Molecules for modulating the immune system and their use

Abstract

Embodiments provided herein provide polypeptides, pharmaceutical compositions, and methods that can be used, for example, to target at least two types of cells and modulate their activity in order to treat disorders such as autoimmune disorders or cancer.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 462,096 filed on 26 April 2023, U.S. Provisional Application No. 63 / 601,426 filed on 21 November 2023, and U.S. Provisional Application No. 63 / 609,741 filed on 13 December 2023, each of which is incorporated herein by reference in whole.

[0002] Reference to electronically submitted sequence listings This application includes a sequence listing submitted electronically in XML file format, the entirety of which is incorporated herein by reference. The XML copy, created on 23 April 2024, is named "SES-009WO_SEQ.xml" and is 697,658 bytes in size.

[0003] Embodiments provided herein relate to compositions that target different cells to control the immune response. [Background technology]

[0004] Cell-mediated immunity plays a crucial role in the body's immune response. Unfortunately, uncontrolled cell-mediated immunity can lead to disease or autoimmune conditions. Most treatments available today control the body's immune response by targeting a single factor. However, these treatments are not always effective, and therefore, the need for treatments that control cell-mediated immunity remains. In contrast, cancer treatment requires activating the body's immune response to target cancer cells. Molecular immuno-oncology products approved today generally target only one type of cell through binding to a single receptor, which can lead to incomplete activation of the immune response to treat such cancers. The embodiments provided herein satisfy these and other requirements. [Overview of the project]

[0005] In some embodiments, an anti-PD-1 antibody or its antigen-binding fragment is provided, comprising a polypeptide such as that provided herein.

[0006] In some embodiments, an anti-FcγRIIb antibody or its antigen-binding fragment is provided, comprising a polypeptide such as that provided herein.

[0007] In some embodiments, a polypeptide is provided comprising i) an anti-PD-1 antibody or its antigen-binding fragment, ii) an Fc polypeptide, and iii) an anti-FcγRIIb antibody or its antigen-binding fragment, wherein the Fc polypeptide selectively binds to FcγRIIb or is effectorless.

[0008] In some embodiments, a polypeptide is provided comprising an anti-PD-1 antibody or its antigen-binding fragment and an Fc polypeptide, wherein the Fc polypeptide selectively binds to FcγRIIb. In some embodiments, a polypeptide comprising an anti-PD-1 antibody or its antigen-binding fragment and an Fc polypeptide is provided, wherein the Fc polypeptide selectively binds to FcγRIIb and does not contain an antibody that selectively binds to FcγRIIb.

[0009] In some embodiments, methods are provided for treating autoimmune disorders in subjects, which include administering polypeptides, molecules, or compositions such as those provided herein to the subject.

[0010] In some embodiments, methods are provided for treating cancer in a subject, which include administering a polypeptide, molecule, or composition to the subject as provided herein.

[0011] In some embodiments, a method for conditioning two types of cells with polypeptides, comprising contacting two types of cells, polypeptides, molecules, or compositions as provided herein.

[0012] In some embodiments, a method of modulating the activity of two types of cells in a subject is provided, the method comprising administering to the subject a polypeptide, molecule, or composition as provided herein.

[0013] In some embodiments, a method of inhibiting the activity of i) activated immune cells (e.g., T cells), and ii) B cells, antigen-presenting cells (APCs), or myeloid cells, the method comprising administering to the subject a polypeptide, molecule, or composition as provided herein, or contacting a polypeptide, molecule, or composition as provided herein with activated immune cells and B cells or antigen-presenting cells.

[0014] In some embodiments, a method of inhibiting or improving the activity of activated immune cells (e.g., T cells), and B cells, antigen-presenting cells (APCs), or myeloid cells is provided, the method comprising administering to the subject a polypeptide, molecule, or composition as provided herein, or contacting a polypeptide, molecule, or composition as provided herein with activated immune cells and B cells or antigen-presenting cells.

[0015] In some embodiments, a nucleic acid molecule encoding a polypeptide as provided herein is provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] [Figure 1] Describe non-limiting examples of how the therapeutic compounds provided herein can function. [Figure 2A] Describe non-limiting examples of the therapeutic compounds provided herein. [Figure 2B] Describe non-limiting examples of the therapeutic compounds provided herein. [Figure 3] Describe non-limiting examples of the therapeutic compounds provided herein. [Figure 4] Describe non-limiting examples of the therapeutic compounds provided herein. [Figure 5] Describe non-limiting exemplary therapeutic compounds provided herein. [Figure 6] Describe non-limiting exemplary therapeutic compounds provided herein. [Figure 7] Describe non-limiting exemplary therapeutic compounds provided herein. [Figure 8] Describe non-limiting exemplary therapeutic compounds provided herein. [Figure 9] Describe non-limiting exemplary therapeutic compounds provided herein. [Figure 10] Describe non-limiting exemplary therapeutic compounds provided herein. [Figure 11] Describe non-limiting exemplary therapeutic compounds provided herein. [Figure 12] Describe non-limiting exemplary therapeutic compounds provided herein. [Figure 13] Describe non-limiting exemplary therapeutic compounds provided herein. [Figure 14] Describe non-limiting exemplary therapeutic compounds provided herein. [Figure 15] Illustrate the binding affinity of various test articles. [Figure 16] Illustrate the PD-1 agonism of various test articles. [Figure 17] Illustrate the PD-1 agonism of various test articles in the presence or absence of FcγRIIb. [Figure 18A] Illustrate the PD-1 agonism mediated by selective anchoring to FcγRIIb via the scFv portion of various test articles. [Figure 18B] Illustrate the absence of PD-1 agonism mediated by selective anchoring to FcγRIIb via the scFv portion of various test articles in FcγRIIb-deficient cells. [Figure 19] Illustrate TNF production stimulated by various test articles. [Figure 20]Examples of PD-1 agonism induced by various test substances are provided. [Figure 21] Examples of PD-1 agonism induced by various test substances are provided. [Figure 22] This illustrates the absence of PD-1 agonism induced by various test materials. [Figure 23] This illustrates the absence of PD-1 antagonistism induced by various test materials. [Figure 24A] This illustrates the bonding affinity of various materials. [Figure 24B] This illustrates the bonding affinity of various materials. [Figure 24C] This illustrates the bonding affinity of various materials. [Figure 25] This illustrates TNF-alpha production in response to various substances. [Figure 26] Examples of granzyme B and IFN-gamma production in response to various substances are provided. [Figure 27A] Examples of ADCC inductions that respond to various objects are provided. [Figure 27B] Examples of ADCC inductions that respond to various objects are provided. [Figure 28A] Examples of IL-2 expression in response to various items are presented. [Figure 28B] This paper illustrates IFN-gamma expression in response to various substances. [Figure 28C] This example illustrates TNF-alpha expression in response to various substances. [Figure 29] Examples of C1q bonding to various materials are provided. [Figure 30A] Examples of ADCC inductions that respond to various objects are provided. [Figure 30B] Examples of ADCC inductions that respond to various objects are provided. [Figure 31A] The PD-1 binding affinity of various materials is illustrated. [Figure 31B] Examples of IL-2 expression in response to various items are presented. [Figure 32] This illustrates surface PD-1 loss in response to various materials. [Figure 33A] FcγRIIβ agonism data is provided as an example. [Figure 33B] FcγRIIβ agonism data is provided as an example. [Modes for carrying out the invention]

[0017] Where used herein, and unless otherwise indicated, the term “about” means that the numerical value is approximate and that small variables do not significantly affect the implementation of the disclosed embodiment. Where numerical limits are used, unless otherwise indicated by the context, “about” means that the numerical value can vary by ±10% and remain within the scope of the disclosed embodiment.

[0018] As used herein and in the appended claims, the singular forms "a," "an," and "the" refer to multiple subjects unless the context clearly indicates otherwise.

[0019] As used herein, the term “animal” includes, but is not limited to, humans and non-human vertebrates, such as wild animals, livestock, and farm animals. Therefore, as used herein, the term “mammal” means rodents (i.e., mice, rats, or guinea pigs), monkeys, cats, dogs, cattle, horses, pigs, or humans. In some embodiments, the mammal is a human.

[0020] As used herein, the term “contact” means bringing together two elements in an in vitro or in vivo system. For example, “contact” a therapeutic compound with an individual or patient or cells includes administering the compound or composition to an individual or patient such as a human, and introducing the compound into a sample containing, for example, a cell preparation or purified preparation containing a target.

[0021] As used herein, the terms “comprising” (and any form of “comprising,” e.g., “comprise,” “comprises,” and “comprised”), “having” (and any form of “having,” e.g., “have” and “has”), “including” (and any form of “including,” e.g., “includes” and “include”), or “containing” (and any form of “containing,” e.g., “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unenumerated elements or method steps. Any composition or method that enumerates the term “containing” should also be understood to describe a composition that consists of, or is essentially composed of, any of the enumerated components or elements.

[0022] As used herein, the terms “fused” or “linked” mean that, when used in reference to proteins or molecules having different domains or heterologous sequences, the protein domains are part of the same peptide chain, connected to one another by either peptide bonds or other covalent bonds. Domains or sections may be directly linked or fused to one another, or another domain or peptide sequence may lie between two domains or sequences, and such sequences would still be considered fused or linked to one another.

[0023] As used herein, the terms “individual,” “subject,” or “patient” can be used interchangeably to mean any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates such as humans.

[0024] As used herein, the term “inhibit” means a reduction in the resulting symptoms or activity compared to the activity or results in the absence of the compound whose activity or activity is to be inhibited. In some embodiments, the resulting symptoms or activity are inhibited by about or at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%. The resulting symptoms or activity may also be inhibited if it is completely eliminated or absent.

[0025] As used herein, the phrase “needs” means that the subject has been identified as having a need for a particular method or treatment. In some embodiments, identification may be by any means of diagnosis. In some embodiments, the subject may require any of the methods and treatments described herein. In some embodiments, the subject is in or moves into an environment where a particular disease, disorder, or condition is prevalent.

[0026] As used herein, the phrase "an integer from X to Y" means any integer including the endpoint. For example, the phrase "an integer from 1 to 5" means 1, 2, 3, 4, or 5.

[0027] As used herein, the phrase “ophthalmologically acceptable” means that it does not cause any lasting adverse effects on the treated eye or its function, or on the general health of the object being treated. However, transient effects such as mild irritation or a “stinging” sensation are common with topical ophthalmic administration of drugs, and it is recognized that the presence of such transient effects is not inconsistent with the composition, formulation, or component (e.g., excipient) being “ophthalmologically acceptable” as defined herein. In some embodiments, a pharmaceutical composition may be ophthalmologically acceptable or suitable for ophthalmic administration.

[0028] As used herein, the term "position" means a location within the sequence of a polypeptide. Positions may be numbered sequentially or may be numbered by a numbering system based on an established format, such as, but not limited to, the EU index, or the Kabat amino acid positions for an antibody or Fc domain.

[0029] In some embodiments, the term "therapeutic molecule" can be used interchangeably with "therapeutic compound", "molecule", or "therapeutic agent" and refers to any polypeptide or protein described herein.

[0030] "Specific binding" or "specifically binds to" or "specific for" a particular antigen, target, or epitope means a binding that is measurably different from non-specific interactions. Specific binding can be measured, for example, by determining the binding of a molecule compared to the binding of a control molecule that is a molecule of similar structure that generally does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target.

[0031] Specific binding to a particular antigen, target, or epitope can be, for example, at least about 10 -4M , at least about 10 -5M , at least about 10 -6M , at least about 10 -7M , at least about 10 -8M , at least about 10 -9M , alternatively at least about 10 -10M , at least about 10 -11M , at least about 10 -12M , or greater K D and can be demonstrated by an antibody having a K DK is the dissociation rate of a specific antibody-target interaction. Typically, an antibody that specifically binds to an antigen or target has a K that is 2, 4, 5, 10, 20, 50, 100, 500, 1000, 5,000, 10,000 or more greater than the control molecule compared to the antigen or epitope, or at least 2, 4, 5, 10, 20, 50, 100, 500, 1000, 5,000, 10,000 or more greater than the K D It has.

[0032] In some embodiments, specific binding to a particular antigen, target, or epitope is, for example, at least 2 times, 4 times, 5 times, 20 times, 50 times, 100 times, 500 times, 1000 times, 5,000 times, 10,000 times, or more than 2 times, 4 times, 5 times, 20 times, 50 times, 1000 times, 10,000 times, or more than 10,000 times greater than the control for the target, antigen, or epitope. A or K a This can be shown by an antibody containing K A or K a This refers to the association rate of a specific antibody-antigen interaction.

[0033] As provided herein, the compounds and compositions provided herein can be used in the therapeutic methods provided herein. Where used herein, the terms “to treat,” “to be treated,” or “to treat” mean both therapeutic and prophylactic measures whose purpose is to slow (reduce) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical outcome. For the purposes of these embodiments, beneficial or desired clinical outcomes include, but are not limited to, relief of symptoms; reduction of the degree of a condition, disorder, or disease; stabilization (i.e., no worsening) of the condition, disorder, or disease; delay of onset or slowing of the progression of a condition, disorder, or disease; mitigation or remission (whether partial or whole) of the condition, disorder, or disease, whether detectable or undetectable; improvement of at least one measurable physical parameter, which is not necessarily identifiable by the patient; or improvement or mitigation of a condition, disorder, or disease. Treatment includes inducing a clinically significant response without excessive levels of side effects. Treatment also includes, where applicable to a particular disease, extending survival compared to expected survival without treatment. Therefore, “treatment of an autoimmune condition” or “treating autoimmunity” means, when used in conjunction with the condition to which the terms “treat,” “be treated,” or “treat” apply, any action that reduces or alleviates any of the primary or secondary symptoms associated with any other condition of the autoimmune condition described herein.

[0034] As used herein, the terms “variant,” “molecule,” “therapeutic,” “therapeutic compound,” “compound,” “polypeptide,” or “protein” may be used interchangeably with respect to the variants, molecules, therapeutics, therapeutic compounds, compounds, polypeptides, and proteins disclosed herein.

[0035] This specification provides compounds, such as antibodies, polypeptides, or fusion proteins, that can be used as therapeutic agents comprising two or more effector domains that bind to at least two different immune cell types. In some embodiments, the compound comprises two, three, or four effector domains, e.g., inhibitory receptor effector domains. In some embodiments, the compound binds to at least two different cell surface receptor molecules, at least one of which is on two different cell types. In some embodiments, the compound may comprise three effector domains, at least two of which may be inhibitory receptor effector domains, binding to different cell surface receptors, but at least two of which bind to different cell surface receptors on the same cell or cell type. For example, a polypeptide may include an inhibitory receptor effector domain that binds to PD-1 and a second inhibitory receptor effector domain that binds to LAG-3. The interaction of these domains with PD-1 and LAG-3 may, for example, be on the same cell or it may be on the same cell type, but PD-1 and LAG-3 are on different cells. In some embodiments, effector domains can modulate the activity of the cell to which they bind by modulating the activity of the cell surface receptor to which they bind. In some embodiments, each effector domain independently agonizes the activity of the molecule to which it binds. In some embodiments, each effector domain independently antagonizes the activity of the molecule to which it binds.

[0036] Without being constrained by any particular theory, by binding to two different cells simultaneously, nearly simultaneously, or in the same local environment, the effector domains, the compounds provided herein, can modulate cell-mediated immunity controlled by those cells. In some embodiments, the immune response is suppressed. In some embodiments, the immune response is activated. When the immune response is suppressed, the polypeptide can be used to treat autoimmune diseases or conditions, such as those provided herein. When the immune response is activated, the polypeptide can be used to treat cancer or other proliferative disorders, such as those provided herein.

[0037] Methods for using and preparing the compounds are also provided.

[0038] In some embodiments, polypeptides comprising a) an inhibitory receptor effector domain, b) an Fc domain, and c) an FcγRII-binding effector domain are provided. In some embodiments, polypeptides comprising a) an inhibitory receptor effector domain and b) an Fc domain are provided. In some embodiments, polypeptides comprising a) an inhibitory receptor effector domain and b) an FcγRII-binding effector domain are provided. In some embodiments, polypeptides comprising a) an inhibitory receptor effector domain, b) an Fc domain, and c) an FcγRII-binding effector domain are provided. In some embodiments, polypeptides comprising an inhibitory receptor effector domain and an FcγRII-binding effector domain, i.e., without an Fc domain, are provided. In some embodiments, polypeptides comprising multiple inhibitory receptor effector domains and Fc domains ligated to each inhibitory receptor effector domain are provided. The Fc polypeptides ligated to each inhibitory receptor effector domain may be the same or different. In some embodiments, polypeptides are provided that each comprises one, two, three, or four inhibitory receptor effector domains, each ligated to an Fc domain. The Fc polypeptides ligated to each inhibitory receptor effector domain may be the same or different. In some embodiments, the inhibitory receptor domains are ligated to the N-terminus and / or C-terminus of the Fc polypeptide. In some embodiments, each Fc domain has one or two inhibitory receptor domains ligated to the Fc polypeptide. In some embodiments, the Fc polypeptide has inhibitory effector domains ligated to the N-terminus and C-terminus of the Fc polypeptide. In some embodiments, the inhibitory effector domains bind to the same inhibitory receptor. In some embodiments, the inhibitory effector domains bind to different inhibitory receptors.

[0039] In some embodiments, the polypeptide comprises, from the N-terminus to the C-terminus, a) an inhibitory receptor effector domain, b) an Fc domain, and c) an FcγRII-binding effector domain.

[0040] In some embodiments, the polypeptide comprises an inhibitory receptor effector domain and an FcγRII-binding effector domain from the N-terminus to the C-terminus.

[0041] In some embodiments, the polypeptide comprises an a) inhibitory receptor effector domain and an Fc domain from the N-terminus to the C-terminus.

[0042] In each of the embodiments provided herein, the domains can be linked to one another with or without an intervening peptide linker, such as in the non-limiting examples provided herein.

[0043] In some embodiments, the polypeptide comprises multiple inhibitory receptor effector domains that can bind to either the same inhibitory receptor or two different inhibitory receptors. As provided herein, in some embodiments, the polypeptide comprises two inhibitory receptor effector domains that bind to the same or different inhibitory receptors.

[0044] As used herein, the term “suppressive receptor effector domain” refers to a polypeptide, such as an antibody, that binds to suppressive receptors present on immune cells, such as T cells, but is not limited to this definition. In some embodiments, the T cells are activated T cells. In some embodiments, the T cells are not activated. In some embodiments, the polypeptide comprises one or more suppressive receptor effector domains. In some embodiments, the polypeptide comprises two, three, or four suppressive receptor effector domains. In some embodiments, the suppressive receptor effector domains bind to the same suppressive receptor. In some embodiments, different suppressive receptor effector domains bind to different suppressive receptors. For example, if the polypeptide comprises two suppressive receptor effector domains that bind to different suppressive receptors, the first suppressive receptor effector domain may bind to the first suppressive receptor, and the second suppressive receptor effector domain may bind to a second suppressive receptor different from the first suppressive receptor. In some embodiments, the suppressive receptor effector domain is an antibody. In some embodiments, the antibody is a Fab-format antibody. In some embodiments, the antibody is an scFv antibody. In some embodiments, the antibody is an antibody as provided herein. In some embodiments, the polypeptide comprises an inhibitory receptor effector domain which is an antibody in Fab format, and an inhibitory receptor effector domain which is an scFv antibody.

[0045] In some embodiments, the antibody is bound to PD-1. In some embodiments, the polypeptide includes an Fc domain that selectively binds to FcγRIIβ. In some embodiments, the molecule includes an antibody that binds to PD-1 and includes an Fc domain that selectively binds to FcγRIIβ. Examples of each of these types of molecules are provided herein.

[0046] In some embodiments, the molecules provided herein include an antibody that selectively binds to FcγRIIβ. In some embodiments, the antibody that selectively binds to FcγRIIβ includes an Fc domain. The Fc domain may be an effectorless Fc domain, or it may include mutations that enable the Fc domain to selectively bind to FcγRIIβ as well. As used herein, with respect to an antibody that selectively binds to FcγRIIβ, the term “selectively binds to” means that the antibody preferentially binds to FcγRIIβ, i.e., has a higher affinity for FcγRIIβ compared to other Fcγ receptors such as FcγRIIα.

[0047] Additionally, in some embodiments, the molecule may include other domains that bind to other molecules or other molecules of interest. In some embodiments, the polypeptides are LAG3, PDCD1, BTLA / CD272, CD200R1, CD22 / Siglec2, CD300A, CD300LF / CD300F, CD33 / Siglec3, CD5, CD72, CEACAM1, CLEC12A, CLEC4A, CTLA4 / CD152, FCGR2B / CD32B, KIR, KLRB1 / CD161, KLRC1, KLRG1, LAIR1, LILRB1, LILRB2, LILRB4, LILRB5, NCR2 / NKp44, PECAM1 / CD31, PILRA, PVR / CD155, SIGLEC11, SIGLEC5, SIGLEC7, SIGLEC8, SIGLEC9, SIRPA, TIGIT, VSTM1 / SIRL1, Contains inhibitory receptor effector domains that also bind to MAFA, NKG2A, CMRF35H, CD66a, CD66d, CD33, SIGLEC6, ILT2, 3, 4, 5, LIR8, KIR2DL, KIR2DL1, KIR3DL, SIRPa, KIR2DL2 / 3, KIR2DL5, KIRDL1, KIRDL2, KIRDL3, TIM3, Tactile, IRp60, NKRP1, IAP, PIR-B, CD5, 2B4, GP49B, Ly49Q, MICL, CD160, FCRL4, KIR3DL1, KIR2DL2, LILRB3, DCIR, NKRP-1D, LY49, MAIR-I, CD79a, CD79b, CD19, CD21, CD40, TLR3, CD28, CCR5, or CCR1.

[0048] In some embodiments, the other molecule is LAG3.

[0049] In some embodiments, the other molecule is an antibody that binds to FcγRIIβ. Therefore, the molecule may be bispecific or triplicately specific to different proteins such as PD-1, LAG3, and / or FcγRIIβ. Additionally, the molecule may include an Fc domain that specifically binds to FcγRIIβ, such as, but not limited to, those provided herein.

[0050] In some embodiments, the polypeptide comprises an inhibitory receptor effector domain that binds to PD-1 and a second inhibitory receptor that binds to LAG-3.

[0051] As used herein, “isotype” refers to an immunoglobulin class encoded by a heavy chain constant domain gene (e.g., IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE antibodies). The full-length amino acid sequences of each wild-type human IgG constant region (including all domains, i.e., the CH1 domain, hinge, CH2 domain, and CH3 domain) are cataloged in the UniProt database, which is available online, as, for example, P01857(IgG1), P01859(IgG2), P01860(IgG3), and P01861(IgG4), or their different allotypes (SEQ ID NOs. 1, 2, 3, and 4, respectively). As used herein, a domain in the heavy chain constant region, for example, a hinge, is of the "IgG1 isotype," "IgG2 isotype," "IgG3 isotype," or "IgG4 isotype" if the domain contains the amino acid sequence or a variant thereof of the corresponding domain of the respective isotype (having higher homology to the corresponding domain of the respective isotype than that of other isotypes).

[0052] "Allotype" refers to a naturally occurring variant within a particular isotype group, which differs in several amino acids (see, for example, Jefferies et al. (2009) mAbs 1:1). The molecules described herein may be of any allotype.

[0053] A "wild-type" protein or portion thereof is the naturally occurring version of the protein. The amino acid sequence of a wild-type protein, for example, the heavy chain constant region, is the amino acid sequence of a naturally occurring protein. Due to allotyping differences, there may be more than one amino acid sequence for a wild-type protein. For example, there are several allotypes of the naturally occurring human IGg1 heavy chain constant region (e.g., Jeffries et al. (2009) mAbs 1:1).

[0054] Immunoglobulins may be from any of the generally known isotypes, including but not limited to IgA, secretory IgA, IgG, and IgM. IgG isotypes are divided into subclasses in certain species: IgG1, IgG2, IgG3, and IgG4 in humans, and IgG1, IgG2a, IgG2b, and IgG3 in mice. In certain embodiments, the antibodies described herein are of the human IgG1 or IgG2 subtype. Immunoglobulins, such as human IgG1, exist in several allotypes that differ from each other in at most a few amino acids.

[0055] In some embodiments, the IgG protein (with the hinge region underlined) is as provided in Table 1. [Table 1]

[0056] The terms "Fc polypeptide" (fragment crystallizable region), "Fc domain," "Fc," or "constant domain," or "antibody" refer to the C-terminal region of the antibody heavy chain that mediates the binding of immunoglobulins to host tissues or factors, including binding to Fc receptors located on various cells of the immune system (e.g., effector cells) or to the first component (C1q) of the classical complement system. Therefore, the Fc polypeptide of an antibody of isotype IgG includes the constant region of the antibody's heavy chain, excluding the first constant-region immunoglobulin domain (CH1). In IgG, IgA, and IgD antibody isotypes, the Fc polypeptide contains CH2 and CH3 constant domains in each of the two heavy chains of the antibody, while IgM and IgE Fc polypeptides contain three heavy chain constant domains (CH domains 2-4) in each polypeptide chain. In the case of IgG, the Fc polypeptide contains an immunoglobulin domain consisting of a hinge, CH2, and CH3. For the purposes of this specification, an Fc polypeptide is defined as one beginning at amino acid 216 and ending at amino acid 447, numbered according to the EU index, as in Kabat, Kabat et al. (1991) Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, MD, and as shown in Figures 3c–3f of U.S. Patent Application Publication No. 2008 / 0248028. The “EU index” may also be referred to as the “EU numbering.” In some embodiments, the Fc polypeptide includes a hinge region. Fc may be a natural (or naturally occurring or wild-type) Fc containing any allotype variant, or a variant Fc (e.g., a naturally non-natural Fc) containing, for example, 1, 2, 3, 4, 5, 1–5, 1–10, or 5–10 or more amino acid mutations, e.g., substitutions, additions, or deletions. For example, variant Fc may contain an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to wild-type Fc. Modified or mutated Fc may have improved or reduced effector function and / or half-life.In isolation, or in the context of protein polypeptides containing Fc, such as "binding proteins containing Fc polypeptides" (e.g., antibodies or immunoadhesins), also referred to as "Fc fusion proteins," Fc may refer to this region. In some embodiments, modified or variant Fc molecules have improved binding to FcγRIIβ.

[0057] The terms "hinge," "hinge domain," "hinge region," or "antibody hinge region" refer to the domain of the heavy chain constant region that binds the CH1 domain to the CH2 domain, including the upper, middle, and lower parts of the hinge (Roux et al. J.Immunol. 1998 161:4083). The hinge provides varying levels of flexibility between the antibody binding region and the effector region, and also provides a site for intermolecular disulfide bonding between the two heavy chain constant regions. The term "hinge" includes the wild-type hinge (as listed in Table 2, for example) and its variants (e.g., hinges that do not exist naturally or modified hinges). For example, the term "IgG1 hinge" includes the wild-type IgG1 hinge as shown below, as well as variants with 1, 2, 3, 4, 5, 1-3, 1-5, 3-5, and / or up to 5, 4, 3, 2, or 1 mutation, e.g., substitution, deletion, or addition. In some embodiments, the hinge region is as provided in Table 2. [Table 2]

[0058] The term "CH1 domain" refers to the heavy chain constant region that links the variable domain to a hinge within the heavy chain constant domain. As used herein, the CH1 domain includes the wild-type CH1 domain and its variants (e.g., CH1 domains or modified CH1 domains that do not exist in nature). As used herein, the CH1 domain includes amino acid residues 1-98 of IgG1, 1-98 of IgG2, 1-98 of IgG3, and 1-98 of IgG4. For example, the term "CH1 domain" includes the wild-type CH1 domain and its variants having 1, 2, 3, 4, 5, 1-3, 1-5, 3-5, and / or up to 5, 4, 3, 2, or 1 mutation, e.g., substitution, deletion, or addition.

[0059] The term "CH2 domain" refers to the heavy chain constant region that hinges the CH3 domain within the heavy chain constant domain. As used herein, the CH2 domain includes the wild-type CH2 domain and its variants (e.g., CH2 domains or modified CH2 domains that do not exist in nature). As used herein, the CH2 domain includes amino acid residues 111-223 of IgG1, 111-219 of IgG2, 161-270 of IgG3, and 111-220 of IgG4. For example, the term "CH2 domain" includes the wild-type CH2 domain and its variants having 1, 2, 3, 4, 5, 1-3, 1-5, 3-5, and / or up to 5, 4, 3, 2, or 1 mutation, e.g., substitution, deletion, or addition.

[0060] The term "CH3 domain" refers to the heavy chain constant region at the C-terminus of the CH2 domain within the heavy chain constant domain. As used herein, the CH3 domain includes the wild-type CH3 domain and its variants (e.g., CH3 domains or modified CH3 domains that do not exist naturally). As used herein, the CH3 domain includes amino acid residues 224-330 of IgG1, 220-326 of IgG2, 271-376 of IgG3, and 226-322 of IgG4. For example, the term "CH3 domain" includes the wild-type CH3 domain and its variants having 1, 2, 3, 4, 5, 1-3, 1-5, 3-5, and / or up to 5, 4, 3, 2, or 1 mutation, e.g., substitution, deletion, or addition.

[0061] In some embodiments, the hinge / CH2 domain has an amino acid sequence such as that provided in Table 3 below. [Table 3]

[0062] Without being bound by any particular theory, mutations or isotype swapping of the entire hinge region or CH2 region, or a specific portion of the hinge region or CH2 region, in IgG1 result in modified IgG1 having improved or altered properties compared to IgG1 having the wild-type IgG1 constant region. For example, IgG1 may have residues 111-223 replaced by residues 111-220 of IgG4. Other non-limiting examples include IgG1 having at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% of residues 111-223 replaced by at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% of residues 111-223 of IgG4.

[0063] In some embodiments, the variant Fc molecule is a hybrid Fc molecule containing sequences from at least two IgG isotypes. For example, the variant Fc molecule may contain CH2 or CH3 regions from one or more other isotypes. For instance, the variant Fc can be an IgG1 / IgG4 Fc molecule.

[0064] In some embodiments, variant Fc includes a CH2 region swapped from another IgG isotype. An example of a CH2 region is: SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA (IgG1 CH2, SEQ ID NO: 528), or Examples include, but are not limited to, SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKA (IgG4 CH2, SEQ ID NO: 529).

[0065] This specification provides variant Fc molecules containing a variant Fc domain. Exemplary variant Fc molecules containing a variant Fc domain include an IgG1 hinge, a CH1 domain, a CH2 domain, and a CH3 domain, wherein at least one amino acid residue is mutated, and the mutation is a substitution, insertion, or deletion. In some embodiments, the insertion can be 1 to 5 residues. In some embodiments, the variant Fc molecule includes an IgG1 hinge and an IgG4 CH2 domain. In some embodiments, the variant Fc molecule includes a mutated variant IgG1 hinge and an IgG4 CH2 domain. Variant Fc molecules may have effector function similar to that of wild-type IgG, or may be manipulated to have improved effector function compared to that of wild-type IgG. In some embodiments, the variant Fc molecule may have FcγRIIβ binding affinity similar to that of wild-type IgG. In some embodiments, the variant Fc molecule may have FcγRIIβ binding affinity improved to that of wild-type IgG. The variant Fc molecule may contain wild-type CH1, hinge, CH2, and / or CH3 domains, or variants thereof, for example, having one or more amino acid substitutions, deletions, or additions compared to the corresponding wild-type domain, and / or having an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical or better to the corresponding wild-type sequence.

[0066] In some embodiments, the variant Fc molecule includes a mutation that confers selective binding to FcγRIIβ rather than FcγRIIα. As used herein, the term “selective binding” with respect to FcγRIIβ means that the Fc polypeptide preferentially binds to FcγRIIβ rather than FcγRIIα, i.e., has a higher affinity for FcγRIIβ than for FcγRIIα. Examples of such mutations are provided, for example, in US7662926, US7655229, US2009 / 0087428, US10919952, US2007 / 0253948, and US2006 / 0073142, each of which includes the described specific mutations affecting FcγRIIβ binding, and which are incorporated herein by reference in their entirety. In some embodiments, the mutations are as described in Shields et al., J. Biol. Chem. 2001, 276:6591-6604, which are incorporated herein by reference in their entirety.

[0067] In some embodiments, the polypeptide includes an Fc domain as an effector domain for modulating the response to the polypeptide of interest, which may include a bifunctional antibody (two antigen-binding domains that bind to the same or different targets provided herein). In some embodiments, the Fc polypeptide includes a mutation that selectively binds to FcγRIIb. In some embodiments, the Fc polypeptide includes a mutation that selectively binds to FcγRIIb rather than FcγRIIa. As used herein, the term “selectively binds to” with respect to FcγRIIb means that the Fc polypeptide preferentially binds to FcγRIIb, i.e., has a higher affinity for FcγRIIb compared to other Fcγ receptors such as FcγRIIα. Examples of such mutations are provided, for example, in US7662926, US7655229, US2009 / 0087428, US2007 / 0253948, and US2006 / 0073142, each of which includes described specific mutations affecting FcγRIIb or FcγRIIa binding, and which are incorporated herein by reference in their entirety. In some embodiments, the mutations are as described in Shields et al., J. Biol. Chem. 2001, 276:6591-6604, which includes described specific mutations affecting FcγRIIb or FcγRIIa binding, and which are incorporated herein by reference in their entirety. In some embodiments, the mutations in the Fc polypeptide are at positions S298, E333, or K334, or any combination thereof (numbered according to EU numbering). In some embodiments, the Fc polypeptide includes mutations corresponding to S298A, E333A, or K334A, or any combination thereof. In some embodiments, the Fc polypeptide includes mutations of S298A, E333A, and K334A. In some embodiments, the mutations correspond to G236A, I332E, G236A, S239D, or I332E, or any combination thereof. In some embodiments, the Fc polypeptide includes mutations of G236A, I332E, G236A, S239D, and I332E.Mutations can also be as provided in Richards et al., Mol Cancer Ther 2008;7(8). August 2008, which includes described specific mutations affecting FcγRIIb or FcγRIIa binding, and are incorporated herein by reference in their entirety. In some embodiments, the Fc polypeptide includes N235S or L328F mutations. In some embodiments, the Fc polypeptide includes N235S and L328F mutations. Mutations can also be as provided in Shang et al., The Journal of Biological Chemistry VOL.289, NO.22, pp.15309-15318, May 30, 2014, which includes described specific mutations affecting FcγRIIb or FcγRIIa binding, and are incorporated herein by reference in their entirety.

[0068] In some embodiments, the Fc variant is U.S. Patent No. 10,618,965; EP serial number 2679681; EP serial number 3604330, U.S. 2014 / 0093496, U.S. 2015 / 0203577, U.S. Patent No. 9,540,451; EP serial number 2331578; EP serial number 3190128; U.S. Patent No. 9,902,773; EP serial number 3342782, U.S. Publication No. 2020 / 0332024; EP serial number 2796469; EP serial number 2331578; EP serial number 3190128; U.S. Patent No. 9,902,773; EP serial number 2331578; EP serial Such as those described in AL number 3190128, U.S. Patent No. 9,493,578, U.S. Patent No. 9,394,366, U.S. Patent No. 9,914,778, EP serial number 2940043, U.S. 9,890,218, EP serial number 2940135; U.S. Patent No. 10,766,960, U.S. Patent No. 10,919,953, EP3721900, EP2889377, U.S. 2016 / 0039912, EP2982689, or EP3783017, each of which includes described specific mutations affecting FcγRIIb or FcγRIIa binding, are incorporated herein by reference in their entirety.

[0069] In some embodiments, the Fc polypeptide includes mutations, mutations, or sets of mutations that increase selectivity for FcγRIIb. In some embodiments, the Fc polypeptide includes mutations, mutations, or sets of mutations that increase affinity for FcγRIIb. In some embodiments, the Fc polypeptide includes mutations, mutations, or sets of mutations that increase selectivity and affinity for FcγRIIb. In some embodiments, the Fc polypeptide includes mutations, mutations, or sets of mutations that increase selectivity for FcγRIIb compared to FcγRIIa. In some embodiments, the Fc polypeptide includes mutations, mutations, or sets of mutations that increase affinity for FcγRIIb compared to FcγRIIa. In some embodiments, the Fc polypeptide includes mutations, mutations, or sets of mutations that increase selectivity and affinity for FcγRIIb compared to FcγRIIa. In some embodiments, the mutations, mutations, or sets of mutations are those described herein.

[0070] In some embodiments, the Fc polypeptide is G237E and P238E; P238D; P238D and E233D; P238D and L234W; P238D and L234Y; P238D and G237W; P238D and G237F; P238D and G237A; P238D and G237D; P238D and G237E; P238D and G237L; P238D and G237M; P238D and G237Y; P238D and S239D; P238D and S267V; P238D and S267Q; P238D and S26 7A;P238D and H268N;P238D and H268D;P238D and H268E;P238D and P271G;P238D and Y296D;P238D and V323I;P238D and V323L;P238D and V323M;P238D and K326L;P238D and K326Q;P238D and K326E;P238D and K326M;P238D and K326D;P238D and K326S;P238D and K326T;P238D and K326A;P238D and K326N;P238D and L328E; P238D and A330K; P238D and A330R; P238D and A330M; S239P; S239P and P230E; S239P and A231D; S239P and P232E; S239P and P238E; S239P, P230E and A231D; S239P, P230E and P232E; S239P, P230E and P238E; S239P, P230E, A231D and P232E; S239P, P230E, A231D and P238E; S239P, P230E, A231D, P232E and P 238E;S239P, A231D and P232E;S239P, A231D and P238E;S239P, A231D, P232E and P238E;S239P, P232E and P238E;S267E;S267D;S267E and L328F;G236D and S267E;S239D and S267E;S239D and I332E;K409E;L368K;S364D and K370G;S364Y and K370R;S364D;Y349K;K409D;K392E;D399K;S364E;L368E and K409E;S364E and F405A; Y349K and T394F; S364H and Y349K; P395T, V397S and F405A; T394F; T394S, P395V, P396T, V397E and F405S; V397S and F405A; S364H, D401K and F405A; Y349T, T394F and T411E; L351K, S364H and D401K; Y349T, L351E and T411E; S364H; Y349T; S364H and D401K; Y349T and T411E; S364H and T394F; Y349T and F405A; S364H and F405A; Y349T and T394F; F405A; S364E and T394F; Y349K and F405A; V397T and F405S; S364E and F405S; Y349K and T394Y; S364E, T411E and F405A; Y349K, T394F and D401K; S364E and T411E; Y349K and D401K; L351E and S364D; Y349K and L351K; L351E and S364E; Y349C and S 364E;Y349K and S354C;S364H, F405A and T411E;Y349T, T394F and D401K;S364D and T394F;L235Y;L235R;G236D;L328F;L235Y, G236D, S267D and L328F;L235Y, G236D and S267D;L235Y, G236D and S267E;L235Y and G236D;L235Y, S267D and L328F;L235Y, S267E and L328F;L235Y and L328F;L235R, G236D , S267D and L328F; L235R, G236D and S267D; L235R, G236D and S267E; L235R and G236D; L235R, S267D and L328F; L235R, S267E and L328F; L235R and L328F; G236D, S267E and L328F; G236D, S267D and L328F; G236D and L328F; S267D and L328F; G236N and S267E; G236N; L234Y, L235Y, G236W, H268D and S298A;L234Y, L235Y, G236W, H268D, D270E and S298A; L234Y, L235Q, G236W, S239M, H268D, D270E and S298A; L234Y, L235Y, G236W, H268D, S298A and A327D; L234Y, L235Y, G236W, S239M, H268D, S298A and A327D; L234Y, L235Y, G236W, S239M, H268D, S298A, A327D, L328W and K334L; Second IgG1 CH2 domain; K326D, A330M and K334E; D270E, K326D, A330M and K334E; D270E, K326D, A330K and K334E; L234E, L235Y, G236W, S239M, H268D, S298A and A327D; L234S, L235Y, G236W, S239M, H268D, S298A and A327D; L235Q, G236W, S239M, H268D, D270E and S298A; L235Y, G236W, S239M, H268D, S298A and A327D; L234 S, L235Q, G236W, S239M, H268D, D270E and S298A; L234F, L235Q, G236W, S239M, H268D, D270E and S298A; L234E, L235Q, G236W, S239M, H268D, D270E and S298A; L234F, L235Y, G236W, S239M, H268D, S298A and A327D; L234V, L235Q, G236W, S239M, H268D, D270E and S298A; L234D, L235Q, G236W, S239M, H268D, D2 70E and S298A; L234Q, L235Q, G236W, S239M, H268D, D270E and S298A; L234I, L235Q, G236W, S239M, H268D, D270E and S298A; L234M, L235Q, G236W, S239M, H268D, D270E and S298A; L234T, L235Q, G236W, S239M, H268D, D270E and S298A; L234A, L235Q, G236W, S239M, H268D, D270E and S298A; L234G, L235Q, G236 W, S239M, H268D, D270E and S298A; L234H, L235Q, G236W, S239M, H268D, D270E and S298A; L234V, L235Y, G236W, S239M, H268D, S298A and A327D; L234D, L235Y, G236W, S239M, H268D, S298A and A327D; L234Q, L235Y, G236W, S239M, H268D, S298A and A327D; L234I, L235Y, G236W, S239M, H268D, S298A and A327D;L234M, L235Y, G236W, S239M, H268D, S298A and A327D; L234T, L235Y, G236W, S239M, H268D, S298A and A327D; L234A, L235Y, G236W, S239M, H268D, S298A and A327D; L234G, L235Y, G236W, S239M, H268D, S298A and A327D; L234H, L235Y, G236W, S239M, H268D, S298A and A327D; L234F, L235Q, G236W, S 239I, H268D, D270E and S298A; L234E, L235Q, G236W, S239I, H268D, D270E and S298A; L234D, L235Q, G236W, S239I, H268D, D270E and S298A; L234V, L235Y, G236W, S239I, H268D, S298A and A327D; L234I and L235Y, G236W, S239I, H268D, S298A, A327D; L235Y, G236W, S239I, H268D, S298A, A327D; L2 34E, L235Y, G236W, S239I, H268D, S298A and A327D; L234D, L235Y, G236W, S239I, H268D, S298A and A327D; L234F, L235Y, G236W, S239I, H268D, S298A and A327D; L234T, L235Y, G236W, S239I, H268D, S298A and A327D; second polypeptide; D270E, K326D and K334E; D270E, K326D, A330F and K334E; D270E, K32 6D, A330I and K334E; D270E, K326D, A330Y and K334E; D270E, K326D, A330H and K334E; P238D, E233D, G237D, H268D, P271G, Y296D and A330R; P238D, G237D, H268D, P271G, Y296D and A330R; P238D, G237D, H268E, P271G, Y296D and A330R; P238D, E233D, G237D, H268D, P271G, Y296D, A330R and I332T;P238D, E233D, G237D, V264I, S267G, H268E, P271G and A330R; P238D, E233D, G237D, V264I, S267A, H268E, P271G and A330R; P238D, E233D, G237D, S267A, H268E, P271G, Y296D, A330R and I332T; P238D, G237D, S267A, H268E, P271G, Y296D, A330R and I332T; P238D, E233D, G237D, V264I, S267A, H268E and P271G; P238D, E233D, G237D, V264I, S267A, H268E, P271G, Y296D and A330R; P238D, E233D, G237D, V264I, S267A, H268E, P271G, Y296D, A330R and P396M; P238D, E233D, G237D, V264I, S267A, H268E, P271G, Y296D, A330R and P396L; P238D, G237D, V264I, S267A, H268E, P271G and A330R; P238D, G237 D, V264I, S267A, H268E, P271G, Y296D and A330R; P238D, V264I, S267A, H268E and P271G; P238D, V264I, S267A, H268E, P271G and Y296D; P238D, G237D, S267A, H268E, P271G, Y296D and A330R; P238D, G237D, S267G, H268E, P271G, Y296D and A330R; P238D, E233D, G237D, V264I, S267A, H268E, P271G, A3 30R and P396M; P238D, E233D, G237D, V264I, S267A, H268E, P271G, A330R and P396L; P238D, E233D, G237D, V264I, S267A, H268E, P271G, Y296D, A327G, A330R and P396M; P238D, E233D, G237D, V264I, S267A, H268E, P271G, E272D and Y296D; P238D, G237D, V264I, S267A, H268E, P271G, E272P and A330R; P238D, G237D, V264I, S267A, H268E, P271G, E272P, Y296D and A330R; P238D, E233D, V264I, S267A, H268E and P271G; P238D, G237D, S267E, H268D, P271G, Y296D and A330R; P238D, V264I, S267A, H268E, P271G, E272D and Y296D; P238D, E233D, V264I, S267A, H268E, P271G and Y296D; P238D, E233D, L234Y, L235F , G237D, V264I, D265E, V266F, S267A, H268D, E269D, P271G, E272D, K274Q, Y296D, K326A, A327G, A330K, P331S, I332K, E333K, K334R, R355A, D356E, L358M, P396A, K409R and Q419E; G237Q, P238D, F241M, Y296E, A330H and S324H; G237Q, P238D, F241M, H268P, Y296E and A330H; G237Q, P238D, L235F, F241M, Y2 96E and S324H; G237Q, P238D, L235F, F241M, H268P and Y296E; G237Q, P238D, F241M, H268P, Y296E and S324H; G237Q, P238D, L235F, F241M, H268P, Y296E and S324H; G237Q, P238D, L235F, F241M, Y296E, S324H and A330H; G237Q, P238D, L235F, F241M, H268P, Y296E and A330H; G237Q, P238D, F241M, H268P, Y296E , S324H and A330H; G237Q, P238D, E233D, V264I, S267R, H268P, P271G and Y296E; G237Q, P238D, F241M and Y296E; G237Q, P238D, F241M, Y296E and A330H; G237Q, P238D, L235F, F241M and Y296E; G237Q, P238D, L235F, F241M, Y296E and A330H; G237Q and P238D; P238D and F241M; P238D and F241L; P238D and H268P;P238D and Q295V; P238D and Y296E; P238D and Y296H; P238D and S298M; P238D and S324N; P238D and S324H; P238D and A330H; P238D and A330Y; P238D and F241M, H268P, Y296E and S324H; G237Q, P238D, F241M, Y296E and A330H; L235F, G237Q, P238D, F241M and Y296E; P238D, P271G and E233D; P238D, P271G and L234R; P238D, P271G and G237D; P238D, P271G and G237K; P238D, P271G and V264I; P238D, P271G and S267A; P238D, P271G and H268E; P238D, P271G and H268P; P238D, P271G and Y296D; P238D, P271G and Y296E; P238D, P271G, E233D, L234K, V264I, S267A and H268E; P238D, P271G, E233D, L234R, V264I, S26 7A and H268E; P238D, P271G, E233D, G237K, V264I, S267A and H268E; P238D, P271G, E233D, V264I, D265N, S267A and H268E; P238D, P271G, E233D, V264I, S267R and H268E; P238D, P271G, E233D, G237D, V264I, S267Y, H268E, Y296D, A330R and P396M; P238D, P271G, E233D, G237D, V264I, S267A, H268E, Y2 96D / Y296A, A330R and P396M; P238D, P271G, E233D, V264I, S267R, H268E and Y296E; P238D, P271G, E233D, V264I, S267R and H268P; P238D, P271G, E233D, F241M, V264I, S267R and H268E; P238D, P271G, E233D, V264I, S267R, H268P and Y296E; P238D, P271G, E233D, G237Q, V264I, S267R, H268P and Y296E;Includes the mutations, mutations, or mutation sets of E233D, G237D, P238D, H268D, P271G, and A330R.

[0071] In some embodiments, the Fc polypeptide includes mutations or variants of G237E and P238E. In some embodiments, the Fc polypeptide includes mutations or variants of P238D. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and E233D. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and L234W. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and L234Y. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and G237W. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and G237F. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and G237A. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and G237D. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and G237E. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and G237L. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and G237M. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and G237Y. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and S239D. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and S267V. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and S267Q. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and S267A. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and H268N. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and H268D. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and H268E. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and P271G.In some embodiments, the Fc polypeptide includes mutations or variants of P238D and Y296D. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and V323I. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and V323L. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and V323M. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and K326L. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and K326Q. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and K326E. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and K326M. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and K326D. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and K326S. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and K326T. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and K326A. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and K326N. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and L328E. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and A330K. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and A330R. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and A330M. In some embodiments, the Fc polypeptide includes mutations or variants of S239P. In some embodiments, the Fc polypeptide includes mutations or variants of S239P and P230E. In some embodiments, the Fc polypeptide includes S239P and A231D mutations or variants. In some embodiments, the Fc polypeptide includes S239P and P232E mutations or variants.In some embodiments, the Fc polypeptide includes mutations or variants of S239P and P238E. In some embodiments, the Fc polypeptide includes mutations or variants of S239P, P230E, and A231D. In some embodiments, the Fc polypeptide includes mutations or variants of S239P, P230E, and P232E. In some embodiments, the Fc polypeptide includes mutations or variants of S239P, P230E, and P238E. In some embodiments, the Fc polypeptide includes mutations or variants of S239P, P230E, A231D, and P232E. In some embodiments, the Fc polypeptide includes mutations or variants of S239P, P230E, A231D, and P238E. In some embodiments, the Fc polypeptide includes mutations or variants of S239P, P230E, A231D, P232E, and P238E. In some embodiments, the Fc polypeptide includes mutations or variants of S239P, A231D, and P232E. In some embodiments, the Fc polypeptide includes mutations or variants of S239P, A231D, and P238E. In some embodiments, the Fc polypeptide includes mutations or variants of S239P, A231D, P232E, and P238E. In some embodiments, the Fc polypeptide includes mutations or variants of S239P, P232E, and P238E. In some embodiments, the Fc polypeptide includes mutations of S267E. In some embodiments, the Fc polypeptide includes mutations of S267D. In some embodiments, the Fc polypeptide includes mutations or variants of S267E and L328F. In some embodiments, the Fc polypeptide includes mutations or variants of G236D and S267E. In some embodiments, the Fc polypeptide includes mutations or variants of S239D and S267E. In some embodiments, the Fc polypeptide includes the S239D and I332E mutations or variants. In some embodiments, the Fc polypeptide includes the K409E mutation. In some embodiments, the Fc polypeptide includes the L368K mutation. In some embodiments, the Fc polypeptide includes the S364D and K370G mutations or variants. In some embodiments, the Fc polypeptide includes the S364Y and K370R mutations or variants. In some embodiments, the Fc polypeptide includes the S364D mutation. In some embodiments, the Fc polypeptide includes the Y349K mutation. In some embodiments, the Fc polypeptide includes the K409D mutation. In some embodiments, the Fc polypeptide includes the K392E mutation. In some embodiments, the Fc polypeptide includes the D399K mutation. In some embodiments, the Fc polypeptide includes the S364E mutation. In some embodiments, the Fc polypeptide includes the L368E and K409E mutations or variants. In some embodiments, the Fc polypeptide includes mutations or variants of S364E and F405A. In some embodiments, the Fc polypeptide includes mutations or variants of Y349K and T394F.In some embodiments, the Fc polypeptide includes mutations or variants of S364H and Y349K. In some embodiments, the Fc polypeptide includes mutations or variants of P395T, V397S, and F405A. In some embodiments, the Fc polypeptide includes mutations or variants of T394F. In some embodiments, the Fc polypeptide includes mutations or variants of T394S, P395V, P396T, V397E, and F405S. In some embodiments, the Fc polypeptide includes mutations or variants of V397S and F405A. In some embodiments, the Fc polypeptide includes mutations or variants of S364H, D401K, and F405A. In some embodiments, the Fc polypeptide includes mutations or variants of Y349T, T394F, and T411E. In some embodiments, the Fc polypeptide includes mutations or variants of L351K, S364H, and D401K. In some embodiments, the Fc polypeptide includes mutations or variants of Y349T, L351E, and T411E. In some embodiments, the Fc polypeptide includes a mutation of S364H. In some embodiments, the Fc polypeptide includes a mutation of Y349T. In some embodiments, the Fc polypeptide includes mutations or variants of S364H and D401K. In some embodiments, the Fc polypeptide includes mutations or variants of Y349T and T411E. In some embodiments, the Fc polypeptide includes mutations or variants of S364H and T394F. In some embodiments, the Fc polypeptide includes mutations or variants of Y349T and F405A. In some embodiments, the Fc polypeptide includes mutations or variants of S364H and F405A. In some embodiments, the Fc polypeptide includes mutations or variants of Y349T and T394F. In some embodiments, the Fc polypeptide includes a mutation of F405A. In some embodiments, the Fc polypeptide includes mutations or variants of S364E and T394F. In some embodiments, the Fc polypeptide includes mutations or variants of Y349K and F405A. In some embodiments, the Fc polypeptide includes mutations or variants of V397T and F405S.In some embodiments, the Fc polypeptide includes mutations or variants of S364E and F405S. In some embodiments, the Fc polypeptide includes mutations or variants of Y349K and T394Y. In some embodiments, the Fc polypeptide includes mutations or variants of S364E, T411E, and F405A. In some embodiments, the Fc polypeptide includes mutations or variants of Y349K, T394F, and D401K. In some embodiments, the Fc polypeptide includes mutations or variants of S364E and T411E. In some embodiments, the Fc polypeptide includes mutations or variants of Y349K and D401K. In some embodiments, the Fc polypeptide includes mutations or variants of L351E and S364D. In some embodiments, the Fc polypeptide includes mutations or variants of Y349K and L351K. In some embodiments, the Fc polypeptide includes mutations or variants of L351E and S364E. In some embodiments, the Fc polypeptide includes mutations or variants of Y349C and S364E. In some embodiments, the Fc polypeptide includes mutations or variants of Y349K and S354C. In some embodiments, the Fc polypeptide includes mutations or variants of S364H, F405A, and T411E. In some embodiments, the Fc polypeptide includes mutations or variants of Y349T, T394F, and D401K. In some embodiments, the Fc polypeptide includes mutations or variants of S364D and T394F. In some embodiments, the Fc polypeptide includes the mutation of L235Y. In some embodiments, the Fc polypeptide includes the mutation of L235R. In some embodiments, the Fc polypeptide includes the mutation of G236D. In some embodiments, the Fc polypeptide includes the mutation of L328F. In some embodiments, the Fc polypeptide includes mutations or variants of L235Y, G236D, S267D, and L328F. In some embodiments, the Fc polypeptide includes mutations or variants of L235Y, G236D, and S267D. In some embodiments, the Fc polypeptide includes mutations or variants of L235Y, G236D, and S267E. In some embodiments, the Fc polypeptide includes mutations or variants of L235Y and G236D. In some embodiments, the Fc polypeptide includes mutations or variants of L235Y, S267D, and L328F. In some embodiments, the Fc polypeptide includes mutations or variants of L235Y, S267E, and L328F. In some embodiments, the Fc polypeptide includes mutations or variants of L235Y and L328F. In some embodiments, the Fc polypeptide includes mutations or variants of L235R, G236D, S267D, and L328F. In some embodiments, the Fc polypeptide includes mutations or variants of L235R, G236D, and S267D. In some embodiments, the Fc polypeptide includes mutations or variants of L235R, G236D, and S267E. In some embodiments, the Fc polypeptide includes mutations or variants of L235R and G236D. In some embodiments, the Fc polypeptide includes mutations or variants of L235R, S267D, and L328F.In some embodiments, the Fc polypeptide includes mutations or variants of L235R, S267E, and L328F. In some embodiments, the Fc polypeptide includes mutations or variants of L235R and L328F. In some embodiments, the Fc polypeptide includes mutations or variants of G236D, S267E, and L328F. In some embodiments, the Fc polypeptide includes mutations or variants of G236D, S267D, and L328F. In some embodiments, the Fc polypeptide includes mutations or variants of G236D and L328F. In some embodiments, the Fc polypeptide includes mutations or variants of S267D and L328F. In some embodiments, the Fc polypeptide includes mutations or variants of G236N and S267E. In some embodiments, the Fc polypeptide includes a mutation of G236N.

[0072] In some embodiments, the Fc polypeptide includes mutations or variants of L234Y, L235Y, G236W, H268D, and S298A. In some embodiments, the Fc polypeptide includes mutations or variants of L234Y, L235Y, G236W, H268D, D270E, and S298A. In some embodiments, the Fc polypeptide includes mutations or variants of L234Y, L235Q, G236W, S239M, H268D, D270E, and S298A. In some embodiments, the Fc polypeptide includes mutations or variants of L234Y, L235Y, G236W, H268D, S298A, and A327D. In some embodiments, the Fc polypeptide includes mutations or variants of L234Y, L235Y, G236W, S239M, H268D, S298A, and A327D. In some embodiments, the Fc polypeptide includes mutations or variants of L234Y, L235Y, G236W, S239M, H268D, S298A, A327D, L328W, and K334L. In some embodiments, the Fc polypeptide includes mutations or variants of a second IgG1 CH2 domain. In some embodiments, the Fc polypeptide includes mutations or variants of K326D, A330M, and K334E. In some embodiments, the Fc polypeptide includes mutations or variants of D270E, K326D, A330M, and K334E. In some embodiments, the Fc polypeptide includes mutations or variants of D270E, K326D, A330K, and K334E. In some embodiments, the Fc polypeptide includes mutations or variants of L234E, L235Y, G236W, S239M, H268D, S298A, and A327D. In some embodiments, the Fc polypeptide includes mutations or variants of L234S, L235Y, G236W, S239M, H268D, S298A, and A327D. In some embodiments, the Fc polypeptide includes mutations or variants of L235Q, G236W, S239M, H268D, D270E, and S298A. In some embodiments, the Fc polypeptide includes mutations or variants of L235Y, G236W, S239M, H268D, S298A, and A327D.In some embodiments, the Fc polypeptide includes mutations or variants of L234S, L235Q, G236W, S239M, H268D, D270E, and S298A. In some embodiments, the Fc polypeptide includes mutations or variants of L234F, L235Q, G236W, S239M, H268D, D270E, and S298A. In some embodiments, the Fc polypeptide includes mutations or variants of L234E, L235Q, G236W, S239M, H268D, D270E, and S298A. In some embodiments, the Fc polypeptide includes mutations or variants of L234F, L235Y, G236W, S239M, H268D, S298A, and A327D. In some embodiments, the Fc polypeptide includes mutations or variants of L234V, L235Q, G236W, S239M, H268D, D270E, and S298A. In some embodiments, the Fc polypeptide includes mutations or variants of L234D, L235Q, G236W, S239M, H268D, D270E, and S298A. In some embodiments, the Fc polypeptide includes mutations or variants of L234Q, L235Q, G236W, S239M, H268D, D270E, and S298A. In some embodiments, the Fc polypeptide includes mutations or variants of L234I, L235Q, G236W, S239M, H268D, D270E, and S298A. In some embodiments, the Fc polypeptide includes mutations or variants of L234M, L235Q, G236W, S239M, H268D, D270E, and S298A. In some embodiments, the Fc polypeptide includes mutations or variants of L234T, L235Q, G236W, S239M, H268D, D270E, and S298A. In some embodiments, the Fc polypeptide includes mutations or variants of L234A, L235Q, G236W, S239M, H268D, D270E, and S298A. In some embodiments, the Fc polypeptide includes mutations or variants of L234G, L235Q, G236W, S239M, H268D, D270E, and S298A.In some embodiments, the Fc polypeptide includes mutations or variants of L234H, L235Q, G236W, S239M, H268D, D270E, and S298A. In some embodiments, the Fc polypeptide includes mutations or variants of L234V, L235Y, G236W, S239M, H268D, S298A, and A327D. In some embodiments, the Fc polypeptide includes mutations or variants of L234D, L235Y, G236W, S239M, H268D, S298A, and A327D. In some embodiments, the Fc polypeptide includes mutations or variants of L234Q, L235Y, G236W, S239M, H268D, S298A, and A327D. In some embodiments, the Fc polypeptide includes mutations or variants of L234I, L235Y, G236W, S239M, H268D, S298A, and A327D. In some embodiments, the Fc polypeptide includes mutations or variants of L234M, L235Y, G236W, S239M, H268D, S298A, and A327D. In some embodiments, the Fc polypeptide includes mutations or variants of L234T, L235Y, G236W, S239M, H268D, S298A, and A327D. In some embodiments, the Fc polypeptide includes mutations or variants of L234A, L235Y, G236W, S239M, H268D, S298A, and A327D. In some embodiments, the Fc polypeptide includes mutations or variants of L234G, L235Y, G236W, S239M, H268D, S298A, and A327D. In some embodiments, the Fc polypeptide includes mutations or variants of L234H, L235Y, G236W, S239M, H268D, S298A, and A327D. In some embodiments, the Fc polypeptide includes mutations or variants of L234F, L235Q, G236W, S239I, H268D, D270E, and S298A. In some embodiments, the Fc polypeptide includes mutations or variants of L234E, L235Q, G236W, S239I, H268D, D270E, and S298A.In some embodiments, the Fc polypeptide includes mutations or variants of L234D, L235Q, G236W, S239I, H268D, D270E, and S298A. In some embodiments, the Fc polypeptide includes mutations or variants of L234V, L235Y, G236W, S239I, H268D, S298A, and A327D. In some embodiments, the Fc polypeptide includes mutations or variants of L234I and L235Y, G236W, S239I, H268D, S298A, and A327D. In some embodiments, the Fc polypeptide includes mutations or variants of L235Y, G236W, S239I, H268D, S298A, and A327D. In some embodiments, the Fc polypeptide includes mutations or variants of L234E, L235Y, G236W, S239I, H268D, S298A, and A327D. In some embodiments, the Fc polypeptide includes mutations or variants of L234D, L235Y, G236W, S239I, H268D, S298A, and A327D. In some embodiments, the Fc polypeptide includes mutations or variants of L234F, L235Y, G236W, S239I, H268D, S298A, and A327D. In some embodiments, the Fc polypeptide includes mutations or variants of L234T, L235Y, G236W, S239I, H268D, S298A, and A327D. In some embodiments, the Fc polypeptide includes mutations or variants of a second polypeptide. In some embodiments, the Fc polypeptide includes mutations or variants of D270E, K326D, and K334E. In some embodiments, the Fc polypeptide includes mutations or variants of D270E, K326D, A330F, and K334E. In some embodiments, the Fc polypeptide includes mutations or variants of D270E, K326D, A330I, and K334E. In some embodiments, the Fc polypeptide includes mutations or variants of D270E, K326D, A330Y, and K334E. In some embodiments, the Fc polypeptide includes mutations or variants of D270E, K326D, A330H, and K334E.

[0073] In some embodiments, the Fc polypeptide includes mutations or variants of P238D, E233D, G237D, H268D, P271G, Y296D, and A330R. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, G237D, H268D, P271G, Y296D, and A330R. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, G237D, H268E, P271G, Y296D, and A330R. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, E233D, G237D, H268D, P271G, Y296D, A330R, and I332T. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, E233D, G237D, V264I, S267G, H268E, P271G, and A330R. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, E233D, G237D, V264I, S267A, H268E, P271G, and A330R. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, E233D, G237D, S267A, H268E, P271G, Y296D, A330R, and I332T. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, G237D, S267A, H268E, P271G, Y296D, A330R, and I332T. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, E233D, G237D, V264I, S267A, H268E, and P271G. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, E233D, G237D, V264I, S267A, H268E, P271G, Y296D, and A330R. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, E233D, G237D, V264I, S267A, H268E, P271G, Y296D, A330R, and P396M.In some embodiments, the Fc polypeptide includes mutations or variants of P238D, E233D, G237D, V264I, S267A, H268E, P271G, Y296D, A330R, and P396L. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, G237D, V264I, S267A, H268E, P271G, and A330R. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, G237D, V264I, S267A, H268E, P271G, Y296D, and A330R. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, V264I, S267A, H268E, and P271G. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, V264I, S267A, H268E, P271G, and Y296D. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, G237D, S267A, H268E, P271G, Y296D, and A330R. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, G237D, S267G, H268E, P271G, Y296D, and A330R. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, E233D, G237D, V264I, S267A, H268E, P271G, A330R, and P396M. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, E233D, G237D, V264I, S267A, H268E, P271G, A330R, and P396L. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, E233D, G237D, V264I, S267A, H268E, P271G, Y296D, A327G, A330R, and P396M. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, E233D, G237D, V264I, S267A, H268E, P271G, E272D, and Y296D.In some embodiments, the Fc polypeptide includes mutations or variants of P238D, G237D, V264I, S267A, H268E, P271G, E272P, and A330R. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, G237D, V264I, S267A, H268E, P271G, E272P, Y296D, and A330R. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, E233D, V264I, S267A, H268E, and P271G. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, G237D, S267E, H268D, P271G, Y296D, and A330R. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, V264I, S267A, H268E, P271G, E272D, and Y296D. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, E233D, L234Y, L235F, G237D, V264I, D265E, V266F, S267A, H268D, E269D, P271G, E272D, K274Q, Y296D, K326A, A327G, A330K, P331S, I332K, E333K, K334R, R355A, D356E, L358M, P396A, K409R, and Q419E.

[0074] In some embodiments, the Fc polypeptide includes mutations or variants of G237Q, P238D, F241M, Y296E, A330H, and S324H. In some embodiments, the Fc polypeptide includes mutations or variants of G237Q, P238D, F241M, H268P, Y296E, and A330H. In some embodiments, the Fc polypeptide includes mutations or variants of G237Q, P238D, L235F, F241M, Y296E, and S324H. In some embodiments, the Fc polypeptide includes mutations or variants of G237Q, P238D, L235F, F241M, H268P, and Y296E. In some embodiments, the Fc polypeptide includes mutations or variants of G237Q, P238D, F241M, H268P, Y296E, and S324H. In some embodiments, the Fc polypeptide includes mutations or variants of G237Q, P238D, L235F, F241M, H268P, Y296E, and S324H. In some embodiments, the Fc polypeptide includes mutations or variants of G237Q, P238D, L235F, F241M, Y296E, S324H, and A330H. In some embodiments, the Fc polypeptide includes mutations or variants of G237Q, P238D, L235F, F241M, H268P, Y296E, and A330H. In some embodiments, the Fc polypeptide includes mutations or variants of G237Q, P238D, F241M, H268P, Y296E, S324H, and A330H. In some embodiments, the Fc polypeptide includes mutations or variants of G237Q, P238D, E233D, V264I, S267R, H268P, P271G, and Y296E. In some embodiments, the Fc polypeptide includes mutations or variants of G237Q, P238D, F241M, and Y296E. In some embodiments, the Fc polypeptide includes mutations or variants of G237Q, P238D, F241M, Y296E, and A330H. In some embodiments, the Fc polypeptide includes mutations or variants of G237Q, P238D, L235F, F241M, and Y296E.In some embodiments, the Fc polypeptide includes variants or mutations of G237Q, P238D, L235F, F241M, Y296E, and A330H.

[0075] In some embodiments, the Fc polypeptide includes mutations or variants of G237Q and P238D. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and F241M. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and F241L. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and H268P. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and Q295V. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and Y296E. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and Y296H. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and S298M. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and S324N. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and S324H. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and A330H. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and A330Y. In some embodiments, the Fc polypeptide includes mutations or variants of P238D and F241M, H268P, Y296E, and S324H. In some embodiments, the Fc polypeptide includes mutations or variants of G237Q, P238D, F241M, Y296E, and A330H. In some embodiments, the Fc polypeptide includes mutations or variants of L235F, G237Q, P238D, F241M, and Y296E.

[0076] In some embodiments, the Fc polypeptide includes mutations or variants of P238D, P271G, and E233D. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, P271G, and L234R. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, P271G, and G237D. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, P271G, and G237K. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, P271G, and V264I. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, P271G, and S267A. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, P271G, and H268E. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, P271G, and H268P. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, P271G, and Y296D. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, P271G, and Y296E. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, P271G, E233D, L234K, V264I, S267A, and H268E. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, P271G, E233D, L234R, V264I, S267A, and H268E. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, P271G, E233D, G237K, V264I, S267A, and H268E. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, P271G, E233D, V264I, D265N, S267A, and H268E. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, P271G, E233D, V264I, S267R, and H268E.In some embodiments, the Fc polypeptide includes mutations or variants of P238D, P271G, E233D, G237D, V264I, S267Y, H268E, Y296D, A330R, and P396M. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, P271G, E233D, G237D, V264I, S267A, H268E, Y296D / Y296A, A330R, and P396M. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, P271G, E233D, V264I, S267R, H268E, and Y296E. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, P271G, E233D, V264I, S267R, and H268P. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, P271G, E233D, F241M, V264I, S267R, and H268E. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, P271G, E233D, V264I, S267R, H268P, and Y296E. In some embodiments, the Fc polypeptide includes mutations or variants of P238D, P271G, E233D, G237Q, V264I, S267R, H268P, and Y296E. In some embodiments, the Fc polypeptide includes mutations or variants of E233D, G237D, P238D, H268D, P271G, and A330R.

[0077] In some embodiments, the Fc polypeptide comprises a polypeptide containing one or more mutations that confer selective binding to FcγRIIβ rather than FcγRIIα. In some embodiments, the Fc polypeptide comprises one or more mutations that improve selective binding to FcγRIIβ rather than FcγRIIα. In some embodiments, the Fc polypeptide comprises one or more mutations selected from mutations associated with any one of VFC-1 to VFC-89, as provided in Table 4 below, which are either listed in the table or immediately apparent when aligned to the amino acid sequence of SEQ ID NO: 516 by either BLASTP or Clustal Omega in the default settings. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11] [Table 4-12] Table 4-13 Table 4-14 Table 4-15 Table 4-16 Table 4-17 Table 4-18 Table 4-19 Table 4-20 Table 4-21 Table 4-22 Table 4-23 Table 4-24 Table 4-25

[0078] In some embodiments, Fc polypeptide is sequence numbers 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 434, 435, 436, 437, 438, 439, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 4 61, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 5 The amino acid sequence contains at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with any one of 01, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 543, 544, 545, 546, 683, 684, 685, 686, 687, 688, 689, and 690, provided that the Fc polypeptide contains mutations or variants to the reference sequence as listed in the above table (Table 4), or as immediately apparent by aligning SEQ ID NO: 516 with the reference sequence using BLASTP or Clustal Omega with default settings.

[0079] In some embodiments, the Fc polypeptide contains an amino acid sequence having at least 90-99% identity with the amino acids included in SEQ ID NO: 516 or SEQ ID NO: 543, provided that the Fc polypeptide contains the EU numbered G237E and P238E mutations.

[0080] In some embodiments, the Fc polypeptide contains an amino acid sequence having at least 90-99% identity with the amino acid sequence containing SEQ ID NO: 516, provided that the Fc polypeptide contains the EU-numbered P238D mutation.

[0081] In some embodiments, the Fc polypeptide includes Leu234Ala, Leu235Ala, and Gly237Ala (EU numbered), which are referred to as "AAA" mutations.

[0082] In some embodiments, the Fc polypeptide includes Leu234Ala and Leu235Ala (EU numbered), which are referred to as "LALA" mutations.

[0083] In some embodiments, the Fc polypeptide includes at least one mutation that extends the half-life of the Fc polypeptide. In some embodiments, the at least one mutation that extends the half-life of the Fc polypeptide is, but is not limited to, those known in the art, such as the M428L and N434S ("LS" mutations) or the M252Y, S254T, and T256E ("YTE" mutations) mutations. The extending mutation can be used in combination with or independently of other Fc mutations provided herein, such as those that provide selective binding to FcgRIIB, or impair the function of the Fc polypeptide, or make the Fc polypeptide effectorless, such as "AAA" or "LALA".

[0084] In some embodiments, Fc quantities are sequence numbers 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 431, 432, 433, 434, 435, 436, 437, 438, 439, 450, 451, 452, 453, 454, 455, 456, 457, 458 ,459,460,461,462,463,464,465,466,467,468,469,470,471,472,473,474,475,476,477,478,479,480,481,482,483,484,485,486,487,488,489,490,491,492,493,494,495,4 The amino acid sequence comprises one of 96, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 543, 544, 545, 546, 683, 684, 685, 686, 687, 688, 689, and 690 and has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity, and comprises a set of M428L and N434S mutations.In some embodiments, Fc quantities are sequence numbers 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 431, 432, 433, 434, 435, 436, 437, 438, 439, 450, 451, 452, 453, 454, 455, 456, 457, 458, 4 59, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 4 The amino acid sequence comprises an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with any one of 97, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 543, 544, 545, 546, 683, 684, 685, 686, 687, 688, 689, and 690, and comprises a set of M252Y, S254T, and T256E mutations.

[0085] In some embodiments, the Fc polypeptide comprises an amino acid sequence that is 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 SEQ ID NO: 543, provided that Fc contains the G237E and P238E mutations. In some embodiments, Fc further comprises the YTE or LS mutation.

[0086] In some embodiments, the Fc polypeptide comprises an amino acid sequence that is 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 SEQ ID NO: 516, provided that Fc contains the P238D mutation. In some embodiments, Fc further comprises the YTE or LS mutation.

[0087] In some embodiments, Fc polypeptide is sequence numbers 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 434, 435, 436, 437, 438, 439, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476 , contains an amino acid sequence selected from any one of the following: 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 543, 544, 545, 546, 683, 684, 685, 686, 687, 688, 689, and 690.

[0088] In some embodiments, the Fc polypeptide includes mutations that make the Fc polypeptide “effectorless,” preventing it from binding to the Fc receptor. Mutations that make an Fc polypeptide effectorless are known in the art, and any mutation or combination of mutations such as AAA and LALA (provided herein) can be used.

[0089] In some embodiments, mutations in the Fc polypeptide according to a known numbering system are selected from the group consisting of L234A, L235A, L234F, L235E, P329G, P331S, N297A, N297G, N297Q, G236A, A330S, S239D, I332E, S267E, H268F, S324T, Y296W, T299A, V308P, H310A, R409K, Y435H, T307A, T309A, T309K, K322A, K326W, K334W, K326A, K334A, G237A, P238S, H268A, or any combination thereof. In some embodiments, Fc includes mutations in L234 and / or L235 and / or G237. In some embodiments, Fc includes L234A and / or L235A mutations, which may be referred to as "LALA" mutations. In some embodiments, Fc includes L234A, L235A, and G237A mutations, which may be referred to as "LALAGA" or "AAA". In some embodiments, Fc includes L234F and L235E mutations, which may be referred to as "LAFE" mutations. In some embodiments, Fc includes L234A, L235A, and P329G mutations, which may be referred to as "LALAPG" mutations. In some embodiments, Fc includes L234A, L235A, P329G, and P331S mutations, which may be referred to as "LALAPGS" mutations. In some embodiments, Fc includes the L234A, L235A, and P329S mutations, which can be referred to as the "LALAPS" mutation. In some embodiments, Fc includes the N297A mutation. In some embodiments, Fc includes the N297G mutation. In some embodiments, Fc includes the N297Q mutation. In some embodiments, Fc includes the P329G mutation. In some embodiments, Fc includes the G236A, A330S, and P331S mutations, which can be referred to as the "GASDALIE" mutation. In some embodiments, Fc includes the S239D and I332E mutations, which can be referred to as the "SIE" mutation.In some embodiments, Fc includes the S267E, H268F, S324T, and I332E mutations, which can be referred to as the "SEHF_STIE" mutation. In some embodiments, Fc includes the Y296W, T299A, and V308P mutations, which can be referred to as the "YTEV" mutation. In some embodiments, Fc includes the H310A, R409K, and Y435H mutations, which can be referred to as the "HRY" mutation. In some embodiments, Fc includes the T307A and T309A mutations, which can be referred to as the "TATA" mutation. In some embodiments, Fc includes the T307A and T309K mutations, which can be referred to as the "TAKA" mutation. In some embodiments, Fc includes the K322A mutation. In some embodiments, Fc includes the K326W and K334W mutations, which can be referred to as the "WKWK" mutation. In some embodiments, Fc includes K326A and K334A mutations, which can be referred to as "AA" mutations. In some embodiments, Fc includes L234A, L235A, G237A, P238S, H268A, A330S, and P331S mutations.

[0090] The mutations and locations of Fc polypeptides, which can also be called Fc polypeptides, are determined by EU numbering.

[0091] As used herein, Fc polypeptides / domains containing mutations at specific positions are defined in a numbering system (EU numbering) as referenced herein, compared to wild-type Fc.

[0092] In some embodiments, the Fc polypeptide sequence includes an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the following: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (Sequence ID 513).

[0093] In some embodiments, the Fc polypeptide contains the amino acid sequence of SEQ ID NO: 513.

[0094] In some embodiments, the Fc polypeptide is ligated to an inhibitory receptor effector domain. In some embodiments, the Fc polypeptide is ligated to the C-terminus of the inhibitory receptor effector domain. In some embodiments, if the inhibitory receptor effector domain is an antibody, the Fc polypeptide is ligated to the C-terminus of the heavy chain of the antibody forming the inhibitory receptor effector domain. In some embodiments, the N-terminus of the Fc polypeptide is ligated to the C-terminus of the inhibitory receptor effector domain. In some embodiments, the Fc polypeptide is ligated directly to the inhibitory receptor effector domain, for example, without a linker sequence. In some embodiments, the Fc polypeptide is ligated to the inhibitory receptor effector domain through a linker, such as a peptide linker. In some embodiments, the linker is such as those provided herein.

[0095] Examples of peptide linkers that can be used are known in the art, and non-limiting examples are provided herein.

[0096] As used herein, the term “FcγRII-binding effector domain” refers to a polypeptide, such as an antibody, that binds to the FcγRII receptor. Examples of such receptors include the FcγRIIa or FcγRIIb receptors. In some embodiments, the FcγRII-binding effector domain is an antibody. In some embodiments, the FcγRII-binding effector domain is an scFv antibody. In some embodiments, the N-terminus of the FcγRII-binding effector domain is bound to the C-terminus of an Fc polypeptide. In some embodiments, the FcγRII-binding effector domain selectively binds to the FcγRIIb receptor. In some embodiments, the FcγRII-binding effector domain selectively binds to the FcγRIIb receptor than to the FcγRIIa receptor.

[0097] Where the term is used herein, an antibody molecule refers to a polypeptide, e.g., an immunoglobulin chain or a fragment thereof, comprising at least one functional immunoglobulin variable domain sequence. An antibody molecule encompasses antibodies (e.g., full-length antibodies) and antibody fragments. In some embodiments, an antibody molecule includes an antigen-binding or functional fragment of a full-length antibody, or a full-length immunoglobulin chain. For example, a full-length antibody is an immunoglobulin (Ig) molecule (e.g., an IgG antibody) that is naturally occurring or formed by a normal immunoglobulin gene fragment recombination process. In embodiments, an antibody molecule refers to an immunologically active antigen-binding portion of an immunoglobulin molecule, e.g., an antibody fragment. An antibody fragment, e.g., a functional fragment, includes portions of an antibody, e.g., Fab, Fab', F(ab')2, F(ab)2, a variable fragment (Fv), a domain antibody (dAb), or a single-stranded variable fragment (scFv). A functional antibody fragment binds to the same antigen recognized by an intact (e.g., full-length) antibody. The terms “antibody fragment” or “functional fragment” also include isolated fragments consisting of variable regions, such as an “Fv” fragment consisting of heavy and light chain variable regions, or recombinant single-chain polypeptide molecules (“scFv proteins”) in which light and heavy variable regions are linked by a peptide linker. In some embodiments, antibody fragments do not include portions of the antibody that do not have antigen-binding activity, such as Fc fragments or single amino acid residues. Exemplary antibody molecules include full-length antibodies and antibody fragments, e.g., dAb (domain antibodies), single-chain, Fab, Fab', and F(ab')2 fragments, as well as single-chain variable fragments (scFv).

[0098] The term "antibody molecule" can also be referred to as "sdAb" or "VHH," and includes whole antibodies, antigen-binding fragments of domain antibodies, or single-domain antibodies. Domain antibodies can act as single-type antibody fragments. H or V LIt includes one of the following. Additionally, domain antibodies include heavy chain-only antibodies (HCAb). Domain antibodies also include the CH2 domain of IgG as a basal scaffold to which the CDR loop is grafted. It can also be defined as a polypeptide or protein containing an amino acid sequence consisting of four framework regions interrupted by three complementarity-determining regions. This is represented as FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. sdAb can be produced in camelids such as llamas, but can also be produced synthetically using techniques well known in the art. The numbering of amino acid residues of sdAb or polypeptide follows the general numbering for the VH domain given by Kabat et al. ("Sequence of proteins of immunological interest," US Public Health Services, NIH Bethesda, MD, Publication No. 91, incorporated herein by reference). According to this numbering, sdAb FR1 contains amino acid residues at positions 1-30, sdAb CDR1 contains amino acid residues at positions 31-36, sdAb FR2 contains amino acids at positions 36-49, sdAb CDR2 contains amino acid residues at positions 50-65, sdAb FR3 contains amino acid residues at positions 66-94, sdAb CDR3 contains amino acid residues at positions 95-102, and sdAb FR4 contains amino acid residues at positions 103-113. Domain antibodies are also described in WO2004 / 041862 and WO2016 / 065323, each of which is incorporated herein by reference. Domain antibodies may be the targeting moieties described herein.

[0099] Antibody molecules can have single specificity (e.g., monovalent or bivalent), bivalent specificity (e.g., bivalent, trivalent, tetravalent, pentavalent, or hexavalent), triple specificity (e.g., trivalent, tetravalent, pentavalent, or hexavalent), or higher-order specificity (e.g., quadruple specificity) and / or higher-order valencies beyond hexavalent. Antibody molecules may contain functional fragments of the light chain variable region and functional fragments of the heavy chain variable region, or the heavy and light chains may be fused together into a single polypeptide. Where the term is used herein, an effector refers to an entity that mediates an immune response, such as a cell or molecule, such as a soluble or cell surface molecule. In some embodiments, the effector is an antibody. In some embodiments, an effector-binding domain, as provided herein, refers to a polypeptide (e.g.) having sufficient binding specificity to bind to an effector with sufficient specificity to function as an effector-binding / regulating molecule. In some embodiments, it binds to the effector with at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95% of the affinity of a naturally occurring counterligand. In some embodiments, it has at least 60, 70, 80, 90, 95, 99, or 100% sequence identity, or substantial sequence identity, with a naturally occurring counterligand for the effector.

[0100] When used herein, increased risk refers to the risk of disability in a subject who has one or more of the following: a medical history of disability or symptoms of disability, a biomarker associated with disability or symptoms of disability, or a family history of disability or symptoms of disability.

[0101] In some embodiments, the inhibitory effector binding domain can be referred to as an inhibitory immune checkpoint molecule. This can refer to a polypeptide that can bind to a checkpoint molecule and agonize its homologous inhibitory activity. For example, the antibody may be an anti-PD-1 antibody or its antigen-binding fragment that binds to PD-1 and agonizes the activity of PD-1. In some embodiments, the antibody inhibits inhibitory checkpoint activity, and as a result, it antagonizes the inhibitory activity. For example, the antibody may be an anti-PD-1 antibody or its antigen-binding fragment that binds to PD-1 and antagonizes the activity of PD-1. The same can be done if the target is one of the inhibitory receptors, such as those provided herein. In some embodiments, the inhibitory checkpoint receptor is LAG-3. In some embodiments, the inhibitory checkpoint receptor is one such as those provided herein. These are non-limiting examples, and other inhibitory checkpoint receptors can be agonized or antagonized as provided herein.

[0102] Inhibitory receptor agonism can be induced either by engagement with the innate ligand of the inhibitory receptor or via antibody crosslinking and higher-order clustering of inhibitory receptors. Therefore, immunohomeostasis may be restored by agonizing multiple inhibitory receptors (IRs) with a single antibody. While not wishing to be bound by a specific theory, IR agonism may modulate network interactions of multiple pathological immune cell types and thus restore immunohomeostasis in cell-mediated immune diseases. Agonizing inhibitory receptors with antibody molecules may require IR superclustering on the cell surface, which is not efficiently induced by Fc-null antibodies. For example, programmed cell death 1 (PD-1) is a negative costimulatory receptor essential for suppressing T cell activation both in vitro and in vivo. The study shows that when PD-1 interacts with its ligand, PD-L1, it forms clusters with the T cell receptor (TCR) and transiently associates with the phosphatase SHP2 (a tyrosine phosphatase containing the Src homology 2 domain). These inhibitory microclusters induce dephosphorylation of nearby TCR signaling molecules, resulting in the suppression of T cell activation (Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, Hashimoto-Tane A, Azuma M, Saito T. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med. 2012 Jun 4;209(6):1201-17. doi:10.1084 / jem.20112741. Epub 2012 May 28.PMID:22641383;PMCID:PMC3371732.) demonstrates this. Therefore, agonist antibody molecules may depend on simultaneous Fc (constant region) anchoring on antigen-presenting cells (APCs), thereby enabling efficient IR superclustering and downstream signaling.Agonist molecules targeting IR and containing IgG1 wild-type Fc bind to both activating and inhibitory Fc receptors, and therefore, as a result of binding to the activating Fc receptor, induce undesirable production of inflammatory cytokines by APCs. However, selective binding to FcγRIIβ (the only inhibitory Fc receptor) can prevent pro-inflammatory cytokine production and may also inhibit pathogenic B cell and APC activity.

[0103] Accordingly, in some embodiments, variant Fc polypeptides comprising a mutation or set of mutations that increase selectivity for the FcγRIIβ receptor are provided herein. In some embodiments, dimer molecules comprising variant Fc polypeptides comprising a mutation or set of mutations that increase selectivity for the FcγRIIβ receptor are provided herein. In some embodiments, the dimer molecule comprising variant Fc polypeptides comprising a mutation or set of mutations that increase selectivity for FcγRIIβ binds to one FcγRIIβ receptor. In some embodiments, the dimer molecule comprises a first variant Fc polypeptide comprising a mutation or set of mutations that increase selectivity for FcγRIIβ, and a second variant Fc polypeptide comprising a mutation or set of mutations that increase selectivity for FcγRIIβ. In some embodiments, the first variant Fc polypeptide and the second variant Fc polypeptide are identical so as to be homodimers with respect to the variant Fc polypeptide. In some embodiments, the first variant Fc polypeptide and the second variant Fc polypeptide are different so as to be heterodimers with respect to the variant Fc polypeptide. In some embodiments, a first variant Fc polypeptide containing a mutation or set of mutations that increases selectivity for FcγRIIβ, and a second variant Fc polypeptide containing a mutation or set of mutations that increases selectivity for FcγRIIβ, both bind to the same FcγRIIβ receptor. In some embodiments, the mutation or set of mutations that increases selectivity for FcγRIIβ may also affect antibody binding to the IR. In some embodiments, the mutation or set of mutations that increases selectivity for FcγRIIβ may also increase antibody binding to the IR. In some embodiments, the mutation or set of mutations that increases selectivity for FcγRIIβ may also decrease antibody binding to the IR. In some embodiments, the variant Fc polypeptide containing a mutation or set of mutations that increases selectivity for FcγRIIβ is conjugated or linked to an antibody.In some embodiments, a variant Fc polypeptide containing a mutation or set of mutations that increases selectivity for FcγRIIβ is conjugated or ligated to an agonist antibody. In some embodiments, a first variant Fc polypeptide containing a mutation or set of mutations that increases selectivity for FcγRIIβ is conjugated or ligated to an antibody. In some embodiments, a first variant Fc polypeptide containing a mutation or set of mutations that increases selectivity for FcγRIIβ is conjugated or ligated to an agonist antibody. In some embodiments, a second variant Fc polypeptide containing a mutation or set of mutations that increases selectivity for FcγRIIβ is conjugated or ligated to an antibody. In some embodiments, a second variant Fc polypeptide containing a mutation or set of mutations that increases selectivity for FcγRIIβ is conjugated or ligated to an agonist antibody. In some embodiments, a first variant Fc polypeptide and a second variant Fc polypeptide, each containing a mutation or set of mutations that increases selectivity for FcγRIIβ, are each conjugated or ligated to an antibody. In some embodiments, a first variant Fc polypeptide and a second variant Fc polypeptide, each containing a mutation or set of mutations that increase selectivity for FcγRIIβ, are conjugated or linked to an agonist antibody. In some embodiments, the antibody binds to IR. In some embodiments, the agonist antibody binds to IR. In some embodiments, the mutation or set of mutations that increase selectivity for FcγRIIβ may also affect the binding of the antibody to IR. In some embodiments, the mutation or set of mutations that increase selectivity for FcγRIIβ may also increase the binding of the antibody to IR. In some embodiments, the mutation or set of mutations that increase selectivity for FcγRIIβ may also decrease the binding of the antibody to IR. In some embodiments, the mutation or set of mutations that increase selectivity for FcγRIIβ may affect the clustering of PD-1.In some embodiments, a mutation or set of mutations that increases selectivity for FcγRIIβ may increase PD-1 clustering. In some embodiments, a mutation or set of mutations that increases selectivity for FcγRIIβ may decrease PD-1 clustering. In some embodiments, a mutation or set of mutations that increases selectivity for FcγRIIβ may affect PD-1 clustering, and affecting PD-1 clustering also affects PD-1 agonism. In some embodiments, a mutation or set of mutations that increases selectivity for FcγRIIβ may increase PD-1 clustering, and increasing PD-1 clustering also increases PD-1 agonism. In some embodiments, a mutation or set of mutations that increases selectivity for FcγRIIβ may decrease PD-1 clustering, and decreasing PD-1 clustering also decreases PD-1 agonism.

[0104] Domains may have similarities to those provided herein or incorporated by reference. Sequence identity, identity percentage, and related terms, when used herein, refer to the relationship between two sequences, e.g., two nucleic acid sequences or two amino acid or polypeptide sequences. In the context of amino acid sequences, the term “substantially identical” is used herein to refer to a first amino acid sequence containing a sufficient or minimum number of amino acid residues that are i) identical to or ii) conserved substitutions of aligned amino acid residues in the second amino acid sequence, such that the first and second amino acid sequences may have a common structural domain and / or common functional activity. For example, an amino acid sequence containing a common structural domain having at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with a reference sequence, e.g., a sequence provided herein.

[0105] In the context of nucleotide sequences, such as those encoding domains, the term “substantially identical” is used herein to refer to a first nucleic acid sequence containing a sufficient or minimum number of nucleotides that are identical to the aligned nucleotides in the second nucleic acid sequence, such that the first and second nucleotide sequences encode a polypeptide having common functional activity or encode a common structural polypeptide domain or common functional polypeptide activity. For example, a nucleotide sequence having at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with a reference sequence, e.g., a sequence provided herein.

[0106] The term "functional variant" refers to a polypeptide that has an amino acid sequence substantially identical to a naturally occurring sequence, or is encoded by a substantially identical nucleotide sequence, and can possess one or more activities of the naturally occurring sequence. For example, an Fc variant may have a sequence of the Fc domain, but includes mutations that affect its binding to the FcγRIIa or FcγRIIb receptor. In some embodiments, the Fc variant selectively binds to the FcγRIIb receptor. In some embodiments, the Fc variant selectively binds to the FcγRIIb receptor rather than the FcγRIIa receptor.

[0107] The calculation of homology or sequence identity between sequences (these terms are used interchangeably herein) can be performed as follows:

[0108] To determine the percentage of identity between two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (for example, gaps can be introduced in one or both of the first and second amino acid or nucleic acid sequences for optimal alignment, and non-homologous sequences can be ignored for comparison purposes). In a preferred embodiment, the length of the reference sequence to be aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, or 100% of the length of the reference sequence. The amino acid residues or nucleotides are then compared at their corresponding amino acid or nucleotide positions. If a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, the molecules are identical at that position (as used herein, "identity" of amino acids or nucleic acids is equivalent to "homology" of amino acids or nucleic acids).

[0109] The percentage of identity between two arrays is a function of the number of identical positions shared by the arrays, taking into account the number of gaps that need to be introduced for optimal alignment of the two arrays and the length of each gap.

[0110] The comparison of sequences and the determination of the percentage of identity between two sequences can be achieved using mathematical algorithms. In a preferred embodiment, the percentage of identity between two amino acid sequences is determined using the algorithm of Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453), which is incorporated into the GAP program in the GCG software package (available at http: / / www.gcg.com), using either the Blossum 62 matrix or the PAM250 matrix, along with gap weights of 16, 14, 12, 10, 8, 6, or 4, and length weights of 1, 2, 3, 4, 5, or 6. In another preferred embodiment, the percentage of identity between two nucleotide sequences is determined using the NWSgapdna.CMP matrix, along with gap weights of 40, 50, 60, 70, or 80, and length weights of 1, 2, 3, 4, 5, or 6, using the GAP program in the GCG software package (available at http: / / www.gcg.com). A particularly preferred set of parameters (and one that should be used unless otherwise specified) is the Blossum 62 scoring matrix, which uses 12 gap penalties, 4 gap extension penalties, and 5 frame shift gap penalties.

[0111] The percentage of identity between two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4:11-17), which is incorporated into the ALIGN program (version 2.0), using the PAM120 weight residue table, a gap length penalty of 12, and a gap length penalty of 4.

[0112] The nucleic acid and protein sequences described herein can be used as "query sequences" to search public databases, for example, to identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) from Altschul, et al. (1990) J. Mol. Biol. 215:403-10. A BLAST nucleotide search can be performed using the NBLAST program with a score of 100 and a word length of 12 to obtain, for example, nucleotide sequences homologous to any nucleic acid sequence provided herein. A BLAST protein search can be performed using the XBLAST program with a score of 50 and a word length of 3 to obtain amino acid sequences homologous to protein molecules provided herein. To obtain gapped alignment for comparison purposes, Gapped BLAST, described in Altschul et al. (1997) Nucleic Acids Res. 25:3389-3402, can be used. When using the BLAST and Gapped BLAST programs, you can use the default settings parameters for each program (e.g., XBLAST and NBLAST). See http: / / www.ncbi.nlm.nih.gov for more information.

[0113] Where used herein, the terms “hybridize under low stringency, moderate stringency, high stringency, or very high stringency” describe the conditions for hybridization and washing. Guidance for performing hybridization reactions can be found in Current Protocols in Molecular Biology, John Wiley & Sons, NY (1989), 6.3.1–6.3.6, which are incorporated by reference. The reference describes aqueous and non-aqueous methods, both of which may be used. The specific hybridization conditions referred to herein are as follows: 1) Low stringency hybridization conditions in 6 × sodium chloride / sodium citrate (SSC) at approximately 45°C, followed by two washes in 0.2 × SSC and 0.1% SDS at at least 50°C (for low stringency conditions, the washing temperature may be increased to 55°C); 2) Moderate stringency hybridization in 6 × SSC at approximately 45°C. 1) High stringency hybridization conditions, followed by one or more washes in 0.2×SSC, 0.1%SDS at 60°C; 2) High stringency hybridization conditions, followed by one or more washes in 0.2×SSC, 0.1%SDS at 65°C; and preferably, 3) Very high stringency hybridization conditions, which include one or more washes in 0.5M sodium phosphate, 7%SDS at 65°C, followed by one or more washes in 0.2×SSC, 1%SDS at 65°C. The very high stringency condition (4) is a preferred condition and should be used unless otherwise specified.

[0114] It should be understood that the molecules and compounds of this embodiment may have additional conserved or non-essential amino acid substitutions that do not substantially affect their function.

[0115] The term “amino acid” is intended to encompass all molecules that may be included in polymers of naturally occurring amino acids, whether natural or synthetic, and including both amino- and acid-functional properties. Exemplary amino acids include naturally occurring amino acids, their analogues, derivatives, and homologues, amino acid analogues with variant side chains, and all stereoisomers of any of the aforementioned. As used herein, the term “amino acid” includes both D- or L-optical isomers and peptide mimetic compounds.

[0116] A "conservative amino acid substitution" is one in which an amino acid residue is replaced by an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains are defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), amino acids with acidic side chains (e.g., aspartic acid, glutamic acid), amino acids with uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), amino acids with nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), amino acids with beta-branched side chains (e.g., threonine, valine, isoleucine), and amino acids with aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

[0117] This disclosure provides effector domains that can act, for example, as PD-1 agonists. Without being bound by any particular theory, PD-1 agonism can inhibit T cell activation / signaling and can be achieved by different mechanisms. For example, crosslinking can result in agonism, and bead-conjugated functional PD-1 agonists have been described (Akkaya. Ph.D. Thesis: Modulation of the PD-1 pathway by inhibitory antibody superagonists. Christ Church College, Oxford, UK, 2012), which is incorporated herein by reference. Crosslinking of PD-1 by two mAbs binding to a non-overlapping epitope induces PD-1 signaling (Davis, US2011 / 0171220), which is incorporated herein by reference. Another example is illustrated through the use of goat anti-PD-1 antiserum (e.g., AF1086, R&D Systems), which is incorporated herein by reference, acting as an agonist when soluble (Said et al., 2010, Nat Med), which is incorporated herein by reference. Non-limiting examples of PD-1 agonists that can be used in this embodiment include, but are not limited to, UCB clone 19 or clone 10, PD1AB-1, PD1AB-2, PD1AB-3, PD1AB-4, and PD1AB-5, PD1AB-6 (Anaptys / Celgene), PD1-17, PD1-28, PD1-33, and PD1-35 (Collins et al, US2008 / 0311117A1).

[0118] The antibody can be a reference-integrated antibody against PD-1 (and its use therefor), or a bispecific, monovalent anti-PD-1 / anti-CD3 (Ono), etc. In some embodiments, the PD-1 agonist antibody can be an antibody that blocks the binding of PD-L1 to PD-1. In some embodiments, the PD-1 agonist antibody can be an antibody that does not block the binding of PD-L1 to PD-1.

[0119] PD-1 agonism can be measured by any method, such as the methods described in the examples. For example, expressing cells can be constructed, including the stable expression of a construct comprising 1) a human PD-1 polypeptide fused to a β-galactosidase "enzyme donor" and 2) an SHP-2 polypeptide fused to a β-galactosidase "enzyme acceptor". Without being bound by any theory, SHP-2 is recruited to PD-1 when PD-1 is engaged. The enzyme acceptor and enzyme donor form a fully active β-galactosidase enzyme that can be assayed. However, the assay does not directly demonstrate PD-1 agonism, but rather demonstrates activation of PD-1 signaling. PD-1 agonism can also be measured by measuring the inhibition of T cell activation, since PD-1 agonism inhibits anti-CD3-induced T cell activation, without being bound by any theory. For example, PD-1 agonism can be measured by pre-activating T cells with PHA (for human T cells) or ConA (for mouse T cells) so that they express PD-1. Then, for a PD-1 agonism assay, cells can be reactivated with anti-CD3 in the presence of anti-PD-1 (or PD-L1). T cells receiving the PD-1 agonist signal in the presence of anti-CD3 show reduced activation compared to anti-CD3 stimulation alone. Activation can be read out by proliferation or cytokine production (IL-2, IFNγ, IL-17), or by other markers such as the CD69 activation marker. Thus, PD-1 agonism can be measured by either cytokine production or cell proliferation. PD-1 agonism can also be measured using other methods.

[0120] In some embodiments, PD-1 agonism increases when a PD-1 agonist is ligated to an effector domain or other binding site that specifically binds to FcγRIIb. In some embodiments, PD-1 agonism increases when a PD-1 agonist is ligated to an effector site that selectively binds to FcγRIIb. In some embodiments, the effector is an antibody that selectively binds to FcγRIIb. In some embodiments, PD-1 agonism increases when a PD-1 agonist is ligated to an Fc polypeptide that selectively binds to FcγRIIb. In some embodiments, the antibody is in scFv format. In some embodiments, the PD-1 agonist is ligated to both an Fc polypeptide and an antibody, each selectively binding to FcγRIIb. In some embodiments, only one of the Fc polypeptide and the antibody selectively binds to FcγRIIb. In some embodiments, the Fc polypeptide is effectorless. In some embodiments, the PD-1 agonist is an antibody that binds to PD-1. In some embodiments, the PD-1 agonist is an anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the antibody has little or no antagonist activity against PD-1. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is in Fab format. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is in scFv format.

[0121] PD-1 is an Ig superfamily member expressed on activated T cells and other immune cells. The native ligands for PD-1 appear to be PD-L1 and PD-L2. Without being bound by any particular theory, when PD-L1 or PD-L2 binds to PD-1 on activated T cells, an inhibitory signaling cascade is initiated, resulting in attenuation of activated T effector cell function. Therefore, blocking the interaction between PD-1 on T cells and PD-L1 / 2 on other cells (e.g., tumor cells) using PD-1 antagonists is known as checkpoint inhibition, freeing T cells from inhibition. In contrast, PD-1 agonist antibodies can bind to PD-1, deliver inhibitory signals, and attenuate T cell function. Thus, PD-1 agonist antibodies can be incorporated into the various embodiments described herein as effector molecule binding / modulation moieties, which, when paired with the targeting moiety, can achieve localized tissue-specific immunomodulation.

[0122] In some embodiments, the antibody is an anti-PD-1 antibody that binds to PD-1. In some embodiments, the antibody binds to an amino acid of the PD-1 epitope. Epitopes are described herein and in the examples, such as those shown in the table.

[0123] In some embodiments, an anti-PD-1 antibody, such as one provided herein, binds to an epitope on PD-1. PD-1 is a type I membrane protein having the amino acid sequence described in SEQ ID NO: 589. MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQTLVVGVVGGLLGSLVLLVWVLAVICSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL (Sequence ID 589).

[0124] In some embodiments, an anti-PD-1 antibody, such as those provided herein, binds to an epitope on PD-1.

[0125] In some embodiments, an anti-PD-1 antibody, such as that provided herein, binds to an epitope on PD-1 containing PD-1 (SEQ ID NO: 589) residues P39, A40, L41, L42, V43, V44, T45, D48, E61, S62, H107, L128, A129, P130, K131, A132, Q133, R143, T145, E146, R147, R148, A149, E150, V151, P152, A154, or any combination thereof. In some embodiments, the epitope contains PD-1 residues P39, A40, L41, L42, V43, V44, T45, D48, H107, R143, T145, R147, and R148. In some embodiments, the epitope includes PD-1 residues E61, S62, L128, A129, P130, K131, A132, and Q133. In some embodiments, the epitope includes PD-1 residues E146, R147, R148, A149, E150, V151, P152, and A154.

[0126] While we do not wish to be bound by any particular theory, the PD-1 receptor may induce a negative immune regulatory mechanism that prevents the overactivation of immune cells and subsequent inflammatory diseases. Therefore, immunomodulatory anti-PD-1 blocking antibodies have become a widely used cancer treatment, but little is known about the characteristics required for anti-PD-1 antibodies to stimulate immunosuppressive activity.

[0127] In some embodiments, the PD-1 agonist antibody binds to a membrane-proximal epitope on PD-1. As used herein, a “membrane-proximal” epitope is an epitope on the PD-1 protein structure that is close to the cell membrane. In some embodiments, the membrane-proximal epitope includes residues P39, A40, L41, L42, V43, V44, T45, D48, H107, R143, T145, R147, and R148 of PD-1. In some embodiments, the membrane-proximal epitope includes residues E146, R147, R148, A149, E150, V151, P152, and A154 of PD-1.

[0128] In some embodiments, the antibody binds to an epitope, such as those provided herein and above, with low affinity. In some embodiments, an antibody that binds to PD-1 with low affinity binds to PD-1 with a binding affinity of 50 nM or less. For example, it will be understood that an antibody that binds to PD-1 with 10 nM of antibody will bind to PD-1 with a higher affinity than an antibody that binds to PD-1 with an affinity of 50 nM. In some embodiments, an antibody that binds to PD-1 with low affinity binds to PD-1 with a binding affinity of 70 nM or less. In some embodiments, an antibody that binds to PD-1 with low affinity binds to PD-1 with a binding affinity of 80 nM or less. In some embodiments, an antibody that binds to PD-1 with low affinity binds to PD-1 with a binding affinity of 90 nM or less. In some embodiments, an antibody that binds to PD-1 with low affinity binds to PD-1 with a binding affinity of 100 nM or less. In some embodiments, an antibody that binds to PD-1 with low affinity binds to PD-1 with a binding affinity of 110 nM or less. In some embodiments, an antibody that binds to PD-1 with low affinity binds to PD-1 with a binding affinity of 120 nM or less. In some embodiments, an antibody that binds to PD-1 with low affinity binds to PD-1 with a binding affinity of 130 nM or less. In some embodiments, an antibody that binds to PD-1 with low affinity binds to PD-1 with a binding affinity of 140 nM or less. In some embodiments, an antibody that binds to PD-1 with low affinity binds to PD-1 with a binding affinity of 150 nM or less. In some embodiments, an antibody that binds to PD-1 with low affinity binds to PD-1 with a binding affinity of 152 nM or less. In some embodiments, an antibody that binds to PD-1 with low affinity binds to PD-1 with a binding affinity of 258 nM or less. In some embodiments, an antibody that binds to PD-1 with low affinity binds to PD-1 with a binding affinity of approximately 50 nM to approximately 500 nM. In some embodiments, an antibody that binds to PD-1 with low affinity binds to PD-1 with a binding affinity of approximately 100 nM to approximately 500 nm. In some embodiments, antibodies that bind to PD-1 with low affinity bind to PD-1 with a binding affinity of approximately 200 nM to approximately 500 nM.In some embodiments, an antibody that binds to PD-1 with low affinity binds to PD-1 with a binding affinity of about 300 nM to about 500 nM. In some embodiments, an antibody that binds to PD-1 with low affinity binds to PD-1 with a binding affinity of about 400 nM to about 500 nM. In some embodiments, an antibody that binds to PD-1 with low affinity binds to PD-1 with a binding affinity of about 100 nM to about 400 nM. In some embodiments, an antibody that binds to PD-1 with low affinity binds to PD-1 with a binding affinity of about 100 nM to about 300 nM. In some embodiments, an antibody that binds to PD-1 with low affinity binds to PD-1 with a binding affinity of about 100 nM to about 200 nM. In some embodiments, an antibody that binds to PD-1 with low affinity binds to PD-1 with a binding affinity of about 200 nM to about 500 nM. In some embodiments, an antibody that binds to PD-1 with low affinity binds to PD-1 with a binding affinity of about 200 nM to about 400 nM. In some embodiments, antibodies that bind to PD-1 with low affinity bind to PD-1 with a binding affinity of about 200 nM to about 300 nM. In some embodiments, antibodies referred to herein bind to an epitope of PD-1, such as those provided herein, with an affinity such as those provided herein. Affinity can be measured by any assay, such as those provided in Example 43. In some embodiments, affinity for PD-1 is measured using biolayer inferometry. In some embodiments, the measurement of the affinity of an antibody for PD-1 includes the step of diluting the anti-PD-1 antibody in assay buffer to a final concentration of 5 μg / mL and titrating recombinant human PD-1. In some embodiments, the measurement of the affinity of an antibody for PD-1 includes the step of capturing the anti-PD-1 antibody on an anti-human IgG Fc biosensor. In some embodiments, the measurement of the affinity of an antibody for PD-1 includes the step of associating the anti-PD-1 antibody in a well with human PD-1 and dissociating it in the well with assay buffer.In some embodiments, the measurement of antibody affinity for PD-1 includes the step of calculating kinetic parameters (kon and kdis) as well as the equilibrium dissociation constant (KD) from a 1:1 Langmuir global Rmax fitting model using Octet RED96 version 10.0 data analysis software.

[0129] Other examples of PD-1 antibodies that can be used include, but are not limited to, those described in JP6278224B2, JP2018 / 518540A, CN1753912B, JP6174321B2, US2020 / 0190187A1, US10676516B2, WO2011 / 082400A2, JP2017 / 537090A, JP2012 / 501670A, US2019 / 0270818, or CC-9000, each of which is incorporated herein by reference in whole.

[0130] In some embodiments, the PD-1 antibody or its antigen-binding fragment or the antigen-binding fragment comprises a variable heavy chain amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the following: QVQLVQSGAEVKKPGASVKVSCKVSGYSLSKYDMSWVRQAPGKGLEWMGIIYTSGYTDYAQKFQGRVTMTEDTSTDTAYMELSSLRSEDTAVYYCATGNPYYTNGFNSWGQGTLVTVSS(Sequence ID 514).

[0131] In some embodiments, the PD-1 antibody or its antigen-binding fragment, or the antigen-binding fragment thereof, includes the variable heavy chain amino acid sequence of SEQ ID NO: 514.

[0132] In some embodiments, the PD-1 antibody or its antigen-binding fragment or the antigen-binding fragment comprises a variable light chain amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the following: DIQMTQSPSSLSASVGDRVTITCQASQSPNNLLAWYQQKPGKAPKLLIYGASDLPSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQNNYYVGPVSYAFGGGTKVEIK (Sequence ID 515).

[0133] In some embodiments, the PD-1 antibody or its antigen-binding fragment, or the antigen-binding fragment thereof, includes the variable light chain amino acid sequence of SEQ ID NO: 515.

[0134] In some embodiments, the PD-1 antibody or its antigen-binding fragment or the antigen-binding fragment comprises a variable heavy chain amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of SEQ ID NO: 514, and a variable light chain amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of SEQ ID NO: 515.

[0135] In some embodiments, the PD-1 antibody or its antigen-binding fragment, or the antigen-binding fragment thereof, includes the variable heavy chain amino acid sequence of SEQ ID NO: 514 and the variable light chain amino acid sequence of SEQ ID NO: 515.

[0136] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a polypeptide comprising any one variable heavy chain and any one variable light chain, or an amino acid sequence that is combined with one another as provided in Table 5 below. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 5-9] [Table 5-10] [Table 5-11] [Table 5-12] [Table 5-13] Table 5-14 Table 5-15 Table 5-16 Table 5-17 Table 5-18 Table 5-19 Table 5-20 Table 5-21 Table 5-22 Table 5-23 Table 5-24 Table 5-25 Table 5-26 Table 5-27 Table 5-28 Table 5-29 Table 5-30 Table 5-31 Table 5-32 Table 5-33 Table 5-34

[0137] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is SEQ ID NOs: 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 18 2, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 2 13, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 2 44, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305 , 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 530, 538, and 540 and at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%,Or it includes a variable heavy chain containing an amino acid sequence having at least 99% sequence identity. In some embodiments, the anti-PD-1 antibody or the antibody having a percentage of identity with the reference VH sequence described above includes an HCDR for a clone number as provided herein.

[0138] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 130. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 131. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 132. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 133.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 134. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 135. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 136. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 137. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 138. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 139. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 140.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 141. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 142. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 143. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 144.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 145. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 146. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 147. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 148.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 149. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 150. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 151. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 152. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 153.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 154. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 155. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 156. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 157. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 158. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 159. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 160.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 161. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 162. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 163. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 164.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 165. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 166. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 167. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 168. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 169. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 170. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 171. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 172.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 173. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 174. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 175. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 176. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 177. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 178. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 179. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 180.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 181. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 182. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 183. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 184.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 185. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 186. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 187. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 188. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 189. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 190. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 191.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 192. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 193. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 194. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 195.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 196. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 197. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 198. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 199. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 200. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 201. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 202. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 203.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 204. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 205. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 206. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 207. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 208. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 209. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 210. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 211.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain comprising an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 212. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain comprising an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 213. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 214. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 215.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 216. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 217. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 218. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 219. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 220. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 221. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 222.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 223. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 224. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 225. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 226. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 227. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 228. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 229. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 230.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 231. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 232. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 233. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 234.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 235. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 236. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 237. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 238. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 239. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 240. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 241. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 242.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 243. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 244. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 245. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 246. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 247. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 248. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 249.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 250. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 251. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 252. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 253. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 254. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 255. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 256.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 257. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 258. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 259. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 260. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 261. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 262. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 263.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 264. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 265. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 266. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 267. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 268. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 269. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 270.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 271. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 272. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 273. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 274. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 275. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 276. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 277.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 278. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 279. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 280. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 281. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 282. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 283. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 284.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 285. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 286. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 287. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 288. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 289. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 290. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 291.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 292. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 293. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 294. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 295. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 296. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 297. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 298.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 299. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 300. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 301. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 302. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 303. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 304. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 305. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 306.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 307. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 308. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 309. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 310.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 311. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 312. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 313. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 314. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 315. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 316. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 317. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 318.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 319. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 320. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 321. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 322.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 538. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 540.

[0139] With respect to the identity percentage claims provided for variable heavy chain domains, in some embodiments, variants include an HCDR as provided in the reference sequence. The CDR can be determined via the KABAT, Chothia, or IMGT system, which are known to those skilled in the art.

[0140] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is represented by SEQ ID NOs: 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 35 4, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, ​​383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, The variable light chain comprises an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with any one of 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 531, 532, 533, 534, 535, 536, 537, 539, 541, and 542. In some embodiments, the variable light chains provided herein may be combined with different VH domains provided herein, as illustrated in the table, without being constrained by any particular theory, so that the light chains allow for flexibility in antigen binding. This is illustrated, for example, in Table 5, which shows multiple antibodies sharing the same VL domain.

[0141] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is SEQ ID NOs: 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 18 2, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 2 13, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 2 44, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305 , 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 530, 538, and 540 and at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%,Alternatively, a variable heavy chain containing an amino acid sequence having at least 99% sequence identity, and SEQ ID NOs: 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353 ,354,355,356,357,358,359,360,361,362,363,364,365,366,367,368,369,370,371,372,373,374,375,376,377,378,379,380,381,382,383,384,385,386,387,388,389,390,391,392,393,39 It comprises one of 4, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 531, 532, 533, 534, 535, 536, 537, 539, 541, and 542, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0142] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 324, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 324.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 325, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 325. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 326, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 326.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 327, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 327. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 328, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 328. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 326, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 326. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 329, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 329. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 330, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 330.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 331, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 331. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 332, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 332. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 333, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 333. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 334, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 334.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 335, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 335. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 336, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 336.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 337, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 337. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 338, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 338. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 339, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 339.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 340, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 340. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 341, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 341.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 342, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 342. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 343, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 343. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 344, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 344. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 344, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 344.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 345, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 345. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 346, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 346.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 347, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 347. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 346, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 346. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 207, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 208, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 210, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 211, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 212, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323.In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 213, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 214, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 323. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable heavy chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with SEQ ID NO: 215, and a variable light chain containing an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at le...

Claims

1. An anti-PD-1 antibody or its antigen-binding fragment that binds to an epitope on PD-1 containing residues P39, A40, L41, L42, V43, V44, T45, D48, E61, S62, H107, L128, A129, P130, K131, A132, Q133, R143, T145, E146, R147, R148, A149, E150, V151, P152, A154, or any combination thereof.

2. The anti-PD-1 antibody or antigen-binding fragment according to claim 1, wherein the anti-PD-1 antibody or antigen-binding fragment binds to an epitope on PD-1 comprising the residues P39, A40, L41, L42, V43, V44, T45, D48, H107, R143, T145, R147, and R148 of PD-1.

3. The anti-PD-1 antibody or antigen-binding fragment according to claim 1, wherein the anti-PD-1 antibody or antigen-binding fragment binds to an epitope on PD-1 comprising the residues E61, S62, L128, A129, P130, K131, A132, and Q133 of PD-1.

4. The anti-PD-1 antibody or antigen-binding fragment according to claim 1, wherein the anti-PD-1 antibody or antigen-binding fragment binds to an epitope on PD-1 comprising the residues E146, R147, R148, A149, E150, V151, P152, and A154 of PD-1.

5. The anti-PD-1 antibody or antigen-binding fragment according to any one of claims 1 to 4, wherein the anti-PD-1 antibody or antigen-binding fragment binds to the PD-1 epitope with low binding affinity.

6. The anti-PD-1 antibody or antigen-binding fragment according to any one of claims 1 to 5, wherein the anti-PD-1 antibody or antigen-binding fragment binds to the PD-1 epitope with a binding affinity of 150 nM or less.

7. The anti-PD-1 antibody or antigen-binding fragment according to any one of claims 1 to 5, wherein the anti-PD-1 antibody or antigen-binding fragment binds to the PD-1 epitope with a binding affinity of 150 nM or less, or with an affinity of about 100 nM to about 300 nM or about 75 nM to about 300 nM.

8. The anti-PD-1 antibody or antigen-binding fragment thereof according to any one of claims 1 to 7, wherein the antibody is a PD-1 agonist.

9. The aforementioned antibody A variable heavy chain comprising HCDR1 having any one amino acid sequence of SEQ ID NO: 553, 547, 550, or 556, HCDR2 having any one amino acid sequence of SEQ ID NO: 554, 548, 551, or 557, and HCDR3 having any one amino acid sequence of SEQ ID NO: 555, 549, 552, or 558, An anti-PD-1 antibody or its antigen-binding fragment according to claim 1, comprising a variable light chain including an LCDR1 having the amino acid sequence of any one SEQ ID NO: 574, 559, 562, 565, 568, 569, 570, 571, 572, or 573, an LCDR2 having the amino acid sequence of any one SEQ ID NO: 563, 560, or 566, and an LCDR3 having the amino acid sequence of any one SEQ ID NO: 564, 561, or 567.

10. The aforementioned antibody A variable heavy chain comprising HCDR1 having any one amino acid sequence of SEQ ID NO: 553, 547, 550, or 556, HCDR2 having any one amino acid sequence of SEQ ID NO: 554, 548, 551, or 557, and HCDR3 having any one amino acid sequence of SEQ ID NO: 555, 549, 552, or 558, An anti-PD-1 antibody or antigen-binding fragment according to any one of claims 1 to 8, comprising a variable light chain including an LCDR1 having the amino acid sequence of any one SEQ ID NO: 574, 559, 562, 565, 568, 569, 570, 571, 572, or 573, an LCDR2 having the amino acid sequence of any one SEQ ID NO: 563, 560, or 566, and an LCDR3 having the amino acid sequence of any one SEQ ID NO: 564, 561, or 567.

11. The anti-PD-1 antibody or the antigen-binding fragment thereof A variable heavy chain comprising HCDR1 having the amino acid sequence of SEQ ID NO: 553, HCDR2 having the amino acid sequence of SEQ ID NO: 554, and HCDR3 having the amino acid sequence of SEQ ID NO: 555; and a variable light chain comprising LCDR1 having the amino acid sequence of SEQ ID NO: 573, LCDR2 having any one of the amino acid sequences of SEQ ID NO: 563, and LCDR3 having the amino acid sequence of SEQ ID NO:

564. A variable heavy chain comprising HCDR1 having the amino acid sequence of SEQ ID NO: 547, HCDR2 having the amino acid sequence of SEQ ID NO: 548, and HCDR3 having the amino acid sequence of SEQ ID NO: 549, and a variable light chain comprising LCDR1 having the amino acid sequence of SEQ ID NO: 559, LCDR2 having one of the amino acid sequences of SEQ ID NO: 560, and LCDR3 having the amino acid sequence of SEQ ID NO:

561. A variable heavy chain comprising HCDR1 having the amino acid sequence of SEQ ID NO: 550, HCDR2 having the amino acid sequence of SEQ ID NO: 551, and HCDR3 having the amino acid sequence of SEQ ID NO: 552; and a variable light chain comprising LCDR1 having the amino acid sequence of SEQ ID NO: 559, LCDR2 having one of the amino acid sequences of SEQ ID NO: 560, and LCDR3 having the amino acid sequence of SEQ ID NO:

561. A variable heavy chain comprising HCDR1 having the amino acid sequence of SEQ ID NO: 553, HCDR2 having the amino acid sequence of SEQ ID NO: 554, and HCDR3 having the amino acid sequence of SEQ ID NO: 555; and a variable light chain comprising LCDR1 having the amino acid sequence of SEQ ID NO: 562, LCDR2 having any one of the amino acid sequences of SEQ ID NO: 563, and LCDR3 having the amino acid sequence of SEQ ID NO:

564. A variable heavy chain comprising HCDR1 having the amino acid sequence of SEQ ID NO: 556, HCDR2 having the amino acid sequence of SEQ ID NO: 567, and HCDR3 having the amino acid sequence of SEQ ID NO: 568; and a variable light chain comprising LCDR1 having the amino acid sequence of SEQ ID NO: 565, LCDR2 having any one of the amino acid sequences of SEQ ID NO: 566, and LCDR3 having the amino acid sequence of SEQ ID NO:

567. A variable heavy chain comprising HCDR1 having the amino acid sequence of SEQ ID NO: 553, HCDR2 having the amino acid sequence of SEQ ID NO: 554, and HCDR3 having the amino acid sequence of SEQ ID NO: 555; and a variable light chain comprising LCDR1 having the amino acid sequence of SEQ ID NO: 568, LCDR2 having any one of the amino acid sequences of SEQ ID NO: 563, and LCDR3 having the amino acid sequence of SEQ ID NO:

564. A variable heavy chain comprising HCDR1 having the amino acid sequence of SEQ ID NO: 553, HCDR2 having the amino acid sequence of SEQ ID NO: 554, and HCDR3 having the amino acid sequence of SEQ ID NO: 555; and a variable light chain comprising LCDR1 having the amino acid sequence of SEQ ID NO: 569, LCDR2 having any one of the amino acid sequences of SEQ ID NO: 563, and LCDR3 having the amino acid sequence of SEQ ID NO:

564. A variable heavy chain comprising HCDR1 having the amino acid sequence of SEQ ID NO: 553, HCDR2 having the amino acid sequence of SEQ ID NO: 554, and HCDR3 having the amino acid sequence of SEQ ID NO: 555; and a variable light chain comprising LCDR1 having the amino acid sequence of SEQ ID NO: 570, LCDR2 having any one of the amino acid sequences of SEQ ID NO: 563, and LCDR3 having the amino acid sequence of SEQ ID NO:

564. A variable heavy chain comprising HCDR1 having the amino acid sequence of SEQ ID NO: 553, HCDR2 having the amino acid sequence of SEQ ID NO: 554, and HCDR3 having the amino acid sequence of SEQ ID NO: 555; and a variable light chain comprising LCDR1 having the amino acid sequence of SEQ ID NO: 571, LCDR2 having any one of the amino acid sequences of SEQ ID NO: 563, and LCDR3 having the amino acid sequence of SEQ ID NO:

564. A variable heavy chain comprising HCDR1 having the amino acid sequence of SEQ ID NO: 553, HCDR2 having the amino acid sequence of SEQ ID NO: 554, and HCDR3 having the amino acid sequence of SEQ ID NO: 555; and a variable light chain comprising LCDR1 having the amino acid sequence of SEQ ID NO: 572, LCDR2 having any one of the amino acid sequences of SEQ ID NO: 563, and LCDR3 having the amino acid sequence of SEQ ID NO:

564. A variable heavy chain comprising HCDR1 having the amino acid sequence of SEQ ID NO: 553, HCDR2 having the amino acid sequence of SEQ ID NO: 554, and HCDR3 having the amino acid sequence of SEQ ID NO: 555; and a variable light chain comprising LCDR1 having the amino acid sequence of SEQ ID NO: 574, LCDR2 having any one of the amino acid sequences of SEQ ID NO: 563, and LCDR3 having the amino acid sequence of SEQ ID NO:

564. A variable heavy chain comprising HCDR1 having the amino acid sequence of SEQ ID NO: 556, HCDR2 having the amino acid sequence of SEQ ID NO: 557, and HCDR3 having the amino acid sequence of SEQ ID NO: 558, and a variable light chain comprising LCDR1 having the amino acid sequence of SEQ ID NO: 565, LCDR2 having any one of the amino acid sequences of SEQ ID NO: 566, and LCDR3 having the amino acid sequence of SEQ ID NO: 567, or The anti-PD-1 antibody or its antigen-binding fragment according to claim 9, comprising a variable heavy chain having HCDR1 having the amino acid sequence of SEQ ID NO: 553, HCDR2 having the amino acid sequence of SEQ ID NO: 554, and HCDR3 having the amino acid sequence of SEQ ID NO: 555, and a variable light chain having LCDR1 having the amino acid sequence of SEQ ID NO: 562, LCDR2 having any one of the amino acid sequences of SEQ ID NO: 563, and LCDR3 having the amino acid sequence of SEQ ID NO:

564.

12. The antibody or the antigen-binding fragment thereof A variable heavy chain domain (VH) comprising an amino acid sequence that is at least 90-99% identical to the amino acid sequence of SEQ ID NO: 530, provided that the VH includes HCDR1 of SEQ ID NO: 553, HCDR2 of SEQ ID NO: 554, and HCDR3 of SEQ ID NO: 555, The anti-PD-1 antibody or its antigen-binding fragment according to claim 1, comprising a variable light chain domain (VL) having an amino acid sequence that is at least 90-99% identical to the amino acid sequence of SEQ ID NO: 537, provided that the VL includes LCDR1 of SEQ ID NO: 574, LCDR2 of SEQ ID NO: 563, and LCDR3 of SEQ ID NO:

564.

13. The antibody according to claim 12, wherein the antibody comprises VH containing the amino acid sequence of SEQ ID NO: 530 and VL containing the amino acid sequence of SEQ ID NO:

537.

14. The antibody according to claim 12 or 13, wherein the antibody comprises a heavy chain (HC) having an amino acid sequence that is at least 90-99% identical to the amino acid sequence of SEQ ID NO: 691, and a light chain (LC) having an amino acid sequence that is at least 90-99% identical to the amino acid sequence of SEQ ID NO:

692.

15. The antibody or antigen fragment according to claim 14, wherein the HC comprises the amino acid sequence of SEQ ID NO: 691, and the LC comprises the amino acid sequence of SEQ ID NO:

692.

16. The anti-PD-1 antibody or antigen-binding fragment thereof, according to any one of claims 1 to 14, wherein the anti-PD-1 antibody containing VH or the antigen-binding fragment thereof is conjugated to an Fc polypeptide.

17. The anti-PD-1 antibody or its antigen-binding fragment according to claim 16, wherein the Fc polypeptide selectively binds to FcγRIIβ.

18. The aforementioned Fc polypeptide corresponds to sequence numbers 543, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, and 444. ,445,446,447,448,449,450,451,452,453,454,455,456,457,458,459,460,461,462,463,464,465,466,467,468,469,470,471,472,473,474,475,476,47 The anti-PD-1 antibody or its antigen-binding fragment according to claim 16 or 17, comprising an amino acid sequence having at least 90-99% sequence identity with any one of 7, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 544, 545, 546, 683, 684, 685, 686, 687, 688, 689, and 690.

19. The aforementioned Fc polypeptide corresponds to sequence numbers 543, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 4 The anti-PD-1 antibody or its antigen-binding fragment according to claim 18, comprising any one of the amino acid sequences 74, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 544, 545, 546, 683, 684, 685, 686, 687, 688, 689, and 690.

20. The anti-PD-1 antibody or its antigen-binding fragment according to claim 12 or 13, wherein the VH is conjugated to an Fc polypeptide.

21. The anti-PD-1 antibody or antigen-binding fragment according to claim 20, wherein the Fc polypeptide selectively binds to FcγRIIβ.

22. The aforementioned Fc polypeptide corresponds to sequence numbers 543, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 4 The anti-PD-1 antibody or its antigen-binding fragment according to claim 20, comprising any one of the amino acid sequences of 74, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 544, 545, 546, 683, 684, 685, 686, 687, 688, 689, and 690.

23. The anti-PD-1 antibody or antigen-binding fragment according to claim 20, wherein the Fc polypeptide contains an amino acid sequence that is at least 90-99% identical to the amino acid sequence of SEQ ID NO: 543, provided that the Fc polypeptide contains the G237E and P238E mutations.

24. The anti-PD-1 antibody or antigen-binding fragment according to claim 20, wherein the Fc polypeptide comprises the amino acid sequence of SEQ ID NO:

543.

25. The anti-PD-1 antibody or its antigen-binding fragment according to claim 20, wherein the VH conjugated to the Fc polypeptide comprises the amino acid sequence of SEQ ID NO:

691.

26. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof according to any one of claims 1 to 25, and a pharmaceutically acceptable excipient.

27. A method for treating an autoimmune disorder in a subject, comprising administering a pharmaceutical composition comprising an antibody or antigen-binding fragment according to any one of claims 1 to 25 and a pharmaceutically acceptable excipient.

28. The aforementioned autoimmune disorders include rheumatoid arthritis, alopecia areata, interstitial cystitis, lupus (e.g., lupus nephritis), chronic kidney disease (CKD), autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, pemphigus vulgaris, psoriasis, systemic scleroderma, vitiligo, Addison's disease, diabetes mellitus type 1, autoimmune thyroiditis, oldo thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjögren's syndrome, and autoimmune diseases. The method according to claim 27, wherein the condition is immune enteropathy, celiac disease, Crohn's disease, microscopic colitis, ulcerative colitis, arthritis (e.g., psoriatic arthritis, IBD-associated arthritis, or reactive arthritis), fibromyalgia, myasthenia gravis, warm antibody hemolytic anemia (wAIHA), immunothrombocytopenia, multiple sclerosis, chronic idiopathic demyelinating polyneuropathy (CIDP), atopic dermatitis, or eczema, or any combination thereof.

29. A method for increasing FoxP3+ Treg in a subject, comprising administering a pharmaceutical composition comprising an antibody or antigen-binding fragment according to any one of claims 1 to 25 and a pharmaceutically acceptable excipient.

30. A method for increasing TIGIT expression in FoxP3+ Treg in a subject, or a method for expanding TIGIT+, FOXP3+ Treg in a subject, comprising administering a pharmaceutical composition comprising an antibody or antigen-binding fragment according to any one of claims 1 to 25 and a pharmaceutically acceptable excipient.

31. A method for regulating T cells expressing PD-1 and / or B cells expressing FcγRIIβ, comprising administering a pharmaceutical composition comprising an antibody or antigen-binding fragment according to any one of claims 1 to 25 and a pharmaceutically acceptable excipient.

32. The method according to claim 31, wherein the antibody inhibits activated T cells that express PD-1.

33. The method according to claim 31 or 32, wherein the antibody inhibits the activation of the B cells.

34. A nucleic acid molecule encoding an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 25.

35. A vector comprising the nucleic acid molecule described in claim 34.

36. A cell comprising the nucleic acid molecule described in claim 34 or the vector described in claim 35.

37. A method for producing an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 25, comprising culturing cells containing a nucleic acid molecule encoding the antibody or the antigen-binding fragment under conditions sufficient to produce the antibody or the antigen-binding fragment.

38. An anti-FcγRIIβ antibody or its antigen-binding fragment, A variable heavy chain comprising HCDR1 having any one amino acid sequence of SEQ ID NO: 606, 575, 578, 590, 595, or 601; HCDR2 having any one amino acid sequence of SEQ ID NO: 607, 576, 579, 591, 596, or 602; and HCDR3 having any one amino acid sequence of SEQ ID NO: 608, 577, 580, 592, 597, or 603, An anti-FcγRIIβ antibody or its antigen-binding fragment comprising a polypeptide comprising a variable light chain including: LCDR1 having any one SEQ ID NO: 609, 581, 584, 593, 598, or 604 amino acid sequence; LCDR2 having any one SEQ ID NO: 610, 582, 585, 594, or 599 amino acid sequence; and LCDR3 having any one SEQ ID NO: 586, 583, 600, or 605 amino acid sequence; and an anti-FcγRIIβ antibody or its antigen-binding fragment.

39. The polypeptide described above, A variable heavy chain comprising HCDR1 having the amino acid sequence of SEQ ID NO: 606, HCDR2 having the amino acid sequence of SEQ ID NO: 607, and HCDR3 having the amino acid sequence of SEQ ID NO: 608; and a variable light chain comprising LCDR1 having the amino acid sequence of SEQ ID NO: 609, LCDR2 having one of the amino acid sequences of SEQ ID NO: 610, and LCDR3 having the amino acid sequence of SEQ ID NO:

586. A variable heavy chain comprising HCDR1 having the amino acid sequence of SEQ ID NO: 575, HCDR2 having the amino acid sequence of SEQ ID NO: 576, and HCDR3 having the amino acid sequence of SEQ ID NO: 577, and a variable light chain comprising LCDR1 having the amino acid sequence of SEQ ID NO: 581, LCDR2 having one of the amino acid sequences of SEQ ID NO: 582, and LCDR3 having the amino acid sequence of SEQ ID NO:

583. A variable heavy chain comprising HCDR1 having the amino acid sequence of SEQ ID NO: 578, HCDR2 having the amino acid sequence of SEQ ID NO: 579, and HCDR3 having the amino acid sequence of SEQ ID NO: 580, and a variable light chain comprising LCDR1 having the amino acid sequence of SEQ ID NO: 584, LCDR2 having one of the amino acid sequences of SEQ ID NO: 585, and LCDR3 having the amino acid sequence of SEQ ID NO:

586. A variable heavy chain comprising HCDR1 having the amino acid sequence of SEQ ID NO: 590, HCDR2 having the amino acid sequence of SEQ ID NO: 591, and HCDR3 having the amino acid sequence of SEQ ID NO: 592; and a variable light chain comprising LCDR1 having the amino acid sequence of SEQ ID NO: 593, LCDR2 having one of the amino acid sequences of SEQ ID NO: 594, and LCDR3 having the amino acid sequence of SEQ ID NO:

583. A variable heavy chain comprising HCDR1 having the amino acid sequence of SEQ ID NO: 595, HCDR2 having the amino acid sequence of SEQ ID NO: 596, and HCDR3 having the amino acid sequence of SEQ ID NO: 597, and a variable light chain comprising LCDR1 having the amino acid sequence of SEQ ID NO: 598, LCDR2 having any one of the amino acid sequences of SEQ ID NO: 599, and LCDR3 having the amino acid sequence of SEQ ID NO: 600, or The anti-FcγRIIβ antibody or its antigen-binding fragment according to claim 38, comprising a variable heavy chain having HCDR1 having the amino acid sequence of SEQ ID NO: 601, HCDR2 having the amino acid sequence of SEQ ID NO: 602, and HCDR3 having the amino acid sequence of SEQ ID NO: 603, and a variable light chain having LCDR1 having the amino acid sequence of SEQ ID NO: 604, LCDR2 having any one of the amino acid sequences of SEQ ID NO: 599, and LCDR3 having the amino acid sequence of SEQ ID NO:

605.

40. The polypeptide described above, A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 44, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

84. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 18, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

54. A variable light chain having an amino acid sequence with at least 90-99% sequence identity with SEQ ID NO: 19, and a variable heavy chain having an amino acid sequence with at least 90-99% sequence identity with SEQ ID NO:

55. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 20, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

56. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 21, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

57. A variable light chain having an amino acid sequence with at least 90-99% sequence identity with SEQ ID NO: 22, and a variable heavy chain having an amino acid sequence with at least 90-99% sequence identity with SEQ ID NO:

58. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 23, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

59. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 24, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

60. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 25, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

61. A variable light chain having an amino acid sequence with at least 90-99% sequence identity with SEQ ID NO: 26, and a variable heavy chain having an amino acid sequence with at least 90-99% sequence identity with SEQ ID NO:

62. A variable light chain having an amino acid sequence with at least 90-99% sequence identity with SEQ ID NO: 27, and a variable heavy chain having an amino acid sequence with at least 90-99% sequence identity with SEQ ID NO:

63. A variable light chain having an amino acid sequence with at least 90-99% sequence identity with SEQ ID NO: 28, and a variable heavy chain having an amino acid sequence with at least 90-99% sequence identity with SEQ ID NO:

64. A variable light chain having an amino acid sequence with at least 90-99% sequence identity with SEQ ID NO: 29, and a variable heavy chain having an amino acid sequence with at least 90-99% sequence identity with SEQ ID NO:

65. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 30, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

66. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 31, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

67. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 32, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

68. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 33, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

69. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 34, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

70. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 35, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

71. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 36, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

72. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 37, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

73. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 38, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

74. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 39, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

75. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 40, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

76. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 41, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

77. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 42, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

78. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 43, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

79. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 44, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

80. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 45, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

81. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 46, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

80. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 47, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

82. A variable light chain having an amino acid sequence with at least 90-99% sequence identity with SEQ ID NO: 48, and a variable heavy chain having an amino acid sequence with at least 90-99% sequence identity with SEQ ID NO:

83. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 49, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

85. A variable light chain having an amino acid sequence with at least 90-99% sequence identity with SEQ ID NO: 44, and a variable heavy chain having an amino acid sequence with at least 90-99% sequence identity with SEQ ID NO:

86. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 50, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

87. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 51, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

88. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 52, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

88. A variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 53, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 89, or It comprises a variable light chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO: 44, and a variable heavy chain having an amino acid sequence having at least 90-99% sequence identity with SEQ ID NO:

90. The anti-FcγRIIβ antibody or its antigen-binding fragment according to claim 38, wherein the variable light chain and the variable heavy chain referred to include the CDR described herein with respect to the variable light chain and the variable heavy chain referred to.

41. The polypeptide described above, A variable light chain having the amino acid sequence of SEQ ID NO: 44, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

84. A variable light chain having the amino acid sequence of SEQ ID NO: 18, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

54. A variable light chain having the amino acid sequence of SEQ ID NO: 19, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

55. A variable light chain having the amino acid sequence of SEQ ID NO: 20, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

56. A variable light chain having the amino acid sequence of SEQ ID NO: 21, and a variable heavy chain having the amino acid sequence of SEQ ID NO: 57, A variable light chain having the amino acid sequence of SEQ ID NO: 22, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

58. A variable light chain having the amino acid sequence of SEQ ID NO: 23, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

59. A variable light chain having the amino acid sequence of SEQ ID NO: 24, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

60. A variable light chain having the amino acid sequence of SEQ ID NO: 25, and a variable heavy chain having the amino acid sequence of SEQ ID NO: 61, A variable light chain having the amino acid sequence of SEQ ID NO: 26, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

62. A variable light chain having the amino acid sequence of SEQ ID NO: 27, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

63. A variable light chain having the amino acid sequence of SEQ ID NO: 28, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

64. A variable light chain having the amino acid sequence of SEQ ID NO: 29, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

65. A variable light chain having the amino acid sequence of SEQ ID NO: 30, and a variable heavy chain having the amino acid sequence of SEQ ID NO: 66, A variable light chain having the amino acid sequence of SEQ ID NO: 31, and a variable heavy chain having the amino acid sequence of SEQ ID NO: 67, A variable light chain having the amino acid sequence of SEQ ID NO: 32, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

68. A variable light chain having the amino acid sequence of SEQ ID NO: 33, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

69. A variable light chain having the amino acid sequence of SEQ ID NO: 34, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

70. A variable light chain having the amino acid sequence of SEQ ID NO: 35, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

71. A variable light chain having the amino acid sequence of SEQ ID NO: 36, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

72. A variable light chain having the amino acid sequence of SEQ ID NO: 37, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

73. A variable light chain having the amino acid sequence of SEQ ID NO: 38, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

74. A variable light chain having the amino acid sequence of SEQ ID NO: 39, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

75. A variable light chain having the amino acid sequence of SEQ ID NO: 40, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

76. A variable light chain having the amino acid sequence of SEQ ID NO: 41, and a variable heavy chain having the amino acid sequence of SEQ ID NO: 77, A variable light chain having the amino acid sequence of SEQ ID NO: 42, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

78. A variable light chain having the amino acid sequence of SEQ ID NO: 43, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

79. A variable light chain having the amino acid sequence of SEQ ID NO: 44, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

80. A variable light chain having the amino acid sequence of SEQ ID NO: 45, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

81. A variable light chain having the amino acid sequence of SEQ ID NO: 46, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

80. A variable light chain having the amino acid sequence of SEQ ID NO: 47, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

82. A variable light chain having the amino acid sequence of SEQ ID NO: 48, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

83. A variable light chain having the amino acid sequence of SEQ ID NO: 49, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

85. A variable light chain having the amino acid sequence of SEQ ID NO: 44, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

86. A variable light chain having the amino acid sequence of SEQ ID NO: 50, and a variable heavy chain having the amino acid sequence of SEQ ID NO: 87, A variable light chain having the amino acid sequence of SEQ ID NO: 51, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

88. A variable light chain having the amino acid sequence of SEQ ID NO: 52, and a variable heavy chain having the amino acid sequence of SEQ ID NO:

88. A variable light chain having the amino acid sequence of SEQ ID NO: 53, and a variable heavy chain having the amino acid sequence of SEQ ID NO: 89, or An anti-FcγRIIβ antibody or its antigen-binding fragment according to any one of claims 38 to 40, comprising a variable light chain having the amino acid sequence of SEQ ID NO: 44 and a variable heavy chain having the amino acid sequence of SEQ ID NO:

90.

42. The anti-FcγRIIβ antibody or its antigen-binding fragment according to any one of claims 38 to 41, wherein the anti-FcγRIIβ antibody or the antigen-binding fragment thereof is conjugated to an Fc polypeptide.

43. The anti-FcγRIIβ antibody or antigen-binding fragment thereof according to claim 42, wherein the Fc polypeptide selectively binds to FcγRIIβ.

44. The aforementioned Fc polypeptide corresponds to sequence numbers 543, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474 The anti-FcγRIIβ antibody or its antigen-binding fragment according to claim 42, comprising any one of the amino acid sequences of 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 544, 545, 546, 683, 684, 685, 686, 687, 688, 689, and 690.

45. The anti-FcγRIIβ antibody or antigen-binding fragment according to claim 42, wherein the Fc polypeptide is effectorless and may have mutations such as LALA (L234A, L235A) or AAA / LALAGA (L234A, L235A, G237A).

46. The anti-FcγRIIβ antibody or antigen-binding fragment according to any one of claims 38 to 45, wherein the antibody is in Fab, Fab', or F(ab')2 format.

47. The anti-FcγRIIβ antibody or the antigen-binding fragment thereof A heavy chain having an amino acid sequence having at least 90-9% sequence identity with any one of sequence numbers 638, 639, 640, 641, 642, 643, 644, 645, 646, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, or 637, The anti-FcγRIIβ antibody or its antigen-binding fragment according to claim 46, comprising: a light chain having an amino acid sequence having at least 90-99% sequence identity with any one of sequence numbers 674, 675, 676, 677, 678, 679, 680, 681, 682, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, or 673.

48. The anti-FcγRIIβ antibody or the antigen-binding fragment thereof A heavy chain having one of the amino acid sequences among sequence numbers 638, 639, 640, 641, 642, 643, 644, 645, 646, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, or 637, The anti-FcγRIIβ antibody or its antigen-binding fragment according to claim 46 or 47, comprising a light chain having any one amino acid sequence from sequence numbers 674, 675, 676, 677, 678, 679, 680, 681, 682, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, or 673.

49. The anti-FcγRIIβ antibody or the antigen-binding fragment thereof A heavy chain having the amino acid sequence of SEQ ID NO: 638, and a light chain having the amino acid sequence of SEQ ID NO: 674, A heavy chain having the amino acid sequence of SEQ ID NO: 639, and a light chain having the amino acid sequence of SEQ ID NO:

675. A heavy chain having the amino acid sequence of SEQ ID NO: 640, and a light chain having the amino acid sequence of SEQ ID NO: 676, A heavy chain having the amino acid sequence of SEQ ID NO: 641, and a light chain having the amino acid sequence of SEQ ID NO: 677, A heavy chain having the amino acid sequence of SEQ ID NO: 642, and a light chain having the amino acid sequence of SEQ ID NO: 678, A heavy chain having the amino acid sequence of SEQ ID NO: 643, and a light chain having the amino acid sequence of SEQ ID NO: 679, A heavy chain having the amino acid sequence of SEQ ID NO: 644, and a light chain having the amino acid sequence of SEQ ID NO: 680, A heavy chain having the amino acid sequence of SEQ ID NO: 645, and a light chain having the amino acid sequence of SEQ ID NO: 681, A heavy chain having the amino acid sequence of SEQ ID NO: 646, and a light chain having the amino acid sequence of SEQ ID NO:

682. A heavy chain having the amino acid sequence of SEQ ID NO: 611, and a light chain having the amino acid sequence of SEQ ID NO: 647, A heavy chain having the amino acid sequence of SEQ ID NO: 612, and a light chain having the amino acid sequence of SEQ ID NO: 648, A heavy chain having the amino acid sequence of SEQ ID NO: 613, and a light chain having the amino acid sequence of SEQ ID NO: 649, A heavy chain having the amino acid sequence of SEQ ID NO: 614, and a light chain having the amino acid sequence of SEQ ID NO: 650, A heavy chain having the amino acid sequence of SEQ ID NO: 615, and a light chain having the amino acid sequence of SEQ ID NO: 651, A heavy chain having the amino acid sequence of SEQ ID NO: 616, and a light chain having the amino acid sequence of SEQ ID NO: 652, A heavy chain having the amino acid sequence of SEQ ID NO: 617, and a light chain having the amino acid sequence of SEQ ID NO: 653, A heavy chain having the amino acid sequence of SEQ ID NO: 618, and a light chain having the amino acid sequence of SEQ ID NO: 654, A heavy chain having the amino acid sequence of SEQ ID NO: 619, and a light chain having the amino acid sequence of SEQ ID NO: 655, A heavy chain having the amino acid sequence of SEQ ID NO: 620, and a light chain having the amino acid sequence of SEQ ID NO: 656, A heavy chain having the amino acid sequence of SEQ ID NO: 621, and a light chain having the amino acid sequence of SEQ ID NO: 657, A heavy chain having the amino acid sequence of SEQ ID NO: 622, and a light chain having the amino acid sequence of SEQ ID NO: 658, A heavy chain having the amino acid sequence of SEQ ID NO: 623, and a light chain having the amino acid sequence of SEQ ID NO: 659, A heavy chain having the amino acid sequence of SEQ ID NO: 624, and a light chain having the amino acid sequence of SEQ ID NO: 660, A heavy chain having the amino acid sequence of SEQ ID NO: 625, and a light chain having the amino acid sequence of SEQ ID NO: 661, A heavy chain having the amino acid sequence of SEQ ID NO: 626, and a light chain having the amino acid sequence of SEQ ID NO: 662, A heavy chain having the amino acid sequence of SEQ ID NO: 627, and a light chain having the amino acid sequence of SEQ ID NO: 663, A heavy chain having the amino acid sequence of SEQ ID NO: 628, and a light chain having the amino acid sequence of SEQ ID NO: 664, A heavy chain having the amino acid sequence of SEQ ID NO: 629, and a light chain having the amino acid sequence of SEQ ID NO:

665. A heavy chain having the amino acid sequence of SEQ ID NO: 630, and a light chain having the amino acid sequence of SEQ ID NO: 666, A heavy chain having the amino acid sequence of SEQ ID NO: 631, and a light chain having the amino acid sequence of SEQ ID NO: 667, A heavy chain having the amino acid sequence of SEQ ID NO: 632, and a light chain having the amino acid sequence of SEQ ID NO: 668, A heavy chain having the amino acid sequence of SEQ ID NO: 633, and a light chain having the amino acid sequence of SEQ ID NO: 669, A heavy chain having the amino acid sequence of SEQ ID NO: 634, and a light chain having the amino acid sequence of SEQ ID NO: 670, A heavy chain having the amino acid sequence of SEQ ID NO: 635, and a light chain having the amino acid sequence of SEQ ID NO: 671, A heavy chain having the amino acid sequence of SEQ ID NO: 636, and a light chain having the amino acid sequence of SEQ ID NO: 672, or The anti-FcγRIIβ antibody or its antigen-binding fragment according to claim 48, comprising a heavy chain having the amino acid sequence of SEQ ID NO: 637 and a light chain having the amino acid sequence of SEQ ID NO:

673.

50. The anti-FcγRIIβ antibody or the antigen-binding fragment thereof according to any one of claims 38 to 49, wherein the anti-FcγRIIβ antibody or the antigen-binding fragment thereof selectively binds to FcγRIIβ.

51. The anti-FcγRIIβ antibody or the antigen-binding fragment thereof according to any one of claims 38 to 50, wherein the anti-FcγRIIβ antibody or the antigen-binding fragment thereof selectively binds to FcγRIIβ rather than FcγRIIα.

52. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof according to any one of claims 38 to 51, and a pharmaceutically acceptable excipient.

53. A method for treating an autoimmune disorder in a subject, comprising administering a pharmaceutical composition comprising an antibody or antigen-binding fragment according to any one of claims 38 to 51 and a pharmaceutically acceptable excipient.

54. The aforementioned autoimmune disorders include rheumatoid arthritis, alopecia areata, interstitial cystitis, lupus (e.g., lupus nephritis), chronic kidney disease (CKD), autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, pemphigus vulgaris, psoriasis, systemic scleroderma, vitiligo, Addison's disease, diabetes mellitus type 1, autoimmune thyroiditis, oldo thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjögren's syndrome, and autoimmune diseases. The method according to claim 53, wherein the patient is an immune enteropathy, celiac disease, Crohn's disease, microscopic colitis, ulcerative colitis, arthritis (e.g., psoriatic arthritis, IBD-associated arthritis, or reactive arthritis), fibromyalgia, myasthenia gravis, warm antibody hemolytic anemia (wAIHA), immunothrombocytopenia, multiple sclerosis, chronic idiopathic demyelinating polyneuropathy (CIDP), atopic dermatitis, or eczema, or any combination thereof.

55. A method for inhibiting B cell activation, comprising administering a pharmaceutical composition comprising an antibody or antigen-binding fragment according to any one of claims 38 to 51 and a pharmaceutically acceptable excipient.

56. The method according to claim 55, wherein the antibody or the antigen-binding fragment thereof selectively binds to FcγRIIβ and inhibits the activation of the B cell.

57. A nucleic acid molecule encoding an antibody or an antigen-binding fragment thereof according to any one of claims 38 to 51.

58. A vector comprising the nucleic acid molecule described in claim 57.

59. A cell comprising the nucleic acid molecule described in claim 57 or the vector described in claim 58.

60. A method for producing an antibody or an antigen-binding fragment thereof according to any one of claims 38 to 51, comprising culturing cells containing a nucleic acid molecule encoding the antibody or the antigen-binding fragment under conditions sufficient to produce the antibody or the antigen-binding fragment.

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