fragment thereof of claim 54 or 55, wherein the cell is an immune cell. 57. The antibody or antigen binding fragment thereof of claim 56, wherein the immune cell is a T cell, a B cell, a macrophage, a natural killer (NK) cell, a dendritic cell (DC), a monocyte, a neutrophil, a fibroblast, or an epithelial cell. 58. The antibody or antigen binding fragment thereof of claim 57, wherein the immune cell is a T cell or a B cell. 59. The antibody or antigen binding fragment thereof of any one of claims 56-58, wherein the immune cell is activated. 60. The antibody or antigen binding fragment thereof of claim 59, wherein the immune cell is an antigen-activated T cell or B cell. 61. The antibody or antigen binding fragment thereof of any one of claims 1-61, wherein the antibody or antigen binding fragment thereof is at least about 60%, about 75%, or about 90% non-fucosylated. 62. The antibody or antigen-binding fragment thereof of any one of claims 1-57, wherein the antibody or antigen-binding fragment thereof is produced in a cell line (a) having an alpha-1,6-fucosyltransferase (Fut8) knockout; or (b) line overexpressing β1,4-N-acetylglucosaminyltransferase III (GnT-III) and optionally overexpressing Golgi μ- mannosidase II (ManII). 63. The antibody or antigen-binding fragment thereof of any one of claims 1-62, wherein the antibody or antigen-binding fragment is capable of binding to human PD-1. Page 96 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO 64. The antibody or antigen-binding fragment thereof of any one of claims 1-63, wherein the antibody or antigen-binding fragment is capable of binding to cynomonguls PD-1. 65. The antibody or antigen-binding fragment thereof of any one of claims 1-64, wherein the antibody or antigen-binding fragment is capable of blocking PD-1/PD-L1 interaction. 66. The antibody or antigen-binding fragment thereof of any one of claims 1-65, wherein the antibody or antigen-binding fragment is capable of inhibiting T cell activation. 67. The antibody or antigen-binding fragment thereof of any one of claims 1-66, wherein the antibody or antigen-binding fragment is capable of inhibiting T cell proliferation. 68. The antibody or antigen-binding fragment thereof of any one of claims 1-67, wherein the antibody or antigen-binding fragment is capable of inhibiting IFN‐γ secretion. 69. The antibody or antigen-binding fragment thereof of any one of claims 1-68, wherein the wherein the antibody or antigen-binding fragment thereof is conjugated to an agent. 70. The antibody or antigen-binding fragment thereof of claim 69, wherein the agent is a cytotoxic agent or label. 71. The antibody or antigen-binding fragment thereof of claim 70, wherein the agent is a therapeutic agent. 72. A composition comprising the antibody or antigen-binding fragment thereof of any one of claims 1-71. 73. The composition of claim 72, wherein the antibody or antigen-binding fragment comprises an Fc region and N-glycoside-linked carbohydrate chains linked to the Fc region, optionally wherein less than 50% of the N-glycoside-linked carbohydrate chains contain a fucose residue. 74. The composition of claim 73, wherein substantially none of the N-glycoside-linked carbohydrate chains contain a fucose residue. Page 97 of 99 IPTS/128817054.1 Attorney Docket No. SANA-007WO 75. A polynucleotide encoding an antibody or antigen binding fragment thereof of any one of claims 1-71. 76. An expression vector comprising the polynucleotide of claim 75. 77. A host cell comprising the polynucleotide of claim 75 or the expression vector of claim 76. 78. The host cell of claim 77, wherein the host cell is a mammalian or insect cell. 79. The host cell of claim 77 or 78, wherein the host cell (a) comprises a Fut8 knockout; and/or (b) overexpresses GnT-III and optionally ManII. 80. A pharmaceutical composition comprising an antibody or antigen binding fragment thereof of any one of claims 1-71, and a pharmaceutically acceptable carrier. 81. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof of any one of claims 1-71, a composition of any one of claims 72-75, or a pharmaceutical composition of claim 80. 82. The method of claim 81, wherein the disease or disorder is an autoimmune disease. 83. The method of claim 81, wherein the disease or disorder is an allergy. 84. The method of claim 81, wherein the disease or disorder is an inflammatory disease. Page 98 of 99 IPTS/128817054.1
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