SIRP gamma antibodies and uses thereof

Abstract

Provided herein are antibodies that bind to the signal regulatory protein SIRPγ, as well as methods of making and using such antibodies. In some embodiments, the antibodies comprise an Fc and are useful for preferential depletion of specific SIRPγ expressing cells. In some embodiments, the antibodies provided herein are useful for treating diseases or conditions associated with cellular dysregulation (e.g., hyperactivation or abnormal proliferation of T cells).

Description

[Technical field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 277,966, filed November 10, 2021, the contents of which are incorporated herein by reference in their entirety.

[0002] INCORPORATION BY REFERENCE TO SEQUENCE LISTING The contents of the electronic sequence listing (ELTH_003_01 WO_SeqList_ST26.xml; size: 459,345 bytes, created on: November 8, 2022) are incorporated herein by reference in their entirety. [Background technology]

[0003] Signal regulatory proteins (SIRPs) are a family of cell surface immune receptors with Ig-like extracellular domains, including three members, SIRPα, SIRPβ1, and SIRPγ. SIRPα and SIRPβ1 are found on myeloid cells, including monocytes, macrophages, and dendritic cells, as well as on granulocytes, such as neutrophils, eosinophils, and basophils. Unlike SIRPα and SIRPβ1, SIRPγ (also called CD172 antigen-like family member B, CD172γ, SIRPβ2, and SIRP-β-2) is not expressed by myeloid cells, but instead is primarily expressed by T cells and has also been found on a subset of activated NK cells and B cells. Like SIRPα, SIRPγ has been found to bind to CD47, a ubiquitously expressed cell surface protein, albeit with a lower affinity compared to SIRPα. Unlike SIRPα, SIRPγ does not have a known signaling mechanism. Rather, SIRPγ has been shown to mediate cell-cell adhesion and is hypothesized to promote T cell-antigen-presenting cell interactions for immune synapse stabilization and immune activation (Blood (2005) 105(6):2421-2427).

[0004] There is a need for agents that bind to specific populations of cells, sparing other cells, and are useful for targeted treatment of various diseases and conditions. Such agents provide a safe and effective approach to treat oncological, autoimmune, and inflammatory disorders driven by the pathological activity of specific cell populations. Provided herein are such agents that target specific populations of SIRPγ-expressing cells, which are useful for targeted treatment of various diseases and conditions. Summary of the Invention

[0005] Provided herein are antibodies specific for SIRPγ, which are useful for targeted depletion of specific cell populations. In some embodiments, SIRPγ may be upregulated upon certain cellular conditions (e.g., stimulation or exhaustion), and the use of the antibodies of the present disclosure induces preferential depletion of such cells in the specific conditions. In some embodiments, different SIRPγ isoforms may be expressed on different subsets of cells, and the use of the antibodies of the present disclosure induces preferential depletion of such different subsets. Further provided herein are methods of making and using SIRPγ antibodies.

[0006] Exemplary antibody amino acid sequences are provided in Tables 1 and 2.

[0007] More specifically, in one aspect, provided herein is an Fc-containing antibody specific for SIRPγ, wherein the antibody has low or no affinity for binding to SIRPα and SIRPβ1, and binding of the antibody to SIRPγ-expressing cells induces effector-mediated depletion of SIRPγ-expressing cells.

[0008] In another aspect, provided herein are SIRPγ antibodies that have low or no affinity for binding to SIRPα and SIRPβ1, and which exhibit preferential binding to and depletion of activated (stimulated) T cells compared to unstimulated T cells.In a related aspect, provided herein are (a) SIRPγ antibodies that have low or no affinity for binding to SIRPα and SIRPβ1, and that exhibit preferential binding to and depletion of CD8+ T cells; (b) SIRPγ antibodies that have low or no affinity for binding to SIRPα and SIRPβ1, and that exhibit preferential binding to and depletion of CD4+ T cells; (c) SIRPγ antibodies that have low or no affinity for binding to SIRPα and SIRPβ1, and that exhibit preferential binding to and depletion of CD4+ T cells; (d) SIRPγ antibodies with low or no affinity for binding to SIRPα and SIRPβ1, which show preferential binding to CD8+ / CD25+ T cells and depletion of CD8+ / CD25+ T cells; (e) SIRPγ antibodies with low or no affinity for binding to SIRPα and SIRPβ1, which show preferential binding to CD8+ T cells and depletion of CD8+ / CD25+ T cells when compared to SIRPγ expressing CD4+ T cells. (f) SIRPγ antibodies that have low or no affinity for binding to SIRPα and SIRPβ1 and that show preferential binding to and depletion of CD4+ T cells when compared to SIRPγ expressing CD8+ T cells; (g) SIRPγ antibodies that have low or no affinity for binding to SIRPα and SIRPβ1 and that show preferential binding to and depletion of CD8+ / CD69+ T cells when compared to SIRPγ expressing CD8+ / CD69− cells. (h) an SIRPγ antibody that has low or no affinity for binding to SIRPα and SIRPβ1 and that exhibits preferential binding to and depletion of CD8+ / CD25+ T cells when compared to SIRPγ-expressing CD8+ / CD25- T cells; or (i) an SIRPγ antibody that has low or no affinity for binding to SIRPα and SIRPβ1 and that exhibits preferential binding to and depletion of PD1+ T cells when compared to SIRPγ-expressing PD1- T cells.

[0009] In another aspect, provided herein is a method of inducing preferential depletion of a population of SIRPγ-expressing cells, the method comprising contacting the population with any of the SIRPγ antibodies of the present disclosure.

[0010] In another aspect, provided herein are methods of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of any of the SIRPγ antibodies of the present disclosure, in some embodiments, the Fc-containing SIRPγ antibodies provided herein are useful for treating an autoimmune, inflammatory, or oncological disease or condition.

[0011] Further provided herein is a pharmaceutical composition comprising any of the SIRPγ antibodies of the present disclosure, and optionally a pharma- ceutically acceptable carrier. Further provided herein are nucleic acids encoding the SIRPγ antibodies of the present disclosure, and methods of making the same. Exemplary nucleic acids are provided in Table 3. [Brief description of the drawings]

[0012] [Figure 1] Binding of Antibody 1 and Antibody 2 to human and cynomolgus monkey (cyno) SIRPγ, SIRPα, and SIRPβ1 by enzyme-linked immunosorbent assay (ELISA). [Figure 2A] Binding curves of selected antibodies to human and cynomolgus SIRPγ by ELISA are shown. [Figure 2B] Binding curves of selected antibodies to human SIRPαV1, SIRPαV2, and SIRPβ1 by ELISA are shown. [Figure 2C] Binding curves of selected antibodies to human and cynomolgus SIRPγ, human SIRPαV1, and human SIRPβ1 by ELISA are shown. [Figure 2D] Binding curves of selected antibodies to human and cynomolgus SIRPγ, human SIRPαV1, and human SIRPβ1 by ELISA are shown. [Figure 2E] Binding curves of selected antibodies to human and cynomolgus SIRPγ, human SIRPαV1, and human SIRPβ1 by ELISA are shown. [Figure 2F] Binding curves of selected antibodies to human and cynomolgus SIRPγ, human SIRPαV1, and human SIRPβ1 by ELISA are shown. [Figure 2G] Binding curves of selected antibodies to human and cynomolgus SIRPγ, human SIRPαV1, and human SIRPβ1 by ELISA are shown. [Figure 3A] Binding curves of selected antibodies to human CD3+ T cells, CD20+ B cells, and CD56+ NK cells in human whole blood by flow cytometry. [Figure 3B] Binding curves of selected antibodies to human CD14+ monocytes and granulocytes in human whole blood by flow cytometry. [Figure 3C] Binding curves of selected antibodies to human CD14+ monocytes and granulocytes in human whole blood by flow cytometry. [Figure 3D] Binding curves of selected antibodies to human CD4+ T cells, CD8+ T cells, CD20+ B cells, and CD56+ NK cells in human whole blood by flow cytometry. [Figure 4A] We show that T cell activation results in differential regulation of cell surface SIRPγ expression, and SIRPγ-specific antibodies can increase binding to such activated T cells. Ex vivo activation of healthy donor T cells with anti-CD3 and anti-CD28 antibodies resulted in upregulation of surface SIRPγ expression (when compared to their unstimulated counterparts). [Figure 4B] We show that T cell activation results in differential regulation of cell surface SIRPγ expression, and SIRPγ-specific antibodies can increase binding to such activated T cells. Ex vivo activation of healthy donor T cells with anti-CD3 and anti-CD28 antibodies resulted in upregulation of surface SIRPγ expression (when compared to their unstimulated counterparts). [Figure 4C] We show that T cell activation results in differential regulation of cell surface SIRPγ expression, and SIRPγ-specific antibodies can increase binding to such activated T cells. Ex vivo activation of healthy donor T cells with anti-CD3 and anti-CD28 antibodies resulted in upregulation of surface SIRPγ expression (when compared to their unstimulated counterparts). [Figure 4D] Model during T cell activation, SIRPγ expression is increased, and such increased target expression allows for preferential depletion of activated T cells. [Figure 5A] 1 shows the binding curves of selected SIRPγ antibodies to human SIRPγ-expressing CHO cells and cynomolgus monkey SIRPγ-expressing CHO cells by flow cytometry. [Figure 5B] 1 shows the binding curves of selected SIRPγ antibodies to human SIRPγ-expressing CHO cells and cynomolgus monkey SIRPγ-expressing CHO cells by flow cytometry. [Figure 5C] 1 shows the binding curves of selected SIRPγ antibodies to human SIRPγ-expressing CHO cells and cynomolgus monkey SIRPγ-expressing CHO cells by flow cytometry. [Figure 5D] 1 shows the binding curves of selected SIRPγ antibodies to human SIRPγ-expressing CHO cells and cynomolgus monkey SIRPγ-expressing CHO cells by flow cytometry. [Figure 5E] 1 shows the binding curves of selected SIRPγ antibodies to human SIRPγ-expressing CHO cells and cynomolgus monkey SIRPγ-expressing CHO cells by flow cytometry. [Figure 5F] 1 shows the binding curves of selected SIRPγ antibodies to human SIRPγ-expressing CHO cells and cynomolgus monkey SIRPγ-expressing CHO cells by flow cytometry. [Figure 5G] Binding curves of selected SIRPγ antibodies to human and cynomolgus monkey SIRPα-expressing CHO cells, and human and cynomolgus monkey SIRPβ1-expressing CHO cells by flow cytometry are shown. [Figure 5H]Binding curves of selected SIRPγ antibodies to human and cynomolgus monkey SIRPα-expressing CHO cells, and human and cynomolgus monkey SIRPβ1-expressing CHO cells by flow cytometry are shown. [Figure 5I] Binding curves of selected SIRPγ antibodies to human and cynomolgus monkey SIRPα-expressing CHO cells, and human and cynomolgus monkey SIRPβ1-expressing CHO cells by flow cytometry are shown. [Figure 5J] Binding curves of selected SIRPγ antibodies to human and cynomolgus monkey SIRPα-expressing CHO cells, and human and cynomolgus monkey SIRPβ1-expressing CHO cells by flow cytometry are shown. [Figure 5K] Binding curves of selected SIRPγ antibodies to human and cynomolgus monkey SIRPα-expressing CHO cells, and human and cynomolgus monkey SIRPβ1-expressing CHO cells by flow cytometry are shown. [Figure 5L] Binding curves of selected SIRPγ antibodies to human and cynomolgus monkey SIRPα-expressing CHO cells, and human and cynomolgus monkey SIRPβ1-expressing CHO cells by flow cytometry are shown. [Figure 6A] The effect of selected antibodies on ADCC of human CD3+ resting (left) and stimulated (right) T cells in vitro is shown. [Figure 6B] The effect of selected antibodies on ADCC of human CD3+ resting (left) and stimulated (right) T cells in vitro is shown. [Figure 6C] The effect of selected antibodies on ADCC of human CD3+ resting (left) and stimulated (right) T cells in vitro is shown. [Figure 7] The effect of selected antibodies on ADCP of human CD3+ resting (left panel) and stimulated (right panel) T cells in vitro is shown. [Figure 8A] 1 shows the results of ELISA experiments assessing the ability of selected antibodies to disrupt CD47 binding to human SIRPγ. [Figure 8B]1 shows the results of ELISA experiments assessing the ability of selected antibodies to disrupt CD47 binding to human SIRPγ. [Figure 9] 1 shows the results of mixed lymphocyte reaction (MLR) experiments assessing the effect of selected antibodies on T cell proliferation. [Figure 10] FIG. 1 shows the effect of selected antibodies on human CD3+ T cell depletion in vivo. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Provided herein are antibodies that bind to SIRPγ. Additionally, methods of making and using such antibodies are provided. Given the restricted and unique pattern of SIRPγ expression, these antibodies may be useful for targeting specific cell types and treating diseases or conditions involving cells or cell states that express SIRPγ, such as activated cells. For example, in some embodiments, the antibodies may be used to treat diseases or conditions that involve dysfunction, dysregulation, overactivation and / or overproliferation of SIRPγ-expressing cells as part of their pathology.

[0014] When elements are presented in list form (eg, in a Markush group), it is to be understood that each possible subgroup of the elements is also disclosed, and any one or more elements can be removed from the list or group.

[0015] Unless expressly indicated, in any method described or disclosed herein that includes two or more acts, the order of the acts is not necessarily limited to the order in which the acts of the method are described, but it is to be understood that the present disclosure includes example embodiments in which the order of the acts is so limited.

[0016] Terms used throughout this specification are defined as follows, unless otherwise limited in certain instances. In the specification and claims, the singular forms "a", "an" and "the" include their plural forms unless otherwise specified. All technical and scientific terms, acronyms and abbreviations used in the specification and claims have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains, unless otherwise defined or stated. All numerical ranges include the values ​​defining the range and all integer values ​​therebetween, unless otherwise indicated or defined.

[0017] The term "antibody" as used throughout this specification is used in the broadest sense and includes monoclonal antibodies, polyclonal antibodies, human antibodies, humanized antibodies, non-human antibodies, chimeric antibodies, monovalent antibodies, and antibody fragments. The term can refer to an intact tetrameric antibody ("full length") containing two light chains and two heavy chains, each with a variable region and a constant region. It can also refer to an antibody fragment.

[0018] Antibody fragments of the present disclosure retain SIRPγ antigen-binding specificity. Antibody fragments include antigen-binding fragments (Fab), variable fragments (Fv) comprising a VH sequence and a VL sequence, single-chain variable fragments (scFv) comprising a VH sequence and a VL sequence linked together in one chain, single-chain antibody fragments (scAb) or other antibody variable region fragments (e.g., Fab', F(ab')2, dsFv diabody, and Fd polypeptide fragments).

[0019] The term "depletion" as used throughout the specification refers to cell death as an Fc-mediated effector function. Without being bound by theory or mechanism, the Fc-containing SIRPγ antibodies of the present disclosure can deplete SIRPγ-expressing target cells, including effector functions for their mechanism of action. Without being bound by theory or mechanism, it is believed that the Fc-containing antibodies of the present disclosure bind to SIRPγ-expressing cells via their complementarity determining regions (CDRs), and the Fc region of the antibody interacts with Fc receptors on the surface of effector immune cells or circulating complement proteins, resulting in depletion (cell death) of SIRPγ-expressing target cells. Depletion can be achieved through immune cell effector processes such as antibody-dependent cell-mediated cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP). Additionally or alternatively, the Fc region can bind complement components and cause complement-dependent cytotoxicity (CDC). The Fc-mediated cell death (depletion) described herein is independent of any CDR-mediated signaling that results in cell death. However, the depletion caused by use of any of the Fc-containing SIRPγ antibodies of the present disclosure may further include a CDR-mediated cell death component, although this is not required.

[0020] The terms "individual," "subject," and "patient" are used interchangeably herein and refer to any subject for whom treatment or therapy is desired. The subject may be a mammalian subject. Mammalian subjects include, for example, humans, non-human primates, rodents (e.g., rats, mice), lagomorphs (e.g., rabbits), ungulates (e.g., cows, sheep, pigs, horses, goats, etc.), and the like. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human primate, e.g., a cynomolgus monkey. In some embodiments, the subject is a companion animal (e.g., cat, dog).

[0021] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0022] I. Antibodies A.SIRPγ antibody Provided herein are antibodies that bind to SIRPγ, which antibodies show little or no binding to SIRPα and SIRPβ1.

[0023] As used herein, "SIRPγ" includes all isoforms from any species. In humans, multiple SIRPγ transcripts exist, including full-length, two alternatively spliced ​​forms that lack a significant portion of their extracellular domain, and one alternatively spliced ​​form that lacks the signal peptide sequence.

[0024] The amino acid sequence of hSIRPγ isoform 1 (full length) is provided as SEQ ID NO:1 (see UniProtKB ID Q9P1W8 isoform 1).

[0025] [ka]

[0026] The amino acid sequence of splice variant hSIRPγ (isoform 2) is provided as SEQ ID NO: 37. (See UniProtKB ID Q9P1W8 isoform 2).

[0027] [ka]

[0028] The amino acid sequence of splice variant hSIRPγ (isoform 3) is provided as SEQ ID NO: 2. (See UniProtKB ID Q9P1W8 isoform 3).

[0029] [ka]

[0030] The amino acid sequence of another splice variant hSIRPγ (isoform 4) is provided as SEQ ID NO:3 (see UniProtKB ID Q9P1W8 isoform 4).

[0031] [ka]

[0032] The amino acid sequence of cynomolgus monkey SIRPγ is provided as SEQ ID NO: 4. (See GenBank: EHH65481.1).

[0033] [ka]

[0034] Thus, the SIRPγ antibodies of the present disclosure may bind to one or more isoforms of SIRPγ of a single species. In some embodiments, the SIRPγ antibodies also bind to one or more isoforms of SIRPγ of two or more species. In some embodiments, the SIRPγ antibodies also bind to one or more isoforms of human SIRPγ. In some embodiments, the SIRPγ antibodies also bind to one or more isoforms of non-human primate SIRPγ, e.g., cynomolgus monkey SIRPγ.

[0035] In some embodiments, a SIRPγ antibody binds to multiple SIRPγ variants or isoforms found in a particular species. For example, a SIRPγ antibody binds to two or more of SIRPγ human isoforms 1-3. In some embodiments, a SIRPγ antibody binds to the extracellular domain of SIRPγ (e.g., amino acids 1-360 of SEQ ID NO:1).

[0036] In some embodiments, a SIRPγ antibody of the disclosure binds to multiple SIRPγ isoforms found in a particular species, e.g., a SIRPγ antibody binds to more than one SIRPγ human isoform (e.g., the antibody binds to full-length and one or more splice variants), while in other embodiments, a SIRPγ antibody binds to some, but not all, SIRPγ isoforms found in a particular species (e.g., the SIRPγ antibody binds to one, but not all, splice variants).

[0037] Those skilled in the art will recognize that an antibody that exhibits little or no binding to a target antigen may be described as having a low affinity for the target antigen and a high equilibrium dissociation constant (KD), e.g., a KD of about 10 μM or more, about 100 μM or more, about 1 mM or more, or about 10 mM or more. Those skilled in the art will further recognize that an antibody that exhibits little or no binding to a target antigen may be described as having a low affinity for the target antigen and a high equilibrium dissociation constant (KD), e.g., a KD of about 10 μM or more, about 100 μM or more, about 1 mM or more, or about 10 mM or more. For example, a SIRPγ antibody that binds SIRPγ may bind SIRPβ1 and / or SIRPα with low affinity. SIRPγ antibodies of the present disclosure having low affinity for SIRPβ1 and / or SIRPα may bind to SIRPβ1 and / or SIRPα with a KD of about 10 μM or more, about 100 μM or more, about 1 mM or more, or about 10 mM or more, but may retain a higher binding affinity for SIRPγ.

[0038] In some embodiments, SIRPγ antibodies are provided that comprise a binding affinity (KD) for SIRPγ of about 0.0001 nM, about 0.0005 nM, about 0.001 nM, about 0.005 nM, about 0.1 nM, about 0.05 nM, about 0.1 nM, about 0.5 nM, about 1 nM, about 5 nM, about 10 nM, about 50 nM, about 100 nM, about 500 nM, about 1 μM, about 2 μM, or about 3 μM.

[0039] In some embodiments, about 0.0001 nM to 5 μM, about 0.0005 nM to 5 μM, about 0.05 nM to 5 μM, about 0.5 nM to 5 μM, about 1 nM to 5 μM, about 5 nM to 5 μM, 0.0001 nM to 2 μM, about 0.0005 nM to 2 μM, about 0.05 nM to 2 μM, about 0.5 nM to 2 μM, about 1 nM to 2 μM, about 5 nM to 2 μM, 0.0001 nM to 1 μM, about 0.0005 nM to 1 μM, about 0.05 nM to 1 μM, about 0.5 nM to 1 μM, about 1 nM to 1 μM Provided herein are SIRPγ antibodies comprising a binding affinity (KD) for SIRPγ of about 5 nM to 1 μM, about 0.0001 nM to 500 nM, about 0.0005 nM to 500 μM, about 0.05 nM to 500 nM, about 0.5 nM to 500 nM, about 1 nM to 500 nM, about 5 nM to 500 nM, about 0.0001 nM to 50 nM, about 0.0005 nM to 50 nM, about 0.05 nM to 50 nM, about 0.5 nM to 50 nM, about 1 nM to 50 nM, or about 5 nM to 50 nM.

[0040] In some embodiments, the SIRPγ antibodies of the present disclosure do not disrupt CD47 binding to SIRPγ present on a cell or other surface. Exemplary antibodies that do not disrupt CD47 binding to SIRPγ include antibodies with the following sequences, see Table 1 below: a. The CDR-H1 amino acid sequence of SEQ ID NO:210; the CDR-H2 amino acid sequence of SEQ ID NO:246; the CDR-H3 amino acid sequence of SEQ ID NO:278; the CDR-L1 amino acid sequence of SEQ ID NO:101; the CDR-L2 amino acid sequence of SEQ ID NO:139; and the CDR-L3 amino acid sequence of SEQ ID NO:168. b. The CDR-H1 amino acid sequence of SEQ ID NO:213; the CDR-H2 amino acid sequence of SEQ ID NO:249; the CDR-H3 amino acid sequence of SEQ ID NO:290; the CDR-L1 amino acid sequence of SEQ ID NO:112; the CDR-L2 amino acid sequence of SEQ ID NO:148; and the CDR-L3 amino acid sequence of SEQ ID NO:179. c. A CDR-H1 amino acid sequence of SEQ ID NO:234; a CDR-H2 amino acid sequence of SEQ ID NO:249; a CDR-H3 amino acid sequence of SEQ ID NO:308; a CDR-L1 amino acid sequence of SEQ ID NO:127; a CDR-L2 amino acid sequence of SEQ ID NO:155; and a CDR-L3 amino acid sequence of SEQ ID NO:196. d. A CDR-H1 amino acid sequence of SEQ ID NO:243; a CDR-H2 amino acid sequence of SEQ ID NO:249; a CDR-H3 amino acid sequence of SEQ ID NO:321; a CDR-L1 amino acid sequence of SEQ ID NO:136; a CDR-L2 amino acid sequence of SEQ ID NO:164; and a CDR-L3 amino acid sequence of SEQ ID NO:207.

[0041] Exemplary antibodies of the disclosure that do not disrupt CD47 binding to SIRPγ include, for example, antibody 5, antibody 6, antibody 8, antibody 59, antibody 73, antibody 80, antibody 85, antibody 92, and antibody 96 (shown in Figures 8A and 8B). The CDR and VH / VL sequences for these antibodies are provided in Tables 1 and 2.

[0042] In other embodiments, the SIRPγ antibodies of the disclosure disrupt binding of CD47 to SIRPγ present on a cell or other surface. In other embodiments, the SIRPγ antibodies of the disclosure enhance or promote binding of CD47 to SIRPγ present on a cell or other surface. Exemplary antibodies that do not disrupt CD47 binding to SIRPγ include antibodies comprising the following sequences, with reference to Table 2: an antibody comprising the CDR-H1 amino acid sequence of SEQ ID NO:209; the CDR-H2 amino acid sequence of SEQ ID NO:245; the CDR-H3 amino acid sequence of SEQ ID NO:277; the CDR-L1 amino acid sequence of SEQ ID NO:100; the CDR-L2 amino acid sequence of SEQ ID NO:138; and the CDR-L3 amino acid sequence of SEQ ID NO:167. Exemplary antibodies of the disclosure that enhance or promote CD47 binding to SIRPγ include antibody 3, antibody 4, and antibody 7. The CDR and VH / VL sequences for these antibodies are provided in Tables 1 and 2.

[0043] Further provided herein are Fc-containing SIRPγ antibodies. In some embodiments, the Fc domain (interchangeably referred to as Fc sequence, Fc region, or simply Fc) of the SIRPγ antibody is a human Fc domain. In some embodiments, the Fc domain of the SIRPγ antibody is human IgG1, human IgG2, human IgG3, or human IgG4. In some embodiments, the Fc domain of the SIRPγ antibody is a mouse Fc domain. In some embodiments, the Fc domain of the SIRPγ antibody is mouse IgG1 or mouse IgG2a. In some embodiments, the Fc domain of the SIRPγ antibody is a rat Fc domain. In some embodiments, the Fc domain of the SIRPγ antibody is rat IgG1 or rat IgG2b. In embodiments, the Fc domain of the SIRPγ antibody is of a non-human primate, e.g., a cynomolgus monkey Fc domain.

[0044] In some embodiments, the SIRPγ antibodies provided herein are full-length antibodies (including intact tetrameric antibodies containing two light chains and two heavy chains, each with a variable region and a constant region). In some embodiments, the constant region of the full-length SIRPγ antibody comprises a human Fc domain. In some embodiments, the Fc domain of the full-length SIRPγ antibody is derived from human IgG1, human IgG2, human IgG3, or human IgG4. In some embodiments, the Fc domain of the full-length SIRPγ antibody is a mouse immunoglobulin Fc domain. In some embodiments, the Fc domain of the full-length SIRPγ antibody is a mouse IgG1 or mouse IgG2a Fc domain. In some embodiments, the Fc domain of the full-length SIRPγ antibody is a rat Fc domain. In some embodiments, the Fc domain of the full-length SIRPγ antibody is derived from rat IgG1 or rat IgG2b. In embodiments, the Fc domain of the full-length SIRPγ antibody is from a non-human primate, e.g., a cynomolgus monkey Fc domain.

[0045] In some embodiments, the SIRPγ antibody contains an Fc domain (referred to as an "Fc-containing antibody"), and binding of the Fc-containing antibody to a SIRPγ-expressing cell can mediate effector cell-mediated depletion of the SIRPγ-expressing cell. In some embodiments, the Fc domain of the SIRPγ antibody is human IgG1 Fc. Exemplary, but non-limiting, sequences of the heavy chain constant region (CH) of human IgG1 encompassing the Fc domain of interest are provided as SEQ ID NOs: 5-27 and SEQ ID NO: 36. SEQ ID NO: 5 provides the standard human IgG1 heavy chain constant region (CH) sequence.

[0046] [ka]

[0047] [ka]

[0048] [ka]

[0049] In some embodiments, the constant region of the human IgG1 heavy chain sequence encompassing the Fc domain of interest is SEQ ID NO:23 and X1 is V or A.

[0050] [ka]

[0051] In some embodiments, the constant region of the human IgG1 heavy chain sequence encompassing the Fc domain of interest is SEQ ID NO:24, wherein X1 is V or A; X2 is G or A; X3 is S or D; and X4 is I or E.

[0052] [ka]

[0053] In some embodiments, the constant region of the human IgG1 heavy chain sequence encompassing the Fc domain of interest is SEQ ID NO:25 and X1 is V or A.

[0054] [ka]

[0055] In some embodiments, the constant region of the human IgG1 heavy chain sequence encompassing the Fc domain of interest is SEQ ID NO:26, where X1 is V or A; X2 is M or L; and X3 is N or S.

[0056] [ka]

[0057] In some embodiments, the constant region of the human IgG1 heavy chain sequence encompassing the Fc domain of interest is SEQ ID NO:27, wherein X1 is K or R; X2 is D or E; and X3 is L or M.

[0058] [ka]

[0059] In some embodiments, the constant region of the human IgG1 heavy chain sequence encompassing the Fc domain of interest is SEQ ID NO: 36 and contains the L234A, L235A, P329G substitutions (referred to as LALA-PG substitutions).

[0060] [ka]

[0061] In some embodiments, the Fc domain of the Fc-containing SIRPγ antibody is human IgG4 Fc. Exemplary, but non-limiting, sequences of the heavy chain constant region (CH) of human IgG4 encompassing the Fc domain of interest are provided as SEQ ID NOs: 28-35. SEQ ID NO: 28 provides the standard human IgG4 heavy chain constant region (CH) sequence.

[0062] [ka]

[0063] In some embodiments, the constant region of the human IgG4 heavy chain sequence encompassing the Fc domain of interest is SEQ ID NO:35, X1 is S or P; X2 is L or E.

[0064] [ka]

[0065] In some embodiments, the SIRPγ antibodies provided herein are chimeric and comprise a variable region from one species and a constant region from another species, e.g., a human variable region and a rat constant region. In some embodiments, the rat constant region comprises a sequence from rat IgG1 or rat IgG2b. In some embodiments, the antibody comprises a human variable region and a mouse constant region. In some embodiments, the mouse constant region is mouse IgG1 or mouse IgG2a. In some embodiments, the antibody comprises a human variable region and a human constant region. In exemplary embodiments, the human constant region comprises a sequence from human IgG1, human IgG2, human IgG3, or human IgG4.

[0066] The EU numbering scheme is one of many available antibody numbering schemes based on residue numbers assigned to standard antibody sequences. Thus, one of skill in the art will understand that a reference to a particular residue using the EU numbering scheme may or may not be the exact residue in one of the SIRPγ antibodies of the present disclosure. For example, if a SIRPγ antibody of the present disclosure contains a V215A substitution in the Fc region of the heavy chain and the position number of the amino acid residue is of the EU numbering scheme, the residue may not be the actual residue 215 in that particular SIRPγ antibody. It may be the actual residue number 213, or residue number 214, or residue number 215, or residue number 216, etc. Thus, one of skill in the art will understand how to correspond a residue listed using the EU numbering scheme to an actual residue in a SIRPγ antibody of the present disclosure. The EU numbering system for antibodies is known in the art and is described, for example, at imgt.org / IMGTScientificChart / Numbering / Hu_IGHGnber.html.

[0067] In some embodiments, the Fc domain of the SIRPγ antibody is derived from a human IgG1 constant heavy chain (e.g., SEQ ID NO:5) and heavy chain Fc substitutions are introduced to increase effector function (e.g., those that exhibit increased affinity for FcγR or that promote complement protein binding).

[0068] In some embodiments, the Fc domain of the SIRPγ antibody is derived from a human IgG1 constant heavy chain (eg, SEQ ID NO:5) and heavy chain Fc substitutions are introduced to reduce (eg, silence) effector function.

[0069] In some embodiments, the Fc domain of the SIRPγ antibody is derived from a human IgG1 constant heavy chain (eg, SEQ ID NO:5) and heavy chain Fc substitutions are introduced to increase antibody half-life.

[0070] In some embodiments, the Fc domain of the SIRPγ antibody is derived from a human IgG4 constant heavy chain (e.g., SEQ ID NO: 28) and heavy chain Fc substitutions are introduced to increase effector function (e.g., those that exhibit increased affinity for FcγR or that promote complement protein binding).

[0071] In some embodiments, the Fc domain of the SIRPγ antibody is derived from a human IgG4 constant heavy chain (eg, SEQ ID NO: 28) and heavy chain Fc substitutions are introduced to reduce (eg, silence) effector function.

[0072] In some embodiments, the Fc domain of the SIRPγ antibody is derived from a human IgG4 constant heavy chain (eg, SEQ ID NO: 28), and heavy chain Fc substitutions are introduced to increase antibody half-life.

[0073] In some embodiments, the Fc domain of the SIRPγ antibody is an IgG1 Fc domain (e.g., an Fc domain derived from any one of the IgG1 constant heavy chain sequences of SEQ ID NOs: 5 to 27, SEQ ID NO: 36) or an IgG4 human Fc domain (e.g., an Fc domain derived from any one of the IgG4 constant heavy chain sequences of SEQ ID NOs: 28 to 35).

[0074] In some embodiments, the Fc domain of the SIRPγ antibody is an IgG1 Fc domain (e.g., an Fc domain derived from any one of the IgG1 constant heavy chain sequences of SEQ ID NOs: 5-27, or SEQ ID NO: 36), or an IgG4 human Fc domain (e.g., an Fc domain derived from any one of the IgG4 constant heavy chain sequences of SEQ ID NO: 28, SEQ ID NO: 29, or SEQ ID NO: 35), and in the heavy chain, and at least one amino acid substitution at a position selected from the group consisting of: 4, 256, 262, 263, 264, 265, 266, 267, 268, 269, 270, 292, 296, 297, 298, 299, 300, 305, 313, 324, 325, 326, 327, 328, 329, 330, 332, 333, 334, 345, 356, 358, 396, 428, 430, 433, 434, and 440, wherein the amino acid residue position numbers are according to the EU numbering scheme.

[0075] In some embodiments, the Fc domain of the SIRPγ antibody is derived from heavy chain SEQ ID NOs:5-27, or SEQ ID NO:36, and optionally includes one or more heavy chain Fc amino acid substitutions, e.g., 214, 215, 221, 222, 228, 234, 235, 236, 239, 240, 241, 243, 244, 245, 247, 250, 252, 254, 256, 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, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 8, 269, 270, 292, 296, 297, 298, 299, 300, 305, 313, 324, 325, 326, 327, 328, 329, 330, 332, 333, 334, 345, 356, 358, 396, 428, 430, 433, 434, 440, where the amino acid residue position numbers are according to the EU numbering scheme. Exemplary substitutions include one or more of K214R, V215A, G236A, S239D, I332E, D356E, L358M, M428L, N434S, where the amino acid residue position numbers are according to the EU numbering scheme.

[0076] In some embodiments, the Fc domain of the SIRPγ antibody is derived from a human IgG1 constant heavy chain (e.g., SEQ ID NOs:5-27 or SEQ ID NO:36), and the heavy chain Fc substitutions include, among other effects, V215A, G236A, S239D, I332E, G236A / S239D, G236A / I332E, S239D / I332E, V215A / G236A / S239D / I332E, G236A / S239D / I332E, V215A / G236A / S239D / I332E, K326W / E333S, S267E / H268F / S324T, E345R, E430G, E345K, S440Y, K326W, E ... and 33S, S267E, H268F, S324T, and E345R / E430G / S440Y, F243L / R292P / Y300L / V305I / P396L, S239D / I332E, S298A / E333A / K334A, L234Y / L235Q / G236W / S239M / H268D / D270E / S298A, and D270E / K326D / A330M / K334E, where amino acid residue position numbers are according to the EU numbering scheme.

[0077] In some embodiments, the Fc domain of the SIRPγ antibody is derived from a human IgG1 constant heavy chain (e.g., SEQ ID NO:5-27, or SEQ ID NO:36) and heavy chain Fc substitutions including one or more of N297A, N297Q, N297G, L235E, L234A, L235A, K214R, P329G, D356E, and L358M have been introduced to reduce (e.g., silence) effector function, and amino acid residue position numbers are according to the EU numbering scheme.

[0078] In some embodiments, the Fc domain of the SIRPγ antibody is derived from a human IgG1 constant heavy chain (e.g., SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:36), and heavy chain Fc substitutions including L234A, L235A, and P329G are introduced to reduce (e.g., silence) effector function, and amino acid residue position numbers are according to the EU numbering scheme.

[0079] In some embodiments, the Fc domain of the SIRPγ antibody is derived from a human IgG4 constant heavy chain (e.g., SEQ ID NO:28, SEQ ID NO:29, or SEQ ID NO:35), and heavy chain Fc substitutions including one or more of L235E and F234A / L235A have been introduced to reduce effector function, and the amino acid residue position numbers are according to the EU numbering scheme.

[0080] In some embodiments, the Fc domain of the SIRPγ antibody is derived from a human IgG2 constant heavy chain, and heavy chain Fc substitutions including H268Q / V309L / A330S / P331S and V234A / G237A / P238S / H268A / V309L / A330S / P331S have been introduced to reduce effector function, where amino acid residue position numbers are according to the EU numbering scheme.

[0081] In some embodiments, the Fc domain of the SIRPγ antibody is derived from a human IgG4 constant heavy chain (e.g., SEQ ID NO: 28), and the antibody is susceptible to the dynamic process of Fab arm exchange. Thus, in some embodiments, the IgG4 heavy chain Fc domain contains a S228P substitution, resulting in reduced Fab arm exchange, and the amino acid residue position numbers are of the EU numbering scheme.

[0082] In some embodiments, the Fc domain of the SIRPγ antibody is derived from a human IgG4 constant heavy chain (e.g., SEQ ID NO:28, SEQ ID NO:29 or SEQ ID NO:35) and one or more of the following heavy chain Fc substitutions have been introduced to reduce effector function: L235A, L235E, S228P, L235E / S228P, S228P / F234A, S228P / F234A / L235A, where the amino acid residue position numbers are according to the EU numbering scheme.

[0083] In other embodiments, the Fc domain of a SIRPγ antibody is modified to increase its serum half-life. Such modifications include human IgG1, human IgG2, human IgG3, or human IgG4 heavy chain Fc substitutions, such as M428L, N343S, T250Q / M428L, M252Y / S254T / T256E, M428L / N434S, S267E / L328F, N325S / L328F, and H433K / N434F, where the amino acid residue position numbers are according to the EU numbering scheme.

[0084] In some embodiments, a SIRPγ antibody comprises a light chain constant region in addition to a SIRPγ antigen-binding light chain variable region, such as the exemplary CDR-containing light chain variable regions provided in Table 2. Exemplary light chain constant region amino acid sequences are provided in SEQ ID NOs: 38-42.

[0085] In some embodiments, the SIRPγ antibody contains a kappa light chain constant region. An exemplary kappa light chain constant region is provided as SEQ ID NO:38.

[0086] [ka]

[0087] In some embodiments, the SIRPγ antibody contains a lambda light chain constant region. Exemplary lambda light chain constant regions are provided as SEQ ID NOs: 39-41.

[0088] [ka]

[0089] In some embodiments, a SIRPγ antibody comprises a light chain constant region and a heavy chain constant region in addition to a SIRPγ antigen-binding light and heavy chain variable region, e.g., the exemplary CDR-containing light and heavy chain variable regions provided in Table 2. Exemplary light chain constant region amino acid sequences of the disclosure are provided in SEQ ID NOs: 38-42, and exemplary heavy chain constant region amino acid sequences of the disclosure are provided in SEQ ID NOs: 5-36.

[0090] In exemplary embodiments, the SIRPγ antibodies provided herein are monoclonal antibodies (mAbs). In exemplary embodiments, the SIRPγ antibodies provided herein are human antibodies. In exemplary embodiments, the SIRPγ antibodies provided herein are humanized antibodies. In exemplary embodiments, the SIRPγ antibodies provided herein are monoclonal human antibodies or monoclonal humanized antibodies. In exemplary embodiments, the SIRPγ antibodies provided herein are chimeric antibodies. In exemplary embodiments, the SIRPγ antibodies provided herein are monoclonal chimeric antibodies. In some embodiments, the SIRPγ antibodies are provided as antibody fragments.

[0091] Also provided herein are SIRPγ antibody-drug conjugates, bispecific antibodies comprising at least one arm specific for SIRPγ, and multispecific antibodies that exhibit binding to SIRPγ.

[0092] i. Exemplary SIRPγ Antibody-CDR Sequences Exemplary SIRPγ antibody sequences of the disclosure are provided herein, including the complementarity determining region (CDR) sequences and variable heavy and light domain sequences (VH, VL) that make up the SIRPγ antigen binding domain of the disclosure.

[0093] As referred to below, the light chain variable (VL) domain CDR1 region is referred to as CDR-L1; the VL CDR2 region is referred to as CDR-L2; the VL CDR3 region is referred to as CDR-L3; the heavy chain variable (VH) domain CDR1 region is referred to as CDR-H1; the VH CDR2 region is referred to as CDR-H2, and the VH CDR3 region is referred to as CDR-H3. Table 1 provides 47 exemplary CDR combinations of the antibodies of the present disclosure.

[0094] [Table 1-1]

[0095] [Table 1-2]

[0096] [Table 1-3]

[0097] [Table 1-4]

[0098] [Table 1-5]

[0099] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:100, SEQ ID NO:138, SEQ ID NO:167; and / or the following three VH CDRs: SEQ ID NO:209, SEQ ID NO:245, SEQ ID NO:277.

[0100] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:101, SEQ ID NO:139, SEQ ID NO:168; and / or the following three VH CDRs: SEQ ID NO:210, SEQ ID NO:246, SEQ ID NO:278.

[0101] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:102, SEQ ID NO:140, SEQ ID NO:169; and / or the following three VH CDRs: SEQ ID NO:211, SEQ ID NO:247, SEQ ID NO:279.

[0102] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:103, SEQ ID NO:141, SEQ ID NO:170; and / or the following three VH CDRs: SEQ ID NO:212, SEQ ID NO:248, SEQ ID NO:280.

[0103] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:104, SEQ ID NO:141, SEQ ID NO:171; and / or the following three VH CDRs: SEQ ID NO:213, SEQ ID NO:249, SEQ ID NO:281.

[0104] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:105, SEQ ID NO:142, SEQ ID NO:172; and / or the following three VH CDRs: SEQ ID NO:214, SEQ ID NO:250, SEQ ID NO:282.

[0105] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:106, SEQ ID NO:143, SEQ ID NO:173; and / or the following three VH CDRs: SEQ ID NO:215, SEQ ID NO:251, SEQ ID NO:283.

[0106] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:106, SEQ ID NO:144, SEQ ID NO:174; and / or the following three VH CDRs: SEQ ID NO:216, SEQ ID NO:252, SEQ ID NO:284.

[0107] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:107, SEQ ID NO:141, SEQ ID NO:175; and / or the following three VH CDRs: SEQ ID NO:217, SEQ ID NO:253, SEQ ID NO:285.

[0108] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:108, SEQ ID NO:144, SEQ ID NO:176; and / or the following three VH CDRs: SEQ ID NO:216, SEQ ID NO:254, SEQ ID NO:286.

[0109] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:109, SEQ ID NO:145, SEQ ID NO:171; and / or the following three VH CDRs: SEQ ID NO:218, SEQ ID NO:255, SEQ ID NO:287.

[0110] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:110, SEQ ID NO:146, SEQ ID NO:177; and / or the following three VH CDRs: SEQ ID NO:219, SEQ ID NO:249, SEQ ID NO:288.

[0111] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:111, SEQ ID NO:147, SEQ ID NO:178; and / or the following three VH CDRs: SEQ ID NO:220, SEQ ID NO:256, SEQ ID NO:289.

[0112] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:112, SEQ ID NO:148, SEQ ID NO:179; and / or the following three VH CDRs: SEQ ID NO:213, SEQ ID NO:249, SEQ ID NO:290.

[0113] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:113, SEQ ID NO:143, SEQ ID NO:180; and / or the following three VH CDRs: SEQ ID NO:221, SEQ ID NO:257, SEQ ID NO:291.

[0114] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:106, SEQ ID NO:149, SEQ ID NO:181; and / or the following three VH CDRs: SEQ ID NO:222, SEQ ID NO:258, SEQ ID NO:292.

[0115] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:114, SEQ ID NO:150, SEQ ID NO:182; and / or the following three VH CDRs: SEQ ID NO:223, SEQ ID NO:250, SEQ ID NO:293.

[0116] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:115, SEQ ID NO:151, SEQ ID NO:183; and / or the following three VH CDRs: SEQ ID NO:219, SEQ ID NO:259, SEQ ID NO:294.

[0117] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:116, SEQ ID NO:152, SEQ ID NO:184; and / or the following three VH CDRs: SEQ ID NO:224, SEQ ID NO:260, SEQ ID NO:295.

[0118] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:117, SEQ ID NO:153, SEQ ID NO:185; and / or the following three VH CDRs: SEQ ID NO:216, SEQ ID NO:261, SEQ ID NO:296.

[0119] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:118, SEQ ID NO:143, SEQ ID NO:186; and / or the following three VH CDRs: SEQ ID NO:222, SEQ ID NO:262, SEQ ID NO:297.

[0120] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:119, SEQ ID NO:154, SEQ ID NO:187; and / or the following three VH CDRs: SEQ ID NO:225, SEQ ID NO:250, SEQ ID NO:298.

[0121] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:120, SEQ ID NO:140, SEQ ID NO:188; and / or the following three VH CDRs: SEQ ID NO:226, SEQ ID NO:263, SEQ ID NO:299.

[0122] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:121, SEQ ID NO:141, SEQ ID NO:189; and / or the following three VH CDRs: SEQ ID NO:227, SEQ ID NO:264, SEQ ID NO:300.

[0123] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:122, SEQ ID NO:155, SEQ ID NO:190; and / or the following three VH CDRs: SEQ ID NO:228, SEQ ID NO:249, SEQ ID NO:301.

[0124] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:123, SEQ ID NO:143, SEQ ID NO:186; and / or the following three VH CDRs: SEQ ID NO:229, SEQ ID NO:265, SEQ ID NO:302.

[0125] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:124, SEQ ID NO:143, SEQ ID NO:191; and / or the following three VH CDRs: SEQ ID NO:216, SEQ ID NO:266, SEQ ID NO:303.

[0126] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:106, SEQ ID NO:156, SEQ ID NO:192; and / or the following three VH CDRs: SEQ ID NO:230, SEQ ID NO:249, SEQ ID NO:304.

[0127] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:106, SEQ ID NO:145, SEQ ID NO:193; and / or the following three VH CDRs: SEQ ID NO:231, SEQ ID NO:267, SEQ ID NO:305.

[0128] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:125, SEQ ID NO:143, SEQ ID NO:194; and / or the following three VH CDRs: SEQ ID NO:232, SEQ ID NO:268, SEQ ID NO:306.

[0129] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:126, SEQ ID NO:157, SEQ ID NO:195; and / or the following three VH CDRs: SEQ ID NO:233, SEQ ID NO:269, SEQ ID NO:307.

[0130] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:127, SEQ ID NO:155, SEQ ID NO:196; and / or the following three VH CDRs: SEQ ID NO:234, SEQ ID NO:249, SEQ ID NO:308.

[0131] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:128, SEQ ID NO:158, SEQ ID NO:197; and / or the following three VH CDRs: SEQ ID NO:235, SEQ ID NO:270, SEQ ID NO:309.

[0132] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:129, SEQ ID NO:159, SEQ ID NO:198; and / or the following three VH CDRs: SEQ ID NO:226, SEQ ID NO:271, SEQ ID NO:310.

[0133] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:106, SEQ ID NO:143, SEQ ID NO:199; and / or the following three VH CDRs: SEQ ID NO:236, SEQ ID NO:272, SEQ ID NO:311.

[0134] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:130, SEQ ID NO:155, SEQ ID NO:200; and / or the following three VH CDRs: SEQ ID NO:237, SEQ ID NO:249, SEQ ID NO:312.

[0135] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:131, SEQ ID NO:141, SEQ ID NO:201; and / or the following three VH CDRs: SEQ ID NO:238, SEQ ID NO:264, SEQ ID NO:313.

[0136] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:132, SEQ ID NO:140, SEQ ID NO:202; and / or the following three VH CDRs: SEQ ID NO:239, SEQ ID NO:273, SEQ ID NO:314.

[0137] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:109, SEQ ID NO:143, SEQ ID NO:203; and / or the following three VH CDRs: SEQ ID NO:240, SEQ ID NO:250, SEQ ID NO:315.

[0138] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:133, SEQ ID NO:160, SEQ ID NO:191; and / or the following three VH CDRs: SEQ ID NO:241, SEQ ID NO:274, SEQ ID NO:316.

[0139] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:134, SEQ ID NO:161, SEQ ID NO:204; and / or the following three VH CDRs: SEQ ID NO:242, SEQ ID NO:275, SEQ ID NO:317.

[0140] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the following three VL CDRs: the amino acid sequences of SEQ ID NO:135, SEQ ID NO:162, SEQ ID NO:189; and / or the following three VH CDRs: the amino acid sequences of SEQ ID NO:216, SEQ ID NO:249, SEQ ID NO:318.

[0141] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:129, SEQ ID NO:155, SEQ ID NO:205; and / or the following three VH CDRs: SEQ ID NO:226, SEQ ID NO:276, SEQ ID NO:319.

[0142] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:131, SEQ ID NO:163, SEQ ID NO:206; and / or the following three VH CDRs: SEQ ID NO:219, SEQ ID NO:267, SEQ ID NO:320.

[0143] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:136, SEQ ID NO:164, SEQ ID NO:207; and / or the following three VH CDRs: SEQ ID NO:243, SEQ ID NO:249, SEQ ID NO:321.

[0144] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:131, SEQ ID NO:165, SEQ ID NO:208; and / or the following three VH CDRs: SEQ ID NO:213, SEQ ID NO:269, SEQ ID NO:322.

[0145] In some embodiments, provided herein is a SIRPγ antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs: SEQ ID NO:137, SEQ ID NO:166, SEQ ID NO:169; and / or the following three VH CDRs: SEQ ID NO:244, SEQ ID NO:256, SEQ ID NO:323.

[0146] ii. Exemplary SIRPγ Antibody-Variable Region Sequences The terms variable domain and variable region are used interchangeably and refer to the portions of the light and heavy chains of an antibody that contain the complementarity determining regions and framework regions (FR).

[0147] Table 2 provides amino acid sequences of the variable domains of exemplary SIRPγ antibodies of the disclosure. Thus, in some embodiments, a SIRPγ antibody of the disclosure comprises a variable heavy chain comprising an amino acid sequence selected from SEQ ID NOs: 324-370, or at least 80% sequence identity thereto; and / or in some embodiments, a SIRPγ antibody of the disclosure comprises a variable light chain comprising an amino acid sequence selected from SEQ ID NOs: 371-417, or at least 80% sequence identity thereto.

[0148] In some embodiments, a SIRPγ antibody of the disclosure comprises a VH / VL variable chain amino acid sequence combination of any one of the 47 combinations shown in Table 2.

[0149] [Table 2-1]

[0150] [Table 2-2]

[0151] [Table 2-3]

[0152] [Table 2-4]

[0153] [Table 2-5]

[0154] [Table 2-6]

[0155] [Table 2-7]

[0156] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 324, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 371, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0157] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 325, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 372, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0158] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 326, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 373, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0159] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 327, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 374, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0160] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 328, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 375, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0161] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 329, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 376, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0162] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 330, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 377, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0163] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 331, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 378, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0164] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 332, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 379, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0165] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 333, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 380, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0166] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 334, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 381, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0167] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 335, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 382, ​​or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0168] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 336, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 383, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0169] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 337, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 384, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0170] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 338, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 385, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0171] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 339, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 386, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0172] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 340, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 387, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0173] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 341, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 388, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0174] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 342, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 389, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0175] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 343, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 390, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0176] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 344, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 391, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0177] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 345, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 392, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0178] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 346, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 393, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0179] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 347, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 394, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0180] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 348, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 395, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0181] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 349, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 396, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0182] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 350, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 397, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0183] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 351, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 398, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0184] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 352, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO: 399, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0185] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 353, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO:400, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0186] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 354, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO:401, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0187] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 355, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO:402, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0188] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 356, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO:403, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0189] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 357, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO:404, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0190] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 358, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO:405, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0191] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 359, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO:406, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0192] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 360, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO:407, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0193] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 361, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO:408, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0194] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 362, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO:409, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0195] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 363, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO:410, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0196] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 364, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO:411, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0197] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 365, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO:412, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0198] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 366, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO:413, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0199] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 367, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO:414, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0200] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 368, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO:415, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0201] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 369, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO:416, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0202] In some embodiments, the heavy chain variable domain (VH) of the antibody comprises an amino acid sequence of SEQ ID NO: 370, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein is a SIRPγ antibody, wherein the light chain variable domain (VL) of the antibody comprises an amino acid sequence of SEQ ID NO:417, or an amino acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0203] For illustration, referring to Tables 1 and 2, 47 combinations of unique antibody sequences are provided (CDR sequences in Table 1; VH / VL sequences in Table 2). By way of example, guidance for reading the tables is as follows: Antibody 1, Antibody 3, Antibody 4, Antibody 7, and Antibody 110 share the same combination of CDR sequences and also share the same combination of VH / VL sequences, but may differ in some other aspects, e.g., have different Fc regions. Similarly, note that Antibody 2, Antibody 5, Antibody 6, Antibody 8, and Antibody 111 share the same combination of CDR sequences and also share the same combination of VH / VL sequences, but may differ in some other aspects, e.g., have different Fc regions.

[0204] Antibody 1 and Antibody 2 contain rat IgG2b Fc.

[0205] Antibody 3, Antibody 5, and Antibodies 83 to 97 comprise the human IgG1 Fc of the present disclosure.

[0206] Antibody 4, Antibody 6, and Antibodies 54-82 comprise a human IgG1 Fc of the disclosure that contains specific substitutions that confer increased effector function and exhibit increased affinity for FcγR.

[0207] Antibody 7 and Antibody 8 comprise a human IgG4 Fc of the disclosure that contains specific substitutions that result in a reduced dynamic process of Fab arm exchange and further reduced effector function.

[0208] Antibodies 98-111 comprise a human IgG1 Fc of the disclosure that contains specific substitutions that result in reduced effector function and silencing of the Fc (eg, may include a LALA-PG substitution).

[0209] iii.SIRPγ antibody-mediated cell depletion The Fc-containing SIRPγ antibodies provided herein can target and preferentially deplete SIRPγ-expressing cells. In some embodiments, the antibodies preferentially deplete activated (interchangeably referred to herein as stimulated) cells as a result of increased surface SIRPγ expression when compared to naive, unactivated (unstimulated) cells.

[0210] In some embodiments, the SIRPγ antibodies provided herein are capable of inducing depletion of T cells, B cells, or NK cells, in some embodiments, the cells are in an activated state.

[0211] Without being bound by any theory or mechanism, the CDR-containing antigen binding domain of the SIRPγ antibody confers binding to SIRPγ-expressing cells, and the Fc portion of the antibody induces depletion and Fc-mediated effector functions. Thus, in some embodiments, cell depletion involves antibody-dependent cellular cytotoxicity (ADCC). In some embodiments, cell depletion involves antibody-dependent cellular phagocytosis (ADCP). In some embodiments, cell depletion involves complement-dependent cytotoxicity (CDC). In some embodiments, cell depletion includes one, two, or all three of ADCC, ADCP, and CDC. The Fc-containing SIRPγ antibodies of the present disclosure include full-length antibodies or antibody fragments linked to an Fc domain, e.g., VH-VL-Fc single chain antibodies.

[0212] In some embodiments, there is differential depletion of T cell subsets, likely driven by differential expression of specific isoforms in different T cell subsets. T cell subsets include cells in different cellular states, e.g., stimulated, exhausted, and the subsets further include T cells expressing different subsets of markers. Thus, in some embodiments, the SIRPγ antibodies provided herein can induce preferential depletion of specific T cell subsets expressing specific SIRPγ isoforms.

[0213] B. Generation of SIRPγ Antibodies The production of the antibodies provided herein can be by using any method known to one of skill in the art. In some embodiments, the antibodies are produced by a hybridoma. In some embodiments, the antibodies are encoded by a nucleic acid, expressed, purified, or isolated.

[0214] The terms polynucleotide and nucleic acid are used interchangeably herein and refer to polymeric forms of nucleotides of any length, which may be either ribonucleotides or deoxyribonucleotides. The terms include, but are not limited to, single-stranded, double-stranded, or multi-stranded DNA or RNA, genomic DNA, cDNA, DNA-RNA hybrids, or polymers containing purine and pyrimidine bases, or other natural, chemically or biochemically modified, non-natural, or derivatized nucleotide bases. These terms encompass nucleic acids that contain known analogs of natural nucleotides, have similar binding properties, and are metabolized in a manner similar to naturally occurring nucleotides, unless otherwise limited or stated.

[0215] Thus, provided herein are nucleic acids encoding any of the antibodies disclosed herein, vectors containing any of the nucleic acids encoding such antibodies, and host cells containing any such vectors. Also provided herein are exemplary nucleic acid sequences encoding the variable heavy and variable light chains of the SIRPγ antibodies disclosed herein.

[0216] Table 3 provides exemplary nucleic acid sequences of SIRPγ antibodies of the disclosure.

[0217] [Table 3-1]

[0218] [Table 3-2]

[0219] [Table 3-3]

[0220]

Table 3-4

[0221]

Table 3-5

[0222]

Table 3-6

[0223]

Table 3-7

[0224]

Table 3-8

[0225]

Table 3-9

[0226]

Table 3-10

[0227]

Table 3-11

[0228]

Table 3-12

[0229]

Table 3-13

[0230] [Table 3-14]

[0231] [Table 3-15]

[0232] [Table 3-16]

[0233] Thus, in some embodiments, a nucleic acid sequence encoding a SIRPγ antibody of the disclosure comprises a variable heavy chain nucleic acid sequence selected from SEQ ID NOs: 418-464, or at least 70% sequence identity thereto. In some embodiments, a nucleic acid sequence encoding a SIRPγ antibody of the disclosure comprises a variable light chain nucleic acid sequence selected from SEQ ID NOs: 465-511, or at least 70% sequence identity thereto. One of skill in the art will appreciate that due to redundancy in the triplet code, multiple nucleic acids may encode the same amino acid sequence. Thus, a nucleic acid sequence that is not identical to a nucleic acid sequence shown in Table 3 may still encode an amino acid sequence shown in the previous section.

[0234] In some embodiments, provided herein is a nucleic acid encoding any of the SIRPγ antibodies disclosed herein. In some embodiments, provided herein is a nucleic acid comprising any one or more of the nucleic acid sequences in Table 3. In some embodiments, the heavy and light chain variable domains of a SIRPγ antibody disclosed herein are encoded by a nucleic acid comprising any one or more of the nucleic acid sequences in Table 3.

[0235] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:418, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:465, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0236] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:419, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:466, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0237] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 420, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:467, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0238] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:421, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:468, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0239] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:422, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:469, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0240] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:423, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:470, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0241] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:424, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:471, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0242] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 425, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:472, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0243] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 426, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:473, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0244] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:427, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:474, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0245] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:428, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:475, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0246] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:429, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:476, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0247] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:430, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:477, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0248] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:431, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:478, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0249] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 432, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:479, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0250] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 433, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:480, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0251] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:434, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:481, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0252] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:435, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:482, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0253] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 436, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:483, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0254] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:437, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:484, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0255] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:438, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:485, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0256] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:439, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:486, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0257] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:440, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:487, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0258] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:441, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:488, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0259] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:442, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:489, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0260] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:443, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:490, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0261] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:444, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:491, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0262] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:445, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:492, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0263] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:446, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:493, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0264] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:447, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:494, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0265] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:448, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:495, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0266] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:449, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:496, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0267] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:450, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:497, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0268] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:451, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:498, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0269] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:452, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:499, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0270] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:453, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:500, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0271] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:454, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:501, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0272] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:455, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:502, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0273] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:456, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:503, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0274] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:457, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:504, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0275] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:458, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:505, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0276] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:459, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:506, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0277] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 460, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:507, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0278] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 461, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or is an antibody that is Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:508, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0279] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 462, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:509, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0280] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 463, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:510, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0281] In some embodiments, the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 464, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or Provided herein are SIRPγ antibodies, wherein the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO:511, or a nucleic acid sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0282] The present disclosure further provides a vector comprising any of the nucleic acids of the present disclosure. In some embodiments, the nucleic acid of the vector comprises any one or more of the nucleic acid sequences selected from Table 3. In some embodiments, the vector is an expression vector or an expression construct. In some embodiments, the vector is a mammalian vector. In some embodiments, the vector is a viral vector.

[0283] In some embodiments, a SIRPγ antibody provided herein is produced by culturing a cell under conditions suitable for expressing the SIRPγ antibody, wherein the cell contains the vector.

[0284] II. Use of SIRPγ Antibodies A. Depletion of SIRPγ-expressing cells Provided herein are methods of inducing Fc-mediated cell depletion, the methods comprising contacting a SIRPγ expressing cell with any of the Fc-containing SIRPγ antibodies of the present disclosure. The methods may be performed in vitro or in vivo. In some embodiments, cell depletion involves antibody-dependent cellular phagocytosis (ADCP). In some embodiments, cell depletion involves antibody-dependent cellular cytotoxicity (ADCC). In some embodiments, cell depletion involves complement-dependent cytotoxicity (CDC). In some embodiments, cell depletion includes one or more of ADCP, ADCC, and CDC. One or more Fc substitutions of the present disclosure can further modulate depletion.

[0285] In some embodiments, the cells are in a stimulated (activated) state. Without being bound by any theory or mechanism, the SIRPγ antibodies of the present disclosure can be used to preferentially deplete pathogenic T cells, activated T cells, exhausted T cells, non-activated T cells (or other cells). In some embodiments, without being bound by theory or mechanism, this can be due to increased expression of SIRPγ in activated T cells. In some embodiments, without being bound by theory or mechanism, this can be due to differential expression of certain SIRPγ isoforms on certain T cell subsets (e.g., isoforms set forth in SEQ ID NOs: 1-3 and SEQ ID NO: 37). T cell subsets include cells in different cellular states, e.g., stimulated, exhausted, and the subsets further include T cells expressing different subsets of markers.

[0286] In some embodiments, the SIRPγ expressing cells are SIRPγ expressing T cells. In some embodiments, the SIRPγ expressing T cells are in a naive state. In some embodiments, the SIRPγ expressing T cells are in an activated (stimulated) state. In some embodiments, the SIRPγ expressing T cells are in an exhausted state. In some embodiments, the SIRPγ expressing T cells are in an undifferentiated state. In some embodiments, the T cells are cytotoxic T cells, helper T cells, memory T cells, regulatory T cells, natural killer T cells, mucosal-associated invariant T cells, or alpha beta (αβ) T cells, or gamma delta (gd) T cells. In some embodiments, the T cells are naive cells, central memory cells, effector memory cells, exhausted cells, or terminal effector memory cells. In some embodiments, the T cells are CD4+ T cells, CD8+ T cells, CD3+ T cells, Th1 cells, Th2 cells, Th17 cells, or T follicular helper cells.

[0287] In some embodiments, the T cells are CD3+ T cells, CD4+ T cells, CD8+ T cells, CD25+ T cells, CD69+ T cells, and / or PD1+ T cells. In some embodiments, the T cells are CD4+ / CD8+ T cells. In some embodiments, the T cells are CD69+ / CD8+ T cells. In some embodiments, the T cells are CD25+ / CD8+ T cells. In some embodiments, the T cells are PD1+ T cells.

[0288] Certain SIRPγ antibodies of the present disclosure further exhibit preferential binding to specific cell types and subsequent Fc-mediated depletion. Without being bound by any theory or mechanism, the SIRPγ antibodies of the present disclosure can be used to preferentially deplete cells of a particular cell type (expressing a particular marker), or of a particular state (stimulated, exhausted). Without being bound by theory or mechanism, this may be due to differential expression of certain SIRPγ isoforms on certain T cell subsets (e.g., the isoforms set forth in SEQ ID NOs: 1-3, and SEQ ID NO: 37).

[0289] The preferential binding can be at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, or even at least 50-fold, compared to the binding observed in a reference cell type or reference cell state.

[0290] The increase in Fc-mediated depletion can be at least a 1.5-fold, at least a 2-fold, at least a 3-fold, at least a 4-fold, at least a 5-fold, at least a 6-fold, at least a 7-fold, at least a 8-fold, at least a 9-fold, at least a 10-fold, at least a 15-fold, at least a 20-fold, at least a 25-fold, or even at least a 50-fold increase in depletion compared to the depletion observed in a reference cell type or reference cell condition.

[0291] In some embodiments, certain SIRPγ antibodies of the disclosure exhibit preferential binding and depletion of activated (stimulated) T cells as compared to unstimulated T cells.

[0292] In some embodiments, certain SIRPγ antibodies of the disclosure exhibit preferential binding to and depletion of SIRPγ-expressing CD8+ T cells.

[0293] In some embodiments, certain SIRPγ antibodies of the disclosure exhibit preferential binding to and depletion of SIRPγ-expressing CD4+ T cells.

[0294] In some embodiments, certain SIRPγ antibodies of the disclosure exhibit preferential binding to and depletion of SIRPγ-expressing CD8+ / CD69+ T cells.

[0295] In some embodiments, certain SIRPγ antibodies of the disclosure exhibit preferential binding to and depletion of SIRPγ-expressing CD8+ / CD25+ T cells.

[0296] In some embodiments, certain SIRPγ antibodies of the disclosure exhibit preferential binding to and depletion of SIRPγ-expressing CD8+ T cells as compared to SIRPγ-expressing CD4+ T cells.

[0297] In some embodiments, certain SIRPγ antibodies of the disclosure exhibit preferential binding to and depletion of SIRPγ-expressing CD4+ T cells as compared to SIRPγ-expressing CD8+ T cells.

[0298] In some embodiments, certain SIRPγ antibodies of the disclosure exhibit preferential binding to and depletion of SIRPγ-expressing CD8+ / CD69+ T cells when compared to SIRPγ-expressing CD8+ / CD69- T cells.

[0299] In some embodiments, certain SIRPγ antibodies of the disclosure exhibit preferential binding to and depletion of SIRPγ-expressing CD8+ / CD25+ T cells when compared to SIRPγ-expressing CD8+ / CD25- T cells.

[0300] In some embodiments, certain SIRPγ antibodies of the disclosure exhibit preferential binding to and depletion of SIRPγ-expressing PD1+ T cells as compared to PD1− T cells.

[0301] In some embodiments, exemplary antibodies that exhibit increased binding to and depletion of stimulated T cells as compared to unstimulated T cells include antibodies with the following sequences, with reference to Table 1 above: a. The CDR-H1 amino acid sequence of SEQ ID NO:211; the CDR-H2 amino acid sequence of SEQ ID NO:247; the CDR-H3 amino acid sequence of SEQ ID NO:279; the CDR-L1 amino acid sequence of SEQ ID NO:102; the CDR-L2 amino acid sequence of SEQ ID NO:140; and the CDR-L3 amino acid sequence of SEQ ID NO:169. b. The CDR-H1 amino acid sequence of SEQ ID NO:216; the CDR-H2 amino acid sequence of SEQ ID NO:254; the CDR-H3 amino acid sequence of SEQ ID NO:286; the CDR-L1 amino acid sequence of SEQ ID NO:108; the CDR-L2 amino acid sequence of SEQ ID NO:144; and the CDR-L3 amino acid sequence of SEQ ID NO:176. c. The CDR-H1 amino acid sequence of SEQ ID NO:213; the CDR-H2 amino acid sequence of SEQ ID NO:249; the CDR-H3 amino acid sequence of SEQ ID NO:290; the CDR-L1 amino acid sequence of SEQ ID NO:112; the CDR-L2 amino acid sequence of SEQ ID NO:148; and the CDR-L3 amino acid sequence of SEQ ID NO:179. d. A CDR-H1 amino acid sequence of SEQ ID NO: 221; a CDR-H2 amino acid sequence of SEQ ID NO: 257; a CDR-H3 amino acid sequence of SEQ ID NO: 291; a CDR-L1 amino acid sequence of SEQ ID NO: 113; a CDR-L2 amino acid sequence of SEQ ID NO: 143; and a CDR-L3 amino acid sequence of SEQ ID NO: 180. e. The CDR-H1 amino acid sequence of SEQ ID NO: 222; the CDR-H2 amino acid sequence of SEQ ID NO: 258; the CDR-H3 amino acid sequence of SEQ ID NO: 292; the CDR-L1 amino acid sequence of SEQ ID NO: 106; the CDR-L2 amino acid sequence of SEQ ID NO: 149; and the CDR-L3 amino acid sequence of SEQ ID NO: 181. f. The CDR-H1 amino acid sequence of SEQ ID NO: 222; the CDR-H2 amino acid sequence of SEQ ID NO: 262; the CDR-H3 amino acid sequence of SEQ ID NO: 297; the CDR-L1 amino acid sequence of SEQ ID NO: 118; the CDR-L2 amino acid sequence of SEQ ID NO: 143; and the CDR-L3 amino acid sequence of SEQ ID NO: 186. g. A CDR-H1 amino acid sequence of SEQ ID NO: 226; a CDR-H2 amino acid sequence of SEQ ID NO: 263; a CDR-H3 amino acid sequence of SEQ ID NO: 299; a CDR-L1 amino acid sequence of SEQ ID NO: 120; a CDR-L2 amino acid sequence of SEQ ID NO: 140; and a CDR-L3 amino acid sequence of SEQ ID NO: 188. h. The CDR-H1 amino acid sequence of SEQ ID NO:216; the CDR-H2 amino acid sequence of SEQ ID NO:266; the CDR-H3 amino acid sequence of SEQ ID NO:303; the CDR-L1 amino acid sequence of SEQ ID NO:124; the CDR-L2 amino acid sequence of SEQ ID NO:143; and the CDR-L3 amino acid sequence of SEQ ID NO:191. i. A CDR-H1 amino acid sequence of SEQ ID NO:234; a CDR-H2 amino acid sequence of SEQ ID NO:249; a CDR-H3 amino acid sequence of SEQ ID NO:308; a CDR-L1 amino acid sequence of SEQ ID NO:127; a CDR-L2 amino acid sequence of SEQ ID NO:155; and a CDR-L3 amino acid sequence of SEQ ID NO:196. j. A CDR-H1 amino acid sequence of SEQ ID NO:240; a CDR-H2 amino acid sequence of SEQ ID NO:250; a CDR-H3 amino acid sequence of SEQ ID NO:315; a CDR-L1 amino acid sequence of SEQ ID NO:109; a CDR-L2 amino acid sequence of SEQ ID NO:143; and a CDR-L3 amino acid sequence of SEQ ID NO:203. k. A CDR-H1 amino acid sequence of SEQ ID NO:216; a CDR-H2 amino acid sequence of SEQ ID NO:249; a CDR-H3 amino acid sequence of SEQ ID NO:318; a CDR-L1 amino acid sequence of SEQ ID NO:135; a CDR-L2 amino acid sequence of SEQ ID NO:162; and a CDR-L3 amino acid sequence of SEQ ID NO:189. l. The CDR-H1 amino acid sequence of SEQ ID NO:243; the CDR-H2 amino acid sequence of SEQ ID NO:249; the CDR-H3 amino acid sequence of SEQ ID NO:321; the CDR-L1 amino acid sequence of SEQ ID NO:136; the CDR-L2 amino acid sequence of SEQ ID NO:164; and the CDR-L3 amino acid sequence of SEQ ID NO:207. m. A CDR-H1 amino acid sequence of SEQ ID NO:244; a CDR-H2 amino acid sequence of SEQ ID NO:256; a CDR-H3 amino acid sequence of SEQ ID NO:323; a CDR-L1 amino acid sequence of SEQ ID NO:137; a CDR-L2 amino acid sequence of SEQ ID NO:166; and a CDR-L3 amino acid sequence of SEQ ID NO:169.

[0302] Referring to the data in Example 4, antibody 83, antibody 84, antibody 85, antibody 86, antibody 88, antibody 89, antibody 90, antibody 92, antibody 94, antibody 95, antibody 96, and antibody 97 show increased binding to stimulated T cells compared to unstimulated T cells. The CDR and VH / VL sequences for these antibodies are provided in Tables 1 and 2.

[0303] In some embodiments, exemplary antibodies that preferentially bind to and deplete CD8+ T cells as compared to CD4+ T cells include antibodies comprising the following sequences, with reference to Table 1 above: a CDR-H1 amino acid sequence of SEQ ID NO:216; a CDR-H2 amino acid sequence of SEQ ID NO:254; a CDR-H3 amino acid sequence of SEQ ID NO:286; a CDR-L1 amino acid sequence of SEQ ID NO:108; a CDR-L2 amino acid sequence of SEQ ID NO:144; and a CDR-L3 amino acid sequence of SEQ ID NO:176.

[0304] With reference to Example 4, antibody 84 preferentially binds to CD8+ T cells as compared to CD4+ T cells. The CDR and VH / VL sequences of this antibody are provided in Tables 1 and 2.

[0305] In some embodiments, exemplary antibodies that preferentially bind to and deplete CD69+ / CD8+ T cells and CD25+ / CD8+ T cells as compared to CD69- / CD8+ T cells and CD25- / CD8+ T cells include, with reference to Table 1 above, antibodies comprising the following sequences: a CDR-H1 amino acid sequence of SEQ ID NO:216; a CDR-H2 amino acid sequence of SEQ ID NO:254; a CDR-H3 amino acid sequence of SEQ ID NO:286; a CDR-L1 amino acid sequence of SEQ ID NO:108; a CDR-L2 amino acid sequence of SEQ ID NO:144; and a CDR-L3 amino acid sequence of SEQ ID NO:176.

[0306] Referring to the data in Example 4, antibody 84 preferentially binds to CD69+ / CD8+ T cells and CD25+ / CD8+ T cells compared to CD69- / CD8+ T cells and CD25- / CD8+ T cells. The CDR and VH / VL sequences of this antibody are provided in Tables 1 and 2.

[0307] In some embodiments, exemplary antibodies that preferentially bind to and deplete PD1+ T cells as compared to PD1- T cells include, with reference to Table 1 above, antibodies comprising the following sequences: a. the CDR-H1 amino acid sequence of SEQ ID NO: 213; the CDR-H2 amino acid sequence of SEQ ID NO: 249; the CDR-H3 amino acid sequence of SEQ ID NO: 290; the CDR-L1 amino acid sequence of SEQ ID NO: 112; the CDR-L2 amino acid sequence of SEQ ID NO: 148; and the CDR-L3 amino acid sequence of SEQ ID NO: 179; b. The CDR-H1 amino acid sequence of SEQ ID NO: 222; the CDR-H2 amino acid sequence of SEQ ID NO: 262; the CDR-H3 amino acid sequence of SEQ ID NO: 297; the CDR-L1 amino acid sequence of SEQ ID NO: 118; the CDR-L2 amino acid sequence of SEQ ID NO: 143; and the CDR-L3 amino acid sequence of SEQ ID NO: 186; c. The CDR-H1 amino acid sequence of SEQ ID NO:216; the CDR-H2 amino acid sequence of SEQ ID NO:249; the CDR-H3 amino acid sequence of SEQ ID NO:318; the CDR-L1 amino acid sequence of SEQ ID NO:135; the CDR-L2 amino acid sequence of SEQ ID NO:162; and the CDR-L3 amino acid sequence of SEQ ID NO:189; d. A CDR-H1 amino acid sequence of SEQ ID NO:244; a CDR-H2 amino acid sequence of SEQ ID NO:256; a CDR-H3 amino acid sequence of SEQ ID NO:323; a CDR-L1 amino acid sequence of SEQ ID NO:137; a CDR-L2 amino acid sequence of SEQ ID NO:166; and a CDR-L3 amino acid sequence of SEQ ID NO:169.

[0308] Referring to the data in Example 4, Antibody 85, Antibody 89, Antibody 95, and Antibody 97 preferentially bind to PD1+ T cells compared to PD1- / T cells. The CDR and VH / VL sequences for these antibodies are provided in Tables 1 and 2.

[0309] In some embodiments, the SIRPγ expressing cells are SIRPγ expressing B cells. In some embodiments, the SIRPγ expressing B cells may be in an activated state and may be preferentially depleted.

[0310] In some embodiments, the SIRPγ expressing cells are NK cells. In some embodiments, the SIRPγ expressing NK cells may be in an activated state or may be preferentially depleted.

[0311] In some embodiments, contacting a SIRPγ expressing cell of the present disclosure with an Fc-containing SIRPγ antibody results in depletion of the SIRPγ expressing cell by ADCC. In some embodiments, the SIRPγ antibody increases ADCC by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. This method can be performed in vitro or in vivo. The SIRPγ expressing cell can be in an activated state. The SIRPγ expressing cell can be a T cell, a B cell, or a NK cell, as described above.

[0312] In some embodiments, contacting a SIRPγ expressing cell of the present disclosure with an Fc-containing SIRPγ antibody results in depletion of the SIRPγ expressing cell by ADCP. In some embodiments, the SIRPγ antibody increases ADCP by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. This method can be performed in vitro or in vivo. The SIRPγ expressing cell can be in an activated state. The SIRPγ expressing cell can be a T cell, a B cell, or a NK cell, as described above.

[0313] In some embodiments, contacting a SIRPγ expressing cell of the present disclosure with an Fc-containing SIRPγ antibody results in depletion of the SIRPγ expressing cell by CDC. In some embodiments, the SIRPγ antibody increases CDC by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. The method can be performed in vitro or in vivo. The SIRPγ expressing cell can be in an activated state. The SIRPγ expressing cell can be a T cell, a B cell, or a NK cell, as described above.

[0314] In some embodiments, contacting a SIRPγ expressing cell of the present disclosure with an Fc-containing SIRPγ antibody results in depletion of the SIRPγ expressing cell by ADCC and ADCP. In some embodiments, the SIRPγ antibody increases ADCC and ADCP by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%, respectively. This method can be performed in vitro or in vivo. The SIRPγ expressing cell can be in an activated state. The SIRPγ expressing cell can be a T cell, a B cell, or a NK cell, as described above.

[0315] In some embodiments, contacting a SIRPγ expressing cell of the present disclosure with an Fc-containing SIRPγ antibody results in depletion of the SIRPγ expressing cell by ADCC and CDC. In some embodiments, the SIRPγ antibody increases ADCC and CDC by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%, respectively. The method may be performed in vitro or in vivo. The SIRPγ expressing cell may be in an activated state. The SIRPγ expressing cell may be a T cell, a B cell, or a NK cell, as described above.

[0316] In some embodiments, contacting a SIRPγ expressing cell of the present disclosure with an Fc-containing SIRPγ antibody results in depletion of the SIRPγ expressing cell by ADCP and CDC. In some embodiments, the SIRPγ antibody increases ADCP and CDC by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%, respectively. This method can be performed in vitro or in vivo. The SIRPγ expressing cell can be in an activated state. The SIRPγ expressing cell can be a T cell, a B cell, or a NK cell, as described above.

[0317] In some embodiments, contacting a SIRPγ expressing cell of the present disclosure with an Fc-containing SIRPγ antibody results in depletion of the SIRPγ expressing cell by ADCC, ADCP, and CDC. In some embodiments, the SIRPγ antibody increases each of ADCC, ADCP, and CDC by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. The method can be performed in vitro or in vivo. The SIRPγ expressing cell can be in an activated state. The SIRPγ expressing cell can be a T cell, a B cell, or a NK cell, as described above.

[0318] B. Therapeutic SIRPγ antibody As discussed in the previous section, the present specification provides an antibody that recognizes and binds to SIRPγ. In some embodiments, the antibody does not disrupt the binding of CD47 to SIRPγ. In some embodiments, the antibody shows increased binding to activated SIRPγ-expressing cells. The antibody disclosed herein can be used for treatment in a subject.

[0319] Thus, provided herein is a method of treating a disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRPγ antibody of the present disclosure or a pharmaceutical composition thereof. In some embodiments, the subject is a mammalian subject. In some embodiments, the mammalian subject is a human subject. In some embodiments, the mammalian subject is a non-human primate, such as a cynomolgus monkey. In some embodiments, the mammalian subject is a model organism, such as a mouse, and the therapeutic effect is modeled. An exemplary model includes a mouse GvHD model.

[0320] In some embodiments, the Fc-containing SIRPγ antibodies provided herein are useful for depleting a population of SIRPγ-expressing cells in a subject for the treatment of a disease or condition. In some embodiments, the disease or condition is associated with hyperactivation, hyperproliferation, abnormal proliferation, dysfunction, and / or dysregulation of SIRPγ-expressing cells. In some embodiments, the SIRPγ-expressing cells are T cells, B cells, or NK cells.

[0321] In some embodiments, the SIRPγ expressing cells are in an activated state. Without being bound by any theory or mechanism, the SIRPγ antibodies of the present disclosure may be used to preferentially deplete pathogenic activated T cells (or other cells), sparing naive T cells (or other cells) and allowing immune surveillance to be maintained.

[0322] In some embodiments, the SIRPγ expressing cells express one or more isoforms of SIRPγ. In some embodiments, a therapeutically effective amount of the antibody or pharmaceutical composition is sufficient to deplete a population of SIRPγ expressing cells in a subject, e.g., by ADCC, ADCP, and / or CDC. In some embodiments, the SIRPγ expressing cells are tissue resident cells. In other embodiments, the SIRPγ expressing cells are circulating. In some embodiments, cell depletion is antibody dose dependent.

[0323] In some embodiments, the Fc-containing SIRPγ antibodies provided herein are useful for treating an autoimmune, inflammatory, or oncological disease or condition, hi some embodiments, the Fc-containing SIRPγ antibodies provided herein are useful for treating a disease or condition selected from the following: Acute and chronic eosinophilic pneumonia, acute disseminated encephalomyelitis, acute disseminated encephalomyelitis, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Addison's disease, adult-onset Still's disease (AOSD), aplastic anemia, ataxia-telangiectasia, atopic dermatitis, autoimmune hepatitis, autoimmune lymphoproliferative syndrome, axial spondyloarthritis (AxSpA), birdshot retinochoroidopathy, Castleman's disease, celiac disease, Chediak-Higashi syndrome, coronary artery disease / peripheral arterial disease, Crohn's disease, transient angioedema with eosinophilia / Gleich syndrome, giant lymphocytic arteritis, post-HSCT graft failure, graft-versus-host disease (GvHD), Graves' disease, hepatosplenic lymphoma, hypothyroidism, idiopathic interstitial pneumonia, IgA nephropathy, inclusion body myositis (IB) M), inflammatory bowel disease (IBD), large granular lymphocytic leukemia, lymphocytic variant hypereosinophilia, multiple sclerosis, myelodysplastic syndromes (MDS), myocarditis, neuromyelitis optica spectrum disorder, paraneoplastic syndromes, primary biliary cholangitis, primary sclerosing cholangitis, Rasmussen's encephalitis, rheumatoid arthritis (RA), sarcoidosis, Schmidt syndrome / autoimmune polyendocrine syndrome type II, stiff-person syndrome, Susac syndrome, sympathetic ophthalmia, systemic juvenile idiopathic arthritis (sJIA), systemic lupus erythematosus (SLE), T-lymphocyte-mediated rejection of solid organ transplants, T-cell prolymphocytic leukemia (TPLL), type 1 diabetes, early-onset type 1 diabetes, ulcerative colitis, uveitis, vitiligo, X-linked hyper-IgM syndrome, and X-linked lymphoproliferative disease.

[0324] In some embodiments, the Fc-containing SIRPγ antibodies provided herein are useful for treating diseases or conditions where the disease or condition is driven by CD8+ T cells (e.g., IBM and early onset type 1 diabetes). It is noted that certain SIRPγ antibodies of the present disclosure exhibit preferential subtype binding.

[0325] In some embodiments, the Fc-containing SIRPγ antibodies provided herein are useful for treating a disease or condition where the disease or condition is driven by CD4+ T cells. It is noted that certain SIRγ antibodies of the present disclosure exhibit preferential T cell subtype binding.

[0326] In some embodiments, the Fc-containing SIRPγ antibodies provided herein are useful for treating a disease or condition where the disease or condition is driven by T cells that are CD8+ and CD4+.

[0327] In some embodiments, the Fc-containing SIRPγ antibodies provided herein are useful for treating a disease or condition where the disease or condition is driven by CD3+ T cells. It is noted that certain SIRγ antibodies of the present disclosure exhibit preferential T cell subtype binding.

[0328] In some embodiments, the Fc-containing SIRPγ antibodies provided herein are useful for treating a disease or condition where the disease or condition is driven by CD25+ T cells. It is noted that certain SIRγ antibodies of the present disclosure exhibit preferential T cell subtype binding.

[0329] In some embodiments, the Fc-containing SIRPγ antibodies provided herein are useful for treating a disease or condition where the disease or condition is driven by CD69+ T cells. It is noted that certain SIRγ antibodies of the present disclosure exhibit preferential T cell subtype binding.

[0330] In some embodiments, the Fc-containing SIRPγ antibodies provided herein are useful for treating a disease or condition where the disease or condition is driven by PD1+ T cells. It is noted that certain SIRγ antibodies of the present disclosure exhibit preferential T cell subtype binding.

[0331] In some embodiments, the Fc-containing SIRPγ antibodies provided herein are useful for treating a disease or condition where the disease or condition is driven by CD4+ / CD8+ T cells. It is noted that certain SIRγ antibodies of the present disclosure exhibit preferential T cell subtype binding.

[0332] In some embodiments, the Fc-containing SIRPγ antibodies provided herein are useful for treating a disease or condition where the disease or condition is driven by CD69+ / CD8+ T cells. It is noted that certain SIRγ antibodies of the present disclosure exhibit preferential T cell subtype binding.

[0333] In some embodiments, the Fc-containing SIRPγ antibodies provided herein are useful for treating a disease or condition where the disease or condition is driven by CD25+ / CD8+ T cells. It is noted that certain SIRγ antibodies of the present disclosure exhibit preferential T cell subtype binding.

[0334] C. Pharmaceutical Compositions The present disclosure further provides a pharmaceutical composition comprising any one of the SIRPγ antibodies disclosed herein, and optionally a pharma- ceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical composition is sterile. The pharmaceutical composition may be formulated to be compatible with their intended route of administration. In some embodiments, the pharmaceutical composition of the present disclosure is suitable for administration to a human subject.

[0335] D. Combination Therapy The administration of any one of the therapeutic SIRPγ antibodies provided herein may be combined with any other known drug or treatment for the above diseases or conditions. For example, an exemplary combination for the treatment of oncology diseases includes one of the SIRPγ antibodies of the present disclosure administered in conjunction with a chemotherapeutic agent, a cytotoxic agent, and a corticosteroid drug. Exemplary agents administered in combination include, but are not limited to, cisplatin, cladribine (2-CdA), fludarabine, 6-thioguanine (6-TG), hydroxyurea, prednisone, dexamethasone, methotrexate (MTX), 6-mercaptopurine (6-MP), azacitidine, and decitabine.

[0336] E. Administration of Therapeutic SIRPγ Antibody In vivo administration of therapeutic SIRPγ antibodies can be intravenous, intramuscular, subcutaneous, topical, oral, transdermal, intraperitoneal, intraorbital, intrathecal, intraventricular, intranasal, transmucosal, implanted, or inhaled. Intravenous administration can be via injection or infusion. In some embodiments, SIRPγ antibodies of the present disclosure are administered intravenously. In some embodiments, SIRPγ antibodies of the present disclosure are administered intraperitoneally. In some embodiments, SIRPγ antibodies of the present disclosure are administered subcutaneously. Administration of therapeutic SIRPγ antibodies can be performed with any suitable excipient, carrier, or other agent to provide suitable or improved tolerance, entry, delivery, and the like.

[0337] Exemplary dosages include administration of one of the SIRPγ antibodies of the disclosure (at a dose of about 0.5 mg / kg, about 1 mg / kg, about 3 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 40 mg / kg, or about 50 mg / kg).

[0338] F. Diagnostic Antibodies The antibodies provided herein can also be used for diagnostic purposes. For example, diagnostic antibodies can be used to detect the presence of a SIRPγ-mediated disorder or to detect SIRPγ levels in a subject prior to administration (e.g., as a companion diagnostic).

[0339] III. KITS AND ARTICLES OF MANUFACTURE The present disclosure further provides a kit or article of manufacture comprising any one of the antibodies disclosed herein, or any pharmaceutical composition disclosed herein. In some embodiments, the kit may further comprise instructional materials for carrying out any of the methods disclosed herein. In some embodiments, the kit may further comprise a sterile container or vial for holding the antibody and / or pharmaceutical composition disclosed herein. In some embodiments, the kit may further comprise a sterile delivery device for administering the antibody and / or pharmaceutical composition disclosed herein. In some embodiments, the article of manufacture comprises any pharmaceutical composition of the present disclosure.

[0340] IV. EXEMPLARY ENumerated embodiments Exemplary enumerated embodiments of the present disclosure are as follows:

[0341] Set I Embodiment I-1. An antibody comprising any one of the CDR combinations in Table 1 or any one of the VH / VL combinations in Table 2.

[0342] Embodiment I-2. The antibody of embodiment I-1, wherein the antibody is a monoclonal antibody.

[0343] Embodiment I-3. An antibody according to any one of embodiments I-1 to I-2, wherein the antibody is an antibody fragment.

[0344] Embodiment I-4. The antibody according to any one of embodiments I-1 to I-3, wherein the antibody is a human antibody.

[0345] Embodiment I-5. The antibody according to any one of embodiments I-1 to I-3, wherein the antibody is a humanized antibody.

[0346] Embodiment I-6. The antibody according to any one of embodiments I-1 to I-3, wherein the antibody is a chimeric antibody.

[0347] Embodiment I-7. The antibody according to any one of embodiments I-1 to I-3, wherein the antibody is a full-length antibody.

[0348] Embodiment I-8. An antibody according to any one of embodiments I-1 to I-7, wherein the Fc domain is selected from the group consisting of human IgG1, human IgG2, human IgG3 and human IgG4.

[0349] Embodiment I-9. The antibody of embodiment I-8, wherein the Fc domain comprises SEQ ID NO:5 or SEQ ID NO:6, optionally with one or more Fc amino acid substitutions.

[0350] Embodiment I-10. The Fc domain is selected from the group consisting of 215, 221, 222, 228, 234, 235, 236, 239, 240, 241, 243, 244, 245, 247, 250, 252, 254, 256, 262, 263, 264, 265, 266, 267, 268, 269, 270, 292, 296, 297, 298, The antibody of embodiment I-9, comprising one or more amino acid substitutions at a position selected from the group consisting of 299, 300, 305, 313, 324, 325, 326, 327, 328, 329, 330, 332, 333, 334, 345, 396, 428, 430, 433, 434, 440, wherein the amino acid residue position numbers are according to the EU numbering scheme.

[0351] Embodiment I-11. An antibody according to any one of embodiments I-1 to I-10, wherein binding of the antibody does not disrupt the interaction between CD47 and SIRPγ.

[0352] Embodiment I-12. An antibody according to any one of embodiments I-1 to I-10, wherein binding of the antibody disrupts the interaction between CD47 and SIRPγ.

[0353] Embodiment I-13. An antibody according to any one of embodiments I-1 to I-10, wherein binding of the antibody stabilizes the interaction between CD47 and SIRPγ.

[0354] Embodiment I-14. An antibody according to any one of embodiments I-1 to I-13, wherein the antibody binds to human SIRPγ and cynomolgus SIRPγ.

[0355] Embodiment I-15. The antibody of any one of embodiments I-1 to I-14, wherein the antibody comprises a binding affinity for SIRPγ of less than about 500 nM.

[0356] Embodiment I-16. Provided herein is an Fc-containing antibody specific for SIRPγ, which has low or no affinity for binding to SIRPα and SIRPβ1, and wherein binding of the antibody to SIRPγ-expressing cells induces effector-mediated depletion of SIRPγ-expressing cells.

[0357] Embodiment I-17. The antibody of embodiment I-16, wherein the SIRPγ-expressing cell is a T cell, a B cell, or a NK cell.

[0358] Embodiment I-18. The antibody of embodiment I-17, wherein the SIRPγ-expressing cell is a T cell.

[0359] Embodiment I-19. The antibody of embodiment I-18, wherein the T cell is a naive cell, an activated cell, a central memory cell, an effector memory cell, an exhausted cell, or a terminal effector memory cell.

[0360] Embodiment I-20. The antibody of embodiment I-18, wherein the T cell is a cytotoxic T cell, a helper T cell, a memory T cell, a regulatory T cell, a natural killer T cell, a mucosal-associated invariant T cell, an alpha beta T cell, or a gamma delta T cell.

[0361] Embodiment I-21. The antibody of embodiment I-18, wherein the T cell is a CD3+ T cell, a CD4+ T cell or a CD8+ T cell.

[0362] Embodiment I-22. The antibody of embodiment I-18, wherein the T cell is a Th1 cell, a Th2 cell, a Th17 cell or a T follicular helper cell.

[0363] Embodiment I-23. The antibody of embodiment I-17, wherein the SIRPγ-expressing cell is a B cell.

[0364] Embodiment I-24. The antibody of embodiment I-17, wherein the SIRPγ-expressing cell is a NK cell.

[0365] Embodiment I-25. The antibody of any one of embodiments I-1 to I-24, wherein the SIRPγ expressing cells are activated.

[0366] Embodiment I-26. An antibody according to any one of embodiments I-1 to I-25, which preferentially depletes activated (stimulated) cells as a result of increased surface SIRPγ expression when compared to naive, unactivated (unstimulated) cells.

[0367] Embodiment I-27. An antibody according to any one of embodiments I-1 to I-26, wherein binding of the antibody does not disrupt the interaction between CD47 and SIRPγ.

[0368] Embodiment I-28. An antibody according to any one of embodiments I-1 to I-26, wherein binding of the antibody stabilizes the interaction between CD47 and SIRPγ.

[0369] Embodiment I-29. An antibody according to any one of embodiments I-1 to I-26, wherein binding of the antibody disrupts the interaction between CD47 and SIRPγ.

[0370] Embodiment I-30. The antibody of any one of embodiments I-1 to I-29, wherein the cell depletion is accompanied by antibody-dependent cellular phagocytosis (ADCP).

[0371] Embodiment I-31. The antibody of any one of embodiments I-1 to I-29, wherein the cell depletion is accompanied by antibody-dependent cellular cytotoxicity (ADCC).

[0372] Embodiment I-32. The antibody of any one of embodiments I-1 to I-29, wherein the cell depletion is accompanied by complement dependent cytotoxicity (CDC).

[0373] Embodiment I-33. The antibody of any one of embodiments I-1 to I-32, wherein the antibody is a monoclonal antibody.

[0374] Embodiment I-34. An antibody according to any one of embodiments I-1 to I-33, wherein the antibody is an antibody fragment.

[0375] Embodiment I-35. The antibody of any one of embodiments I-1 to I-34, wherein the antibody is a human antibody.

[0376] Embodiment I-36. The antibody of any one of embodiments I-1 to I-34, wherein the antibody is a humanized antibody.

[0377] Embodiment I-37. The antibody of any one of embodiments I-1 to I-34, wherein the antibody is a chimeric antibody.

[0378] Embodiment I-38. The antibody of any one of embodiments I-1 to I-34, wherein the antibody is a full-length antibody.

[0379] Embodiment I-39. An antibody according to any one of embodiments I-1 to I-38, wherein the Fc domain is selected from the group consisting of human IgG1, human IgG2, human IgG3 and human IgG4.

[0380] Embodiment I-40. The antibody of embodiment I-39, wherein the Fc domain comprises SEQ ID NO:5 or SEQ ID NO:6, optionally with one or more Fc amino acid substitutions.

[0381] Embodiment I-41. The Fc domain is selected from the group consisting of 215, 221, 222, 228, 234, 235, 236, 239, 240, 241, 243, 244, 245, 247, 250, 252, 254, 256, 262, 263, 264, 265, 266, 267, 268, 269, 270, 292, 296, 297, 298, 299, 3 The antibody of any one of embodiments I-38 to I-40, comprising one or more amino acid substitutions at a position selected from the group consisting of: 00, 305, 313, 324, 325, 326, 327, 328, 329, 330, 332, 333, 334, 345, 396, 428, 430, 433, 434, 440, wherein the amino acid residue position numbers are in the EU numbering scheme.

[0382] Embodiment I-42. An antibody according to any one of embodiments I-1 to I-41, wherein the antibody binds to human SIRPγ and cynomolgus SIRPγ.

[0383] Embodiment I-43. An antibody comprising any one of embodiments I-1 to I-42, wherein the antibody comprises a binding affinity for SIRPγ of less than about 500 nM.

[0384] Embodiment I-44. A pharmaceutical composition comprising any one of the antibodies according to embodiments I-1-43, and optionally a pharma- ceutically acceptable carrier.

[0385] Embodiment I-45. A nucleic acid encoding any one of the antibodies of embodiments I-1 to I-43.

[0386] Embodiment I-46. A vector comprising the nucleic acid according to embodiment I-45.

[0387] Embodiment I-47. A method of inducing depletion of a population of SIRPγ expressing cells, the method comprising contacting the population with an antibody according to any one of embodiments I-1 to I-43.

[0388] The method of embodiment I-47, wherein the SIRPγ-expressing cells are T cells, B cells and / or NK cells.

[0389] Embodiment I-49. The method of embodiment I-47, wherein the SIRPγ-expressing cell is a T cell.

[0390] The method of embodiment I-49, wherein the T cells are naive cells, central memory cells, effector memory cells, exhausted cells, or terminal effector memory cells.

[0391] The method of embodiment I-49, wherein the T cell is a cytotoxic T cell, a helper T cell, a memory T cell, a regulatory T cell, a natural killer T cell, a mucosal-associated invariant T cell, an alpha beta T cell, or a gamma delta T cell.

[0392] The method of embodiment I-49, wherein the T cells are CD3+ T cells, CD4+ T cells or CD8+ T cells.

[0393] The method of embodiment I-49, wherein the T cells are Th1 cells, Th2 cells, Th17 cells or T follicular helper cells.

[0394] The method of embodiment I-47, wherein the SIRPγ-expressing cell is a B cell.

[0395] The method of embodiment I-47, wherein the SIRPγ-expressing cell is a NK cell.

[0396] The method of any one of embodiments I-47 to I-55, wherein the SIRPγ expressing cells are activated.

[0397] Embodiment I-57. The method of any one of embodiments I-47 to I-56, wherein the method is in vitro.

[0398] Embodiment I-58. The method of any one of embodiments I-47 to I-56, wherein the method is in vivo.

[0399] Embodiment I-59. The method of any one of embodiments I-47 to I-58, wherein the population of SIRPγ-expressing cells comprises tissue-resident cells.

[0400] Embodiment I-60. The method of any one of embodiments I-47 to I-59, wherein the population of SIRPγ expressing cells comprises circulating cells.

[0401] Embodiment I-61. The method of any one of embodiments I-47 to I-60, wherein the depletion involves one or more of ADCC, ADCP, and CDC.

[0402] Embodiment I-62. A method for treating a disease or condition in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of an antibody according to any one of embodiments I-1 to I-43 or a pharmaceutical composition according to embodiment I-44.

[0403] Embodiment I-63. The method of embodiment I-62, wherein the disease or condition involves SIRPγ-expressing cells.

[0404] Embodiment I-64. The method of embodiment I-63, wherein the SIRPγ-expressing cell is a T cell, a B cell, or a NK cell.

[0405] Embodiment I-65. The method of embodiment I-64, wherein the SIRPγ-expressing cell is a T cell.

[0406] Embodiment I-66. The method of embodiment I-65, wherein the T cells are activated.

[0407] Embodiment I-67. The method of any one of embodiments I-64 to I-66, wherein the T cells are CD4+ T cells, CD8+ T cells, Th1 cells, Th2 cells, Th17 cells or T follicular helper cells.

[0408] Embodiment I-68. The method of any one of embodiments I-64 to I-66, wherein the T cells are cytotoxic T cells, helper T cells, memory T cells, regulatory T cells, natural killer T cells, mucosal-associated invariant T cells or gamma delta T cells.

[0409] Embodiment I-69. The method of embodiment I-65, wherein the T cells are naive cells, activated cells, central memory cells, effector memory cells, exhausted cells, or terminal effector memory cells.

[0410] Embodiment I-70. The method of embodiment I-64, wherein the SIRPγ-expressing cell is a B cell.

[0411] The method of embodiment I-70, wherein the B cells are activated.

[0412] The method of embodiment I-64, wherein the SIRPγ-expressing cell is a NK cell.

[0413] The method of embodiment I-72, wherein the NK cells are activated.

[0414] Embodiment I-74. The method of embodiments I-62 to I-73, wherein the disease or condition comprises an autoimmune, oncological, or inflammatory disorder.

[0415] Embodiment I-75. The method of embodiments I-64 to I-69, wherein the disease or condition comprises a T cell mediated autoimmune disease, a T cell mediated inflammatory disease, or a T cell mediated oncology disease.

[0416] The method of embodiment I-74, wherein the disease or condition is selected from the following: Acute and chronic eosinophilic pneumonia, acute disseminated encephalomyelitis, acute disseminated encephalomyelitis, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Addison's disease, adult-onset Still's disease (AOSD), aplastic anemia, ataxia-telangiectasia, atopic dermatitis, autoimmune lymphoproliferative syndrome, axial spondyloarthritis (AxSpA), birdshot retinochoroidopathy, Castleman's disease, celiac disease, Chediak-Higashi syndrome, coronary artery disease / peripheral artery disease, Crohn's disease, transient angioedema with eosinophilia / Gleich syndrome, giant lymphocytic arteritis, post-HSCT graft failure, graft-versus-host disease (GvHD), Graves' disease, hepatosplenic lymphoma, hypothyroidism, idiopathic interstitial pneumonia, IgA nephropathy, inclusion body myositis (IB) M), inflammatory bowel disease (IBD), large granular lymphocytic leukemia, lymphocytic variant hypereosinophilia, multiple sclerosis, myelodysplastic syndromes (MDS), myocarditis, neuromyelitis optica spectrum disorder, paraneoplastic syndromes, primary biliary cholangitis, primary sclerosing cholangitis, Rasmussen's encephalitis, rheumatoid arthritis (RA), sarcoidosis, Schmidt syndrome / autoimmune polyendocrine syndrome type II, stiff-person syndrome, Susac syndrome, ophthalmia, systemic juvenile idiopathic arthritis (sJIA), systemic lupus erythematosus (SLE), T-lymphocyte-mediated rejection of solid organ transplants, T-cell prolymphocytic leukemia (TPLL), type 1 diabetes, ulcerative colitis, uveitis, vitiligo, X-linked hyper IgM syndrome, autoimmune hepatitis, and X-linked lymphoproliferative disorders.

[0417] Embodiment I-77. The method of any one of embodiments I-62 to I-76, wherein the subject is a human.

[0418] Embodiment I-78. A cell expressing SIRPγ, wherein the cell is bound to an antibody according to any one of embodiments I-1 to I-43, wherein the antibody binds to SIRPγ.

[0419] Embodiment I-79. A kit or article of manufacture comprising an antibody according to any one of embodiments I-1 to I-43, or a pharmaceutical composition according to embodiment I-44.

[0420] Embodiment I-80. Use of an antibody according to any one of embodiments I-1 to I-43 or a pharmaceutical composition according to embodiment I-44 for treating a disease or condition in a subject in need of such treatment.

[0421] Embodiment I-81. Use of an antibody according to any one of embodiments I-1 to I-43 or a pharmaceutical composition according to embodiment I-44 for the manufacture of a medicament for treating a disease or condition in a subject in need of such treatment.

[0422] Set II: Embodiment II-1. Provided herein is an Fc-containing antibody specific for SIRPγ, which has low or no affinity for binding to SIRPα and SIRPβ1, and wherein binding of the antibody to SIRPγ-expressing cells induces effector-mediated depletion of SIRPγ-expressing cells.

[0423] Embodiment II-2. The antibody of embodiment II-1, wherein the SIRPγ-expressing cell is a T cell, a B cell, or a NK cell.

[0424] The antibody of embodiment II-2, wherein the SIRPγ-expressing cell is a T cell.

[0425] Embodiment II-4. The antibody of embodiment II-2, wherein the SIRPγ-expressing cell is a stimulated (activated) T cell.

[0426] The antibody of embodiment II-2, wherein the SIRPγ-expressing cell is an exhausted T cell.

[0427] Embodiment II-6. The antibody of embodiment II-3, wherein the T cell is a naive cell, an activated cell, a central memory cell, an effector memory cell, or a terminal effector memory cell.

[0428] Embodiment II-7. The antibody of embodiment II-3, wherein the T cell is a cytotoxic T cell, a helper T cell, a memory T cell, a regulatory T cell, a natural killer T cell, a mucosal-associated invariant T cell, an alpha beta T cell, or a gamma delta T cell.

[0429] Embodiment II-8. The antibody of embodiment II-3, wherein the T cell is a Th1 cell, a Th2 cell, a Th17 cell or a T follicular helper cell.

[0430] Embodiment II-9. The antibody of embodiment II-3, wherein the T cells are CD3+ T cells, CD4+ T cells, CD8+ T cells, CD25+ T cells, CD69+ T cells, and / or PD1+ T cells.

[0431] The antibody of embodiment II-3, wherein the T cells are CD4+ / CD8+ T cells.

[0432] The antibody of embodiment II-3, wherein the T cells are CD69+ / CD8+ T cells.

[0433] The antibody of embodiment II-3, wherein the T cells are CD25+ / CD8+ T cells.

[0434] The antibody of embodiment II-3, wherein the T cell is a PD1+ T cell.

[0435] Embodiment II-14. The antibody of embodiment II-3, wherein binding of the antibody to SIRPγ-expressing cells is preferential for stimulated T cells compared to unstimulated T cells.

[0436] The antibody of embodiment II-3, wherein binding of the antibody to SIRPγ-expressing cells induces preferential effector-mediated depletion of stimulated T cells.

[0437] The antibody of embodiment II-3, wherein binding of the antibody to SIRPγ-expressing cells induces preferential effector-mediated depletion of exhausted T cells.

[0438] The antibody of embodiment II-9, wherein binding of the antibody to SIRPγ-expressing cells induces preferential effector-mediated depletion of SIRPγ-expressing CD8+ T cells.

[0439] The antibody of embodiment II-9, wherein binding of the antibody to SIRPγ-expressing cells induces preferential effector-mediated depletion of SIRPγ-expressing CD4+ T cells.

[0440] The antibody of embodiment II-9, wherein binding of the antibody to SIRPγ-expressing cells induces preferential effector-mediated depletion of SIRPγ-expressing CD8+ / CD69+ T cells.

[0441] The antibody of embodiment II-9, wherein binding of the antibody to SIRPγ-expressing cells induces preferential effector-mediated depletion of SIRPγ-expressing CD8+ / CD25+ T cells.

[0442] The antibody of embodiment II-9, wherein binding of the antibody to SIRPγ-expressing cells induces preferential effector-mediated depletion of SIRPγ-expressing CD8+ T cells compared to SIRPγ-expressing CD4+ T cells.

[0443] The antibody of embodiment II-9, wherein binding of the antibody to SIRPγ-expressing cells induces preferential effector-mediated depletion of SIRPγ-expressing CD4+ T cells compared to SIRPγ-expressing CD8+ T cells.

[0444] The antibody of embodiment II-9, wherein binding of the antibody to SIRPγ-expressing cells induces preferential effector-mediated depletion of SIRPγ-expressing CD8+ / CD69+ T cells compared to SIRPγ-expressing CD8+ / CD69- T cells.

[0445] The antibody of embodiment II-9, wherein binding of the antibody to SIRPγ-expressing cells induces preferential effector-mediated depletion of SIRPγ-expressing CD8+ / CD25+ T cells compared to SIRPγ-expressing CD8+ / CD25- T cells.

[0446] The antibody of embodiment II-9, wherein binding of the antibody to SIRPγ-expressing cells induces preferential effector-mediated depletion of SIRPγ-expressing PD1+ T cells compared to SIRPγ-expressing PD1− T cells.

[0447] The antibody of embodiment II-2, wherein the SIRPγ-expressing cell is a B cell.

[0448] The antibody of embodiment II-2, wherein the SIRPγ-expressing cell is a NK cell.

[0449] Embodiment II-28. The antibody according to any one of embodiments II-1 to II-27, wherein the SIRPγ expressing cells are stimulated (activated).

[0450] Embodiment II-29. The antibody according to any one of embodiments II-1 to II-27, wherein the SIRPγ expressing cells are exhausted.

[0451] Embodiment II-30. An antibody according to any one of embodiments II-1 to II-29, which preferentially depletes activated (stimulated) cells as a result of increased surface SIRPγ expression when compared to naive, unactivated (unstimulated) cells.

[0452] Embodiment II-31. The antibody of any one of embodiments II-1 to II-30, wherein the cell depletion is accompanied by antibody-dependent cellular phagocytosis (ADCP).

[0453] Embodiment II-32. The antibody of any one of embodiments II-1 to II-30, wherein the cell depletion is accompanied by antibody-dependent cellular cytotoxicity (ADCC).

[0454] Embodiment II-33. The antibody of any one of embodiments II-1 to II-30, wherein the cell depletion is accompanied by complement dependent cytotoxicity (CDC).

[0455] Embodiment II-34. An antibody according to any one of embodiments II-1 to II-33, comprising a CDR amino acid sequence of any one of the combinations in Table 1, as presented in embodiment II-46.

[0456] Embodiment II-35. An antibody according to any one of embodiments II-1 to II-34, comprising the VH and VL amino acid sequences of any one of the combinations in Table 2, or sequences having at least 70% sequence identity thereto, as presented in embodiment II-47.

[0457] Embodiment II-36. A SIRPγ antibody having low or no affinity for binding to SIRPα and SIRPβ1, which antibody exhibits preferential binding to activated (stimulated) T cells compared to unstimulated T cells.

[0458] Embodiment II-37. A SIRPγ antibody that has low or no affinity for binding to SIRPα and SIRPβ1, and which exhibits preferential binding to CD8+ T cells.

[0459] Embodiment II-38. A SIRPγ antibody that has low or no affinity for binding to SIRPα and SIRPβ1, and which exhibits preferential binding to CD4+ T cells.

[0460] Embodiment II-39. A SIRPγ antibody that has low or no affinity for binding to SIRPα and SIRPβ1, and which exhibits preferential binding to CD8+ / CD69+ T cells.

[0461] Embodiment II-40. A SIRPγ antibody that has low or no affinity for binding to SIRPα and SIRPβ1, and which exhibits preferential binding to CD8+ / CD25+ T cells.

[0462] Embodiment II-41. A SIRPγ antibody that has low or no affinity for binding to SIRPα and SIRPβ1, and that exhibits preferential binding to CD8+ T cells as compared to SIRPγ-expressing CD4+ T cells.

[0463] Embodiment II-42. A SIRPγ antibody that has low or no affinity for binding to SIRPα and SIRPβ1, and that exhibits preferential binding to CD4+ T cells as compared to SIRPγ-expressing CD8+ T cells.

[0464] Embodiment II-43. A SIRPγ antibody that has low or no affinity for binding to SIRPα and SIRPβ1, and that exhibits preferential binding to CD8+ / CD69+ T cells as compared to SIRPγ-expressing CD8+ / CD69- cells.

[0465] Embodiment II-44. A SIRPγ antibody that has low or no affinity for binding to SIRPα and SIRPβ1, and that exhibits preferential binding to CD8+ / CD25+ T cells as compared to SIRPγ-expressing CD8+ / CD25- T cells.

[0466] Embodiment II-45. A SIRPγ antibody that has low or no affinity for binding to SIRPα and SIRPβ1, and that exhibits preferential binding to PD1+ T cells compared to SIRPγ expressing PD1− T cells.

[0467] Embodiment II-46. A SIRPγ antibody having low or no affinity for binding to SIRPα and SIRPβ1, wherein the antibody comprises the amino acid sequence of any one of the 47 CDR combinations of Table 1.

[0468] Embodiment II-47. A SIRPγ antibody having low or no affinity for binding to SIRPα and SIRPβ1, wherein the antibody comprises the amino acid sequence of any one of the 47 VH / VL combinations of Table 1, or a sequence having at least 70% identity thereto.

[0469] Embodiment II-48. The antibody of any one of embodiments II-1 to II-47, wherein the antibody is an antibody fragment.

[0470] Embodiment II-49. The antibody of any one of embodiments II-1 to II-48, wherein the antibody is a human antibody.

[0471] Embodiment II-50. The antibody of any one of embodiments II-1 to II-48, wherein the antibody is a humanized antibody.

[0472] Embodiment II-51. The antibody of any one of embodiments II-1 to II-48, wherein the antibody is a chimeric antibody.

[0473] Embodiment II-52. The antibody of any one of embodiments II-1 to II-48, wherein the antibody is a full-length antibody.

[0474] An antibody according to any one of embodiments II-1 to II-52, comprising an Fc domain, wherein the Fc domain is selected from the group consisting of human IgG1, IgG2, IgG3, and IgG4 heavy chain sequences.

[0475] An antibody according to embodiment II-53, wherein the Fc domain is derived from the heavy chain IgG amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 28, and optionally has one or more Fc amino acid substitutions.

[0476] An antibody according to embodiment II-54, wherein the Fc domain is derived from any one of the heavy chain IgG amino acid sequences of SEQ ID NOs: 5 to 36.

[0477] Embodiment II-56. The heavy chain Fc domain is selected from the group consisting of 215, 221, 222, 228, 234, 235, 236, 239, 240, 241, 243, 244, 245, 247, 250, 252, 254, 256, 262, 263, 264, 265, 266, 267, 268, 269, 270, 292, 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, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 339, 340, 341, 343, 344, 345, 347, 250, 252, 254, 256, 262, 263, 264, 265, 266, 267, 268, 269, 270, 292, 296, 297, 298, 299, 308, 309, 310, 311, 3 The antibody of embodiment II-54, comprising one or more amino acid substitutions at a position selected from the group consisting of: 8, 299, 300, 305, 313, 324, 325, 326, 327, 328, 329, 330, 332, 333, 334, 345, 396, 428, 430, 433, 434, 440, wherein the amino acid residue position numbers are in the EU numbering scheme.

[0478] Embodiment II-57. An antibody according to any one of embodiments II-1 to II-56, comprising a light chain constant region derived from an amino acid sequence of any one of SEQ ID NOs: 38 to 42.

[0479] Embodiment II-58. The antibody of any one of embodiments II-1 to II-57, wherein binding of the antibody does not disrupt the interaction between CD47 and SIRPγ.

[0480] Embodiment II-59. The antibody of any one of embodiments II-1 to II-57, wherein binding of the antibody disrupts the interaction between CD47 and SIRPγ.

[0481] Embodiment II-60. An antibody according to any one of embodiments II-1 to II-57, wherein binding of the antibody stabilizes or enhances the interaction between CD47 and SIRPγ.

[0482] Embodiment II-61. The antibody of any one of embodiments II-1 to II-57, wherein the antibody binds to human SIRPγ and cynomolgus SIRPγ.

[0483] Embodiment II-62. An antibody comprising any one of embodiments II-1 to II-57, wherein the antibody comprises a binding affinity to SIRPγ of less than about 500 nM.

[0484] Embodiment II-63. A pharmaceutical composition comprising any one of the antibodies according to embodiments II-1 to II-62, and optionally a pharma- ceutically acceptable carrier.

[0485] Embodiment II-64. A nucleic acid encoding any one of the antibodies according to embodiments II-1 to II-62.

[0486] Embodiment II-65. A vector comprising the nucleic acid according to embodiment II-64.

[0487] Embodiment II-66. A method for inducing preferential depletion of a population of SIRPγ expressing cells, the method comprising contacting the population with an antibody according to any one of embodiments II-1 to II-62.

[0488] The method of embodiment II-66, wherein the SIRPγ-expressing cells are T cells, B cells and / or NK cells.

[0489] The method of embodiment II-66, wherein the SIRPγ-expressing cell is a T cell.

[0490] Embodiment II-69. The method of embodiment II-68, wherein the T cells are activated (stimulated).

[0491] Embodiment II-70. The method of embodiment II-68, wherein the T cells are activated (stimulated) and the depletion is preferential to activated (stimulated) T cells.

[0492] Embodiment II-71. The method of embodiment II-68, wherein the T cells are exhausted.

[0493] Embodiment II-72. The method of embodiment II-68, wherein the T cells are exhausted and the depletion is preferential to exhausted T cells.

[0494] The method of embodiment II-68, wherein the T cells are naive cells, central memory cells, effector memory cells, exhausted cells, or terminal effector memory cells.

[0495] The method of embodiment II-68, wherein the T cell is a cytotoxic T cell, a helper T cell, a memory T cell, a regulatory T cell, a natural killer T cell, a mucosal-associated invariant T cell, an alpha beta T cell, or a gamma delta T cell.

[0496] The method of embodiment II-68, wherein the T cells are Th1 cells, Th2 cells, Th17 cells or T follicular helper cells.

[0497] The method of embodiment II-68, wherein the T cells are CD3+ T cells, CD4+ T cells, CD8+ T cells, CD25+ T cells, CD69+ T cells, and / or PD1+ T cells.

[0498] Embodiment II-77. The method of embodiment II-76, wherein the T cells are CD4+ / CD8+ T cells.

[0499] The method of embodiment II-76, wherein the T cells are CD69+ / CD8+ T cells.

[0500] Embodiment II-79. The method of embodiment II-76, wherein the T cells are CD25+ / CD8+ T cells.

[0501] The method of embodiment II-76, wherein the T cells are PD1+ T cells.

[0502] Embodiment II-81. The method of embodiment II-76, wherein the depletion is preferential to stimulated T cells compared to unstimulated T cells.

[0503] Embodiment II-82. The method of embodiment II-76, wherein the depletion is preferential for SIRPγ-expressing CD8+ T cells.

[0504] Embodiment II-83. The method of embodiment II-76, wherein the depletion is preferential for SIRPγ-expressing CD4+ T cells.

[0505] Embodiment II-84. The method of embodiment II-76, wherein the depletion is preferential for SIRPγ-expressing CD8+ / CD69+ T cells.

[0506] Embodiment II-85. The method of embodiment II-76, wherein the depletion is preferential for SIRPγ-expressing CD8+ / CD25+ T cells.

[0507] Embodiment II-86. The method of embodiment II-76, wherein the depletion is preferential for SIRPγ-expressing CD8+ T cells as compared to SIRPγ-expressing CD4+ T cells.

[0508] Embodiment II-87. The method of embodiment II-76, wherein the depletion is preferential for SIRPγ-expressing CD4+ T cells as compared to SIRPγ-expressing CD8+ T cells.

[0509] Embodiment II-88. The method of embodiment II-76, wherein the depletion is preferential for SIRPγ-expressing CD8+ / CD69+ T cells as compared to SIRPγ-expressing CD8+ / CD69- T cells.

[0510] Embodiment II-89. The method of embodiment II-76, wherein the depletion is preferential for SIRPγ-expressing CD8+ / CD25+ T cells as compared to SIRPγ-expressing CD8+ / CD25- T cells.

[0511] The method of embodiment II-66, wherein the SIRPγ-expressing cell is a B cell.

[0512] The method of embodiment II-66, wherein the SIRPγ-expressing cell is a NK cell.

[0513] The method of any one of embodiments II-66 to II-91, wherein the SIRPγ expressing cells are activated.

[0514] Embodiment II-93. The method according to any one of embodiments II-66 to II-92, wherein the method is in vitro.

[0515] Embodiment II-94. The method according to any one of embodiments II-66 to II-92, wherein the method is in vivo.

[0516] The method of any one of embodiments II-66 to II-94, wherein the population of SIRPγ-expressing cells comprises tissue-resident cells.

[0517] The method of any one of embodiments II-66 to II-95, wherein the population of SIRPγ-expressing cells comprises circulating cells.

[0518] Embodiment II-97. The method of any one of embodiments II-66 to II-96, wherein the depletion involves one or more of ADCC, ADCP, and CDC.

[0519] Embodiment II-98. A method for treating a disease or condition in a subject in need of such treatment, comprising administering to the subject in need thereof a therapeutically effective amount of an antibody described in any one of embodiments II-1 to II-62 or a pharmaceutical composition described in embodiment II-63.

[0520] Embodiment II-99. The method of embodiment II-98, wherein the disease or condition involves SIRPγ-expressing cells.

[0521] The method of embodiment II-99, wherein the SIRPγ-expressing cell is a T cell, a B cell, or a NK cell.

[0522] The method of embodiment II-100, wherein the SIRPγ-expressing cell is a T cell.

[0523] The method of embodiment II-101, wherein the T cells are stimulated (activated).

[0524] Embodiment II-103. The method of embodiment II-101, wherein the T cells are exhausted.

[0525] Embodiment II-104. The method of any one of embodiments II-100 to II-102, wherein the T cells are cytotoxic T cells, helper T cells, memory T cells, regulatory T cells, natural killer T cells, mucosal-associated invariant T cells or gamma delta T cells.

[0526] Embodiment II-105. The method of any one of embodiments II-100 to II-102, wherein the T cells are naive cells, central memory cells, effector memory cells, or terminal effector memory cells.

[0527] Embodiment II-106. The method of any one of embodiments II-100 to II-102, wherein the T cells are CD3+ T cells, CD4+ T cells, CD8+ T cells, CD25+ T cells, CD69+ T cells, and / or PD1+ T cells.

[0528] The method of embodiment II-106, wherein the T cells are CD4+ / CD8+ T cells.

[0529] The method of embodiment II-106, wherein the T cells are CD69+ / CD8+ T cells.

[0530] The method of embodiment II-106, wherein the T cells are CD25+ / CD8+ T cells.

[0531] The method of embodiment II-106, wherein the T cells are PD1+ T cells.

[0532] Embodiment II-111. The method of embodiment II-106, wherein binding of the antibody is preferential to stimulated T cells compared to unstimulated T cells.

[0533] Embodiment II-112. The method of embodiment II-106, wherein the binding of the antibody is preferential to SIRPγ-expressing CD8+ T cells.

[0534] Embodiment II-113. The method of embodiment II-106, wherein the binding of the antibody is preferential to SIRPγ-expressing CD4+ T cells.

[0535] The method of embodiment II-106, wherein binding of the antibody to SIRPγ-expressing cells induces preferential effector-mediated depletion of SIRPγ-expressing CD8+ / CD69+ T cells.

[0536] Embodiment II-115. The method of embodiment II-106, wherein the binding of the antibody is preferential to SIRPγ-expressing CD8+ / CD25+ T cells.

[0537] Embodiment II-116. The method of embodiment II-106, wherein the binding of the antibody is preferential to SIRPγ-expressing CD8+ T cells as compared to SIRPγ-expressing CD4+ T cells.

[0538] Embodiment II-117. The method of embodiment II-106, wherein the binding of the antibody is preferential to SIRPγ-expressing CD4+ T cells as compared to SIRPγ-expressing CD8+ T cells.

[0539] Embodiment II-118. The method of embodiment II-106, wherein the binding of the antibody is preferential to SIRPγ-expressing CD8+ / CD69+ T cells as compared to SIRPγ-expressing CD8+ / CD69- T cells.

[0540] Embodiment II-119. The method of embodiment II-106, wherein the binding of the antibody is preferential to SIRPγ-expressing CD8+ / CD25+ T cells as compared to SIRPγ-expressing CD8+ / CD25- T cells.

[0541] The method of embodiment II-100, wherein the SIRPγ-expressing cell is a B cell.

[0542] The method of embodiment II-120, wherein the B cells are activated.

[0543] The method of embodiment II-100, wherein the SIRPγ-expressing cells are NK cells.

[0544] The method of embodiment II-122, wherein the NK cells are activated.

[0545] Embodiment II-124. The method of any one of embodiments II-98 to II-123, wherein the disease or condition comprises an autoimmune, oncological, or inflammatory disorder.

[0546] The method of embodiment II-124, wherein the disease or condition comprises a T cell mediated autoimmune disease, a T cell mediated inflammatory disease, or a T cell mediated oncology disease.

[0547] The method of any one of embodiments II-98 to II-123, wherein the disease or condition is driven by CD8+ T cells.

[0548] The method of any one of embodiments II-98 to II-123, wherein the disease or condition is CD4+ T cell driven.

[0549] The method of any one of embodiments II-98 to II-123, wherein the disease or condition is driven by CD8+ T cells and CD4+ T cells.

[0550] The method of any one of embodiments II-98 to II-125, wherein the disease or condition is selected from the following: Acute and chronic eosinophilic pneumonia, acute disseminated encephalomyelitis, acute disseminated encephalomyelitis, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Addison's disease, adult-onset Still's disease (AOSD), aplastic anemia, ataxia-telangiectasia, atopic dermatitis, autoimmune lymphoproliferative syndrome, axial spondyloarthritis (AxSpA), birdshot retinochoroidopathy, Castleman's disease, celiac disease, Chediak-Higashi syndrome, coronary artery disease / peripheral artery disease, Crohn's disease, transient angioedema with eosinophilia / Gleich syndrome, giant lymphocytic arteritis, post-HSCT graft failure, graft-versus-host disease (GvHD), Graves' disease, hepatosplenic lymphoma, hypothyroidism, idiopathic interstitial pneumonia, IgA nephropathy, inclusion body myositis (IB) M), inflammatory bowel disease (IBD), large granular lymphocytic leukemia, lymphocytic variant hypereosinophilia, multiple sclerosis, myelodysplastic syndromes (MDS), myocarditis, neuromyelitis optica spectrum disorder, paraneoplastic syndromes, primary biliary cholangitis, primary sclerosing cholangitis, Rasmussen's encephalitis, rheumatoid arthritis (RA), sarcoidosis, Schmidt syndrome / autoimmune polyendocrine syndrome type II, stiff-person syndrome, Susac syndrome, ophthalmia, systemic juvenile idiopathic arthritis (sJIA), systemic lupus erythematosus (SLE), T-lymphocyte-mediated rejection of solid organ transplants, T-cell prolymphocytic leukemia (TPLL), type 1 diabetes, ulcerative colitis, uveitis, vitiligo, X-linked hyper IgM syndrome, autoimmune hepatitis, and X-linked lymphoproliferative disorders.

[0551] Embodiment II-130. The method of any one of embodiments II-98 to II-129, wherein the subject is a human.

[0552] Embodiment II-131. A cell expressing SIRPγ, wherein the cell is bound to an antibody according to any one of embodiments II-1 to II-62, wherein the antibody is bound to SIRPγ.

[0553] Embodiment II-132. A kit or article of manufacture comprising an antibody according to any one of embodiments II-1 to II-62, or a pharmaceutical composition according to embodiment II-63.

[0554] Embodiment II-133. Use of an antibody according to any one of embodiments II-1 to II-62 or a pharmaceutical composition according to embodiment II-63 for treating a disease or condition in a subject in need of such treatment.

[0555] Embodiment II-134. Use of an antibody according to any one of embodiments II-1 to II-62 or a pharmaceutical composition according to embodiment II-63 for the manufacture of a medicament for treating a disease or condition in a subject in need of such treatment. EXAMPLES

[0556] Example 1: Hybridoma library screening for identification of anti-human SIRPγ antibodies Anti-human SIRPγ (anti-hSIRPγ) monoclonal antibodies (simply referred to as SIRPγ antibodies in these examples) were identified from a transgenic mouse model. Harbour Mice® H2L2 strain was immunized with the extracellular domain of human SIRPγ (hSIRPγ). Hybridoma libraries (two libraries) were generated from the splenocytes of the immunized animals using standard techniques. Anti-hSIRPγ antibody-producing clones were identified by flow cytometric analysis of hSIRPγ expressing cells exposed to antibody-containing supernatants of individual clones. Anti-hSIRPγ specific clones were selected using counterscreening against human SIRPα and human SIRPβ1 expressing cells via flow cytometry and confirmed using SIRP protein binding via ELISA. All clones obtained from this campaign have human variable regions and rodent constant regions. Selected clones were reformatted into fully human antibodies, i.e., they were reformatted to have human variable regions and human constant regions. It should be noted that the human constant region can include any one of the Fc regions provided in this disclosure, for example, those of SEQ ID NOs: 5-36, standard, modified, or otherwise.

[0557] Example 2: Phage antibody library screening for identification of anti-human SIRPγ antibodies Using another approach, additional SIRPγ antibodies were identified from a fully human phage display library. The library was first enriched for human SIRPγ binding on magnetic beads. Multiple sub-libraries were generated using deselection of SIRPα and SIRPβ1 binders and / or positive selection for cynomolgus monkey SIRPγ cross-reactivity. The resulting specific single clone libraries were generated and sequenced. All clones obtained from this campaign are single chain variable fragment (scFv) antibodies as crude periplasmic extracts (PPE). Selected clones were reformatted into fully human antibodies to include various Fc of the present disclosure (e.g., Fc with increased effector function, Fc with decreased effector function, etc.). That is, they were reformatted to have human variable regions and human constant regions. Note that the human constant region can include any one of the Fc regions provided in the present disclosure, e.g., those of SEQ ID NOs: 5-36, standard, modified, or another.

[0558] Example 3: Binding of SIRPγ antibodies to SIRP proteins Selected hybridoma supernatants from Example 1 were tested for binding to human SIRPγ, cynomolgus SIRPγ, human SIRPαV1, cynomolgus SIRPα, human SIRPβ1, and cynomolgus SIRPβ1 by enzyme-linked immunosorbent assay (ELISA). Briefly, 2 μg / mL of the extracellular domain of SIRP protein was coated on a high protein binding plate and blocked. Undiluted supernatant was added to the coated plate. Antibodies were detected by anti-rat antibody and chemiluminescent substrate. Figure 1 shows the results of binding of antibody 1 and antibody 2 to various SIRP proteins. Data shows relative luminescence units read by a plate reader capable of detecting chemiluminescence.

[0559] Figures 2A-G show binding curves of SIRPγ antibodies and human Fc isotype controls to human SIRPγ, cynomolgus monkey SIRPγ, human SIRPαV1, human SIRPαV2, and human SIRPβ1 by ELISA. Selected SIRPγ antibodies from Examples 1 and 2 were fully humanized as described above. Isotype control 1 was an irrelevant human IgG1 antibody with irrelevant CDRs (non-SIRPγ binding) that contained the same amino acid substitutions in the Fc region as some of the SIRPγ antibodies selected for increased FcγR binding. Isotype control 2 was an irrelevant human IgG1 antibody with irrelevant CDRs without modifications in the Fc region. DNA was transiently transfected into Expi293F cells for 5 days. Antibodies were purified from cell supernatants by Protein A and analyzed in titrations by ELISA as previously described in Figure 1 using anti-human IgG antibodies as detection antibodies.

[0560] Selected antibodies from Example 1 of the present disclosure were tested for their affinity to human SIRPγ, cynomolgus monkey SIRPγ, human SIRPαV1, human SIRPαV2, and human SIRPβ1 using a Biolayer Interferometry (BLI) Octet system (Pall ForteBio). Each antibody was immobilized on a biosensor chip by anti-human IgG capture (AHC). Multiple concentrations of SIRP-His monomeric protein (starting at 300 nM and diluted 1:2 for seven total concentrations) were exposed to the biosensor to measure the on-rate kinetics of SIRPγ antibody binding to the SIRP-His protein. The biosensor was then exposed to wash buffer to measure the off-rate kinetics. The resulting kinetic data was analyzed and fitted using a 1:1 binding model. Affinities were calculated as global KD and are shown in Table 4 below. The table shows the KD (in M) for binding of selected antibodies to monomeric human SIRPγ, cynomolgus monkey SIRPγ, human SIRPαV1, human SIRPαV2, and human SIRPβ1 as assayed by ForteBio Octet.

[0561] The enriched library of scFv antibodies from Example 2 was tested for binding to human SIRPγ using the Octet system. Unique binders were further tested for binding to human SIRPαV1, human SIRPαV2, and human SIRPβ1. Briefly, biotinylated anti-V5 was immobilized on a streptavidin biosensor. Each V5-tagged SIRPγ scFv antibody as crude PPE was captured by anti-V5 antibody. 500 nM of SIRP-His monomer protein was exposed to the biosensor for binding to SIRP scFv. The biosensor was then exposed to wash buffer to measure off-rate kinetics. The resulting association and dissociation kinetics (kdis) were analyzed. The sensorgrams were visually inspected and the antibodies were classified as strong, medium, weak, hetero, or non-binders, with the categories shown in Table 5 below. Similarly, cross-reactivity to cynomolgus SIRPγ, cynomolgus SIRPα, and cynomolgus SIRPβ1 was tested. The antibodies were classified as binders and non-binders, as shown in Table 6 below. With reference to Table 5, strong kdis < 0.001 / sec; medium kdis > 0.001 / sec, but < 0.01 / sec; weak kdis > 0.01 / sec. Heterogeneous (hetero) kinetics showed baseline drift and the binding category could not be determined. With reference to Tables 5 and 6, binders have analyte response levels of 0.02 nm or greater at 115 seconds during association. Non-binders have analyte response levels of less than 0.02 nm at 115 seconds during association.

[0562] Selected antibodies from Example 2 were tested for their affinity to human SIRPγ and cynomolgus monkey SIRPγ using a Biolayer Interferometry (BLI) Octet system (Pall ForteBio). The antibodies were coated onto an anti-human Fc capture (AHC) biosensor. Four concentrations (200 nM, 100 nM, 50 nM, 25 nM) of SIRP-His monomeric protein or bivalent SIRP protein with mouse Fc were exposed to the biosensor to measure the on-rate kinetics of SIRP antibody binding to the SIRP protein. The biosensor was then exposed to a wash buffer to measure the off-rate kinetics. The resulting kinetic data was analyzed and fitted using a global 1:2 binding model. The KD affinity for each antibody is shown in Table 7 below.

[0563] [Table 4]

[0564] [Table 5]

[0565] [Table 6]

[0566] [Table 7]

[0567] Example 4: Binding of SIRPγ antibodies to cells in vitro by flow cytometry Selected antibodies and isotype controls were tested for binding to human T cells, B cells, NK cells, monocytes, and granulocytes. Figures 3A-3D show the results of binding studies performed with exemplary antibodies to T cells, B cells, NK cells, monocytes, and granulocytes in human whole blood compared to isotype controls. Isotype control 1 was an irrelevant human IgG1 antibody with irrelevant CDRs. Isotype control 2 was the same as isotype control 1, but included substitutions in the Fc region (to increase affinity for FcγR) as part of the selected SIRPγ antibody. Up to 50 μg / mL of fluorochrome-conjugated antibodies or isotype controls were incubated with whole blood from three normal donors. T cells were identified as CD14-, CD20-, SSClow, and CD3+ populations, or further identified as CD4+ or CD8+ populations. B cells were identified as CD14-, SSClow, and CD20+ populations. NK cells were identified as CD14-, CD20-, CD3-, and CD56+. Monocytes were identified as the SSClow and CD14+ population. Granulocytes were identified as the CD14-, CD20-, CD3-, SSChigh population. Graph shows median fluorescence intensity (MFI) for each population.

[0568] A commercially available mouse monoclonal antibody against human SIRPγ (clone OX-119, catalog number MA5-28215 from ThermoFisher Scientific) was tested for binding to naive and stimulated T cells via flow cytometry. To stimulate or activate T cells, anti-human CD3 and anti-human CD28 were incubated with naive resting CD3+, CD4+, or CD8+ T cells from individual healthy human donors or cynomolgus monkeys for 7 days in the presence of IL-2. Titrations of the commercially available antibody were added to stimulated cells and naive T cells from the same donors. Figure 4A shows the binding curves of mouse monoclonal antibodies to stimulated CD3+, CD4+, and CD8+ T cells compared to naive T cells. The antibodies showed increased binding to activated (stimulated) T cells and increased expression of SIRPγ on activated T cells. Similarly, select antibodies from Example 2 were evaluated for binding to naive and stimulated human and cynomolgus T cells. Figures 4B-C show binding curves of human monoclonal antibodies to stimulated human and cynomolgus CD3+ T cells compared to naive T cells.

[0569] Selected antibodies were tested for binding to several subpopulations of unstimulated and stimulated T cells via flow cytometry. To stimulate or activate T cells, beads coated with anti-human CD3 and anti-human CD28 were incubated with CD3+ T cells from individual healthy human donors in the presence of IL-2. Activated beads were removed after 3 days. Cells were stained for multiple T cell subpopulation markers, including but not limited to CD3, CD4, CD8, CD69, CD25, and PD-1, at multiple time points for 16 days. Saturating 20 μg / mL of selected SIRPγ antibodies were used. Antibody 83, antibody 84, antibody 85, antibody 86, antibody 88, antibody 89, antibody 90, antibody 92, antibody 94, antibody 95, antibody 96, and antibody 97 showed increased binding to stimulated T cells when compared to unstimulated T cells. Antibody 84 preferentially bound to CD8+ T cells when compared to CD4+ T cells. Antibody 84 bound preferentially to CD69+ / CD8+ T cells and CD25+ / CD8+ T cells compared to CD69- / CD8+ T cells and CD25- / CD8+ T cells. Antibody 85, Antibody 89, Antibody 95, and Antibody 97 bound preferentially to PD1+ T cells compared to PD1- T cells.

[0570] Selected antibodies were tested for binding to stably transfected human SIRPγ, SIRPαV1, or SIRPβ1 (co-transfected with DAP12) Chinese Hamster Ovary (CHO) cells via flow cytometry. Titrations of selected antibodies were added to the cells and detected using fluorescently labeled secondary anti-rat IgG or anti-human IgG antibodies. Graphs show median fluorescence intensity (MFI) at each concentration. Figure 5A and Figure 5G show binding curves of selected antibodies to human SIRPγ, cynomolgus SIRPγ, human SIRPα, cynomolgus SIRPα, human SIRPβ1, or cynomolgus SIRPβ1 expressing CHO cells detected using anti-rat IgG antibodies. Figures 5B-5F and 5H-5L show binding curves of select antibodies to human SIRPγ, cynomolgus SIRPγ, human SIRPα, cynomolgus SIRPα, human SIRPβ1, or cynomolgus SIRPβ1 expressing CHO cells detected using an anti-human IgG antibody. Isotype control 1 was an irrelevant human IgG1 antibody with irrelevant CDRs (non-SIRPg binding) that contained the same amino acid substitutions in the Fc region as some of the SIRPγ antibodies selected for increased FcγR binding. Isotype control 2 was the same as isotype control 1 but contained no mutations in the Fc region. For select antibodies, each myc-tagged SIRPγ scFv antibody as crude PPE was incubated with each of the SIRP expressing cell lines mentioned above along with the parental CHO-K1 cell line. Table 8 below shows the MFI fold change values ​​compared to parental non-transfected CHO cells for the scFv antibodies detected using an anti-myc antibody using the six SIRP expressing cell lines. Fold change values ​​<2.0 are considered non-binders. The SIRPγ antibodies shown in Figures 5A-5L and Table 8 demonstrate preferential binding to human SIRPγ and cynomolgus SIRPγ.

[0571] [Table 8]

[0572] Example 5: Effect of SIRPγ Antibody on ADCC Antibody-dependent cellular cytotoxicity (ADCC) induced by selected SIRPγ antibodies on primary human resting and activated T cells was evaluated. SIRPγ-expressing human primary resting T cells (target) cells were incubated with a reporter cell line (effector) expressing FcγRIIIa at an effector cell to target cell ratio of 8:1 for 6 hours at 37°C. After FcγRIIIa engages the Fc region of the relevant SIRPγ antibody bound to the target cells, these effector cells transmit an intracellular signal resulting in NFAT-mediated luciferase activity. This activity is read as a luminescent signal on a plate reader and is proportional to FcγRIIIa binding. To activate T cells, anti-CD3 and anti-CD28 were pre-incubated with resting T cells for 7 days. FcγRIIIa binding was then measured following the same protocol as above. Figures 6A-C show the fold-induction of ADCC induction of titrations of selected antibodies relative to no-antibody conditions for human CD3+ T cells. Results are shown relative to isotype controls. Isotype control 1 was an irrelevant human IgG4 antibody with irrelevant CDRs. Isotype control 2 was an irrelevant human IgG1 antibody with irrelevant CDRs. Isotype control 3 was the same as isotype control 2, but contained the same high affinity substitutions (to increase affinity for FcγR) in the Fc region as part of the selected SIRPγ antibody. Table 9 below shows the half maximal effective concentration (EC50) of selected antibodies when applying a four-parameter logistic nonlinear regression curve fit.

[0573] ADCC induced by selected SIRP antibodies on primary human T cells (targets) was evaluated using primary NK cells as effector cells. Target cells were loaded with CellTracker™ Green, washed, and exposed to various concentrations of SIRP antibodies. Target cells were then incubated with human NK (effector) cells at an effector cell to target cell ratio of 2:1 for 4 hours at 37°C. Samples were stained with Zombie Violet dye and analyzed by flow cytometry. Activated T cells were generated using the same stimulation protocol as above. %ADCC was calculated as the percent of cells positive for Zombie Violet dye relative to the total cells positive for CellTracker™ Green. Graphs in Figures 6B-6C show the average of three target cell donors normalized to an internal positive control antibody. ADCC effects are antibody dose dependent. Results are shown relative to isotype control.

[0574] [Table 9] NC=Cannot be calculated

[0575] Example 6: Effect of SIRPγ antibody on ADCP Using a reporter cell line expressing FcγRIIa at an effector cell to target cell ratio of 4:1 (effector), antibody-dependent cellular phagocytosis (ADCP) induced by selected SIRPγ antibodies on primary human resting and activated T cells was evaluated in the same manner as in Example 5. Figure 7 shows the fold-induction of ADCP induction of titrations of selected antibodies versus no-antibody conditions on human CD3+ T cells. Results are shown relative to isotype controls. Isotype control 1 was an irrelevant IgG4 antibody with irrelevant CDRs. Isotype control 2 was an irrelevant IgG1 antibody with irrelevant CDRs. Isotype control 3 was the same as isotype control 2, but contained the same high affinity substitutions (to increase affinity for FcγR) in the Fc region as part of the selected SIRPγ antibody.

[0576] Example 7: Determination of SIRPγ antibody competition with CD47 for binding to SIRPγ ELISA analysis was performed to evaluate whether selected SIRPγ antibodies of the present disclosure compete with CD47-Fc for binding to hSIRPγ. To perform the competition experiment, the extracellular binding domain of SIRPγ was coated on a high protein binding plate and blocked. A titration of each SIRPγ antibody was incubated on the plate for 1 hour. Biotinylated CD47-Fc was then added at a concentration of 10 μg / mL and allowed to equilibrate for 1 hour. After washing, streptavidin-HRP was added. The plate was washed again and developed with a chemiluminescent substrate. The plate was read on a plate reader to assess luminescence. Isotype control 1 was an irrelevant human IgG1 antibody with irrelevant CDRs that contained the same amino acid substitutions in the Fc region as some of the selected SIRPγ antibodies and was used as a negative control. Isotype control 2 was the same as isotype control 1 but contained no mutations in the Fc region. A known blocker antibody was used as a positive control. Figures 8A-B show a subset of antibodies that did not affect CD47 / SIRPγ binding (Antibody 5, Antibody 6, Antibody 8, Antibody 59, Antibody 73, Antibody 80, Antibody 85, Antibody 92, and Antibody 96), a second set promoted CD47 / SIRPγ binding (Antibody 3, Antibody 4, and Antibody 7), while the rest inhibited CD47 / SIRPγ binding.

[0577] Example 8: Effect of SIRPγ antibody on T cell proliferation The effect of selected SIRPγ antibodies on T cell proliferation was evaluated via a one-way mixed lymphocyte reaction (MLR). Monocytes were isolated from PBMCs of healthy individuals and differentiated into dendritic cells (moDCs). CD3+ T cells were isolated from different healthy individuals and labeled with a dye (CFSE) used to track cell proliferation. moDCs and T cells were co-cultured for 7 days with a titration of the selected antibodies up to 100 μg / mL. The cells were then analyzed by flow cytometry. The proliferation percentage (% proliferation) is calculated as the % CD3+ T cells with loss of CFSE dye signal indicating proliferation. Figure 9 shows the proliferation % against antibody concentration. In addition to the selected SIRPγ antibodies generated from Example 1 and Example 2, a human SIRPγ antibody with mouse Fc (clone LSB2.20), a human CD47 antibody with mouse Fc (clone B6H12), and two human SIRPα antibodies (clones 18F21A and 17F07A) were tested. The results were compared to an isotype control antibody. Isotype control 1 was a human IgG1 antibody with irrelevant CDRs that contains the same amino acid substitutions in the Fc region as some selected SIRPγ antibodies to reduce FcγR binding. Isotype control 2 was a mouse IgG1 antibody with irrelevant CDRs. Only the CD47 antibody showed inhibition of T cell proliferation.

[0578] Example 9: Effect of SIRPγ antibodies on in vivo depletion of selected cell types The effect of selected SIRPγ antibodies on CD3+ T cell depletion was evaluated in vivo using 8-10 week old female NSG-Tg(Hu-IL15) mice. Mice were administered selected SIRPγ antibodies or isotype control intraperitoneally at a dose of 30 mg / kg 30 min prior to transfer of human PBMCs and stimulated T cells. T cells were stimulated by adding beads coated with human anti-CD3 and anti-CD28 antibodies to isolated CD3+ human T cells for 5-7 days in the presence of IL-2. Stimulatory beads were removed on day 3. Stimulated T cells were stained with CellTracker™ prior to infusion. Mice were injected intravenously with 1.00E+07 human PBMCs and 5.00E+06 stimulated T cells via a single tail vein injection. Mice were euthanized 3 days after cell transfer. Whole blood was obtained by cardiac puncture and collected in EDTA blood collection tubes. Whole blood was lysed with RBC lysis buffer, washed, and blocked with both human and mouse Fc blockers. Cells were washed again and resuspended in antibody cocktail mix diluted to appropriate concentrations. The staining cocktail mix included anti-human CD45, anti-mouse CD45, anti-human CD3, and live / dead cell markers. Cells were analyzed by flow cytometry. Figure 10 shows the % live human CD3+ T cells detected (left panel). Further analysis separated the detection of stimulated and unstimulated human CD3+ T cells (right panel). Data in Figure 10 (left panel) are normalized to the number of live human CD3+ T cells detected in mice treated with isotype control. Selected SIRPγ antibodies induced depletion of human CD3+ T cells when compared to isotype control treatment. Further analysis of CellTracker™ stained cells (i.e. stimulated cells) shows that stimulated cells were preferentially depleted compared to unstimulated cells (Figure 10, right panel).

Claims

1. 1. A SIRPγ-specific antibody, (a) comprising three VL CDRs of the amino acid sequences of SEQ ID NO: 100, SEQ ID NO: 138, and SEQ ID NO: 167; and three VH CDRs of the amino acid sequences of SEQ ID NO: 209, SEQ ID NO: 245, and SEQ ID NO: 277; (b) three VL CDRs of the amino acid sequences of SEQ ID NO: 101, SEQ ID NO: 139, and SEQ ID NO: 168; and three VH CDRs of the amino acid sequences of SEQ ID NO: 210, SEQ ID NO: 246, and SEQ ID NO: 278; (c) three VL CDRs of the amino acid sequences of SEQ ID NO: 102, SEQ ID NO: 140, and SEQ ID NO: 169; and three VH CDRs of the amino acid sequences of SEQ ID NO: 211, SEQ ID NO: 247, and SEQ ID NO: 279; (d) comprising three VL CDRs of the amino acid sequences of SEQ ID NO: 103, SEQ ID NO: 141, and SEQ ID NO: 170; and three VH CDRs of the amino acid sequences of SEQ ID NO: 212, SEQ ID NO: 248, and SEQ ID NO: 280; (e) three VL CDRs having the amino acid sequences of SEQ ID NOs: 104, 141, and 171; and three VH CDRs having the amino acid sequences of SEQ ID NOs: 213, 249, and 281; (f) comprising three VL CDRs of the amino acid sequences of SEQ ID NO: 105, SEQ ID NO: 142, and SEQ ID NO: 172; and three VH CDRs of the amino acid sequences of SEQ ID NO: 214, SEQ ID NO: 250, and SEQ ID NO: 282; (g) comprising three VL CDRs of the amino acid sequences of SEQ ID NO: 106, SEQ ID NO: 143, and SEQ ID NO: 173; and three VH CDRs of the amino acid sequences of SEQ ID NO: 215, SEQ ID NO: 251, and SEQ ID NO: 283; (h) comprising three VL CDRs of the amino acid sequences of SEQ ID NOs: 106, 144, and 174; and three VH CDRs of the amino acid sequences of SEQ ID NOs: 216, 252, and 284; (i) three VL CDRs of the amino acid sequences of SEQ ID NOs: 107, 141, and 175; and three VH CDRs of the amino acid sequences of SEQ ID NOs: 217, 253, and 285; (j) three VL CDRs of the amino acid sequences of SEQ ID NO: 108, SEQ ID NO: 144, and SEQ ID NO: 176; and three VH CDRs of the amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 254, and SEQ ID NO: 286; (k) comprising three VL CDRs of the amino acid sequences of SEQ ID NOs: 109, 145, and 171; and three VH CDRs of the amino acid sequences of SEQ ID NOs: 218, 255, and 287; (l) three VL CDRs of the amino acid sequences of SEQ ID NO: 110, SEQ ID NO: 146, and SEQ ID NO: 177; and three VH CDRs of the amino acid sequences of SEQ ID NO: 219, SEQ ID NO: 249, and SEQ ID NO: 288; (m) comprising three VL CDRs of the amino acid sequences of SEQ ID NO:111, SEQ ID NO:147, and SEQ ID NO:178; and three VH CDRs of the amino acid sequences of SEQ ID NO:220, SEQ ID NO:256, and SEQ ID NO:289; (n) comprising three VL CDRs of the amino acid sequences of SEQ ID NO: 112, SEQ ID NO: 148, and SEQ ID NO: 179; and three VH CDRs of the amino acid sequences of SEQ ID NO: 213, SEQ ID NO: 249, and SEQ ID NO: 290; (o) comprising three VL CDRs of the amino acid sequences of SEQ ID NO: 113, SEQ ID NO: 143, and SEQ ID NO: 180; and three VH CDRs of the amino acid sequences of SEQ ID NO: 221, SEQ ID NO: 257, and SEQ ID NO: 291; (p) comprising three VL CDRs of the amino acid sequences of SEQ ID NO: 106, SEQ ID NO: 149, and SEQ ID NO: 181; and three VH CDRs of the amino acid sequences of SEQ ID NO: 222, SEQ ID NO: 258, and SEQ ID NO: 292; (q) comprising three VL CDRs of the amino acid sequences of SEQ ID NO: 114, SEQ ID NO: 150, and SEQ ID NO: 182; and three VH CDRs of the amino acid sequences of SEQ ID NO: 223, SEQ ID NO: 250, and SEQ ID NO: 293; (r) comprising three VL CDRs of the amino acid sequences of SEQ ID NO: 115, SEQ ID NO: 151, and SEQ ID NO: 183; and three VH CDRs of the amino acid sequences of SEQ ID NO: 219, SEQ ID NO: 259, and SEQ ID NO: 294; (s) comprising three VL CDRs of the amino acid sequences set forth in SEQ ID NOs: 116, 152, and 184; and three VH CDRs of the amino acid sequences set forth in SEQ ID NOs: 224, 260, and 295; (t) comprising three VL CDRs of the amino acid sequences of SEQ ID NOs: 117, 153, and 185; and three VH CDRs of the amino acid sequences of SEQ ID NOs: 216, 261, and 296; (u) three VL CDRs of the amino acid sequences of SEQ ID NO: 118, SEQ ID NO: 143, and SEQ ID NO: 186; and three VH CDRs of the amino acid sequences of SEQ ID NO: 222, SEQ ID NO: 262, and SEQ ID NO: 297; (v) three VL CDRs of the amino acid sequences of SEQ ID NO: 119, SEQ ID NO: 154, and SEQ ID NO: 187; and three VH CDRs of the amino acid sequences of SEQ ID NO: 225, SEQ ID NO: 250, and SEQ ID NO: 298; (w) comprising three VL CDRs of the amino acid sequences of SEQ ID NO: 120, SEQ ID NO: 140, and SEQ ID NO: 188; and three VH CDRs of the amino acid sequences of SEQ ID NO: 226, SEQ ID NO: 263, and SEQ ID NO: 299; (x) comprising three VL CDRs of the amino acid sequences of SEQ ID NOs: 121, 141, and 189; and three VH CDRs of the amino acid sequences of SEQ ID NOs: 227, 264, and 300; (y) comprising three VL CDRs of the amino acid sequences of SEQ ID NOs: 122, 155, and 190; and three VH CDRs of the amino acid sequences of SEQ ID NOs: 228, 249, and 301; (z) comprising three VL CDRs of the amino acid sequences of SEQ ID NOs: 123, 143, and 186; and three VH CDRs of the amino acid sequences of SEQ ID NOs: 229, 265, and 302; (aa) three VL CDRs of the amino acid sequences of SEQ ID NO: 124, SEQ ID NO: 143, and SEQ ID NO: 191; and three VH CDRs of the amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 266, and SEQ ID NO: 303; (ab) three VL CDRs of the amino acid sequences of SEQ ID NOs: 106, 156, and 192; and three VH CDRs of the amino acid sequences of SEQ ID NOs: 230, 249, and 304; (ac) three VL CDRs of the amino acid sequences of SEQ ID NO: 106, SEQ ID NO: 145, and SEQ ID NO: 193; and three VH CDRs of the amino acid sequences of SEQ ID NO: 231, SEQ ID NO: 267, and SEQ ID NO: 305; (ad) three VL CDRs of the amino acid sequences of SEQ ID NO: 125, SEQ ID NO: 143, and SEQ ID NO: 194; and three VH CDRs of the amino acid sequences of SEQ ID NO: 232, SEQ ID NO: 268, and SEQ ID NO: 306; (ae) three VL CDRs of the amino acid sequences of SEQ ID NOs: 126, 157, and 195; and three VH CDRs of the amino acid sequences of SEQ ID NOs: 233, 269, and 307; (af) three VL CDRs of the amino acid sequences of SEQ ID NOs: 127, 155, and 196; and three VH CDRs of the amino acid sequences of SEQ ID NOs: 234, 249, and 308; (ag) comprising three VL CDRs of the amino acid sequences of SEQ ID NOs: 128, 158, and 197; and three VH CDRs of the amino acid sequences of SEQ ID NOs: 235, 270, and 309; (ah) comprising three VL CDRs of the amino acid sequences of SEQ ID NO: 129, SEQ ID NO: 159, and SEQ ID NO: 198; and three VH CDRs of the amino acid sequences of SEQ ID NO: 226, SEQ ID NO: 271, and SEQ ID NO: 310; (ai) three VL CDRs of the amino acid sequences of SEQ ID NOs: 106, 143, and 199; and three VH CDRs of the amino acid sequences of SEQ ID NOs: 236, 272, and 311; (aj) comprising three VL CDRs of the amino acid sequences of SEQ ID NO: 130, SEQ ID NO: 155, and SEQ ID NO: 200; and three VH CDRs of the amino acid sequences of SEQ ID NO: 237, SEQ ID NO: 249, and SEQ ID NO: 312; (ak) comprising three VL CDRs of the amino acid sequences of SEQ ID NOs: 131, 141, and 201; and three VH CDRs of the amino acid sequences of SEQ ID NOs: 238, 264, and 313; (a1) comprising three VL CDRs of the amino acid sequences of SEQ ID NO: 132, SEQ ID NO: 140, SEQ ID NO: 202; and three VH CDRs of the amino acid sequences of SEQ ID NO: 239, SEQ ID NO: 273, SEQ ID NO: 314; (am) comprising three VL CDRs of the amino acid sequences of SEQ ID NO: 109, SEQ ID NO: 143, and SEQ ID NO: 203; and three VH CDRs of the amino acid sequences of SEQ ID NO: 240, SEQ ID NO: 250, and SEQ ID NO: 315; (an) comprising three VL CDRs of the amino acid sequences of SEQ ID NO: 133, SEQ ID NO: 160, SEQ ID NO: 191; and three VH CDRs of the amino acid sequences of SEQ ID NO: 241, SEQ ID NO: 274, SEQ ID NO: 316; (ao) three VL CDRs of the amino acid sequences of SEQ ID NOs: 134, 161, and 204; and three VH CDRs of the amino acid sequences of SEQ ID NOs: 242, 275, and 317; (ap) comprising three VL CDRs of the amino acid sequences of SEQ ID NOs: 135, 162, and 189; and three VH CDRs of the amino acid sequences of SEQ ID NOs: 216, 249, and 318; (aq) comprising three VL CDRs of the amino acid sequences of SEQ ID NOs: 129, 155, and 205; and three VH CDRs of the amino acid sequences of SEQ ID NOs: 226, 276, and 319; (ar) comprising three VL CDRs of the amino acid sequences of SEQ ID NO: 131, SEQ ID NO: 163, SEQ ID NO: 206; and three VH CDRs of the amino acid sequences of SEQ ID NO: 219, SEQ ID NO: 267, SEQ ID NO: 320; (as) three VL CDRs of the amino acid sequences of SEQ ID NOs: 136, 164, and 207; and three VH CDRs of the amino acid sequences of SEQ ID NOs: 243, 249, and 321; (at) three VL CDRs of the amino acid sequences of SEQ ID NO: 131, SEQ ID NO: 165, SEQ ID NO: 208; and three VH CDRs of the amino acid sequences of SEQ ID NO: 213, SEQ ID NO: 269, SEQ ID NO: 322; or (au) comprising three VL CDRs of the amino acid sequences of SEQ ID NOs: 137, 166, and 169; and three VH CDRs of the amino acid sequences of SEQ ID NOs: 244, 256, and 323; The antibody.

2. (a) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 324, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 371, or an amino acid sequence with at least 70% sequence identity thereto; (b) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 325, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 372, or an amino acid sequence with at least 70% sequence identity thereto; (c) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 326, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 373, or an amino acid sequence with at least 70% sequence identity thereto; (d) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 327, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 374, or an amino acid sequence with at least 70% sequence identity thereto; (e) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 328, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 375, or an amino acid sequence with at least 70% sequence identity thereto; (f) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 329, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 376, or an amino acid sequence with at least 70% sequence identity thereto; (g) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 330, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 377, or an amino acid sequence with at least 70% sequence identity thereto; (h) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 331, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 378, or an amino acid sequence with at least 70% sequence identity thereto; (i) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 332, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 379, or an amino acid sequence with at least 70% sequence identity thereto; (j) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 333, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 380, or an amino acid sequence with at least 70% sequence identity thereto; (k) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 334, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 381, or an amino acid sequence with at least 70% sequence identity thereto; (l) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 335, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 382, ​​or an amino acid sequence with at least 70% sequence identity thereto; (m) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 336, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 383, or an amino acid sequence with at least 70% sequence identity thereto; (n) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 337, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 384, or an amino acid sequence with at least 70% sequence identity thereto; (o) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 338, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 385, or an amino acid sequence with at least 70% sequence identity thereto; (p) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 339, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 386, or an amino acid sequence with at least 70% sequence identity thereto; (q) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 340, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 387, or an amino acid sequence with at least 70% sequence identity thereto; (r) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 341, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 388, or an amino acid sequence with at least 70% sequence identity thereto; (s) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 342, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 389, or an amino acid sequence with at least 70% sequence identity thereto; (t) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 343, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 390, or an amino acid sequence with at least 70% sequence identity thereto; (u) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 344, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 391, or an amino acid sequence with at least 70% sequence identity thereto; (v) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 345, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 392, or an amino acid sequence with at least 70% sequence identity thereto; (w) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 346, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 393, or an amino acid sequence with at least 70% sequence identity thereto; (x) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 347, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 394, or an amino acid sequence with at least 70% sequence identity thereto; (y) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 348, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 395, or an amino acid sequence with at least 70% sequence identity thereto; (z) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 349, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 396, or an amino acid sequence with at least 70% sequence identity thereto; (aa) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 350, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 397, or an amino acid sequence with at least 70% sequence identity thereto; (ab) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 351, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 398, or an amino acid sequence with at least 70% sequence identity thereto; (ac) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 352, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 399, or an amino acid sequence with at least 70% sequence identity thereto; (ad) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 353, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 400, or an amino acid sequence with at least 70% sequence identity thereto; (ae) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 354, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 401, or an amino acid sequence with at least 70% sequence identity thereto; (af) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 355, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 402, or an amino acid sequence with at least 70% sequence identity thereto; (ag) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 356, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 403, or an amino acid sequence with at least 70% sequence identity thereto; (ah) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 357, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 404, or an amino acid sequence with at least 70% sequence identity thereto; (ai) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 358, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 405, or an amino acid sequence with at least 70% sequence identity thereto; (aj) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 359, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 406, or an amino acid sequence with at least 70% sequence identity thereto; (ak) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 360, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 407, or an amino acid sequence with at least 70% sequence identity thereto; (a1) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 361, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 408, or an amino acid sequence with at least 70% sequence identity thereto; (am) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 362, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 409, or an amino acid sequence with at least 70% sequence identity thereto; (an) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 363, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 410, or an amino acid sequence with at least 70% sequence identity thereto; (ao) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 364, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 411, or an amino acid sequence with at least 70% sequence identity thereto; (ap) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 365, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 412, or an amino acid sequence with at least 70% sequence identity thereto; (aq) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 366, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 413, or an amino acid sequence with at least 70% sequence identity thereto; (ar) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 367, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 414, or an amino acid sequence with at least 70% sequence identity thereto; (as) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 368, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 415, or an amino acid sequence with at least 70% sequence identity thereto; (at) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 369, or an amino acid sequence with at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 416, or an amino acid sequence with at least 70% sequence identity thereto; or (au) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 370, or an amino acid sequence having at least 70% sequence identity thereto; and / or the VL domain of the antibody comprises the amino acid sequence of SEQ ID NO: 417, or an amino acid sequence having at least 70% sequence identity thereto. SIRPγ-specific antibody.

3. The antibody of claim 1 or 2, wherein the antibody is an antibody fragment or a full-length antibody.

4. The antibody of claim 1 or 2, wherein the antibody is a human antibody, a humanized antibody, or a chimeric antibody.

5. 3. The antibody of claim 1 or 2, wherein the antibody comprises an Fc domain, and the Fc domain is selected from the group consisting of human IgG1, human IgG2, human IgG3, and human IgG4 heavy chain sequences.

6. 6. The antibody of claim 5, wherein the Fc domain is derived from the heavy chain IgG amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 28, optionally with one or more Fc amino acid substitutions.

7. The antibody of claim 6, wherein the Fc domain is derived from a heavy chain IgG amino acid sequence of any one of SEQ ID NOs: 5 to 36.

8. The heavy chain Fc domain is selected from the group consisting of 215, 221, 222, 228, 234, 235, 236, 239, 240, 241, 243, 244, 245, 247, 250, 252, 254, 256, 262, 263, 264, 265, 266, 267, 268, 269, 270, 292, 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, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 339, 340, 341, 343, 344, 345, 347, 250, 252, 254, 256, 262, 263, 264, 265, 266, 267, 268, 269, 270, 292, 296, 297, 298, 299, 309, 316, 317, 318, 319, 32 7. The antibody of claim 6, comprising one or more amino acid substitutions at positions selected from the group consisting of 99, 300, 305, 313, 324, 325, 326, 327, 328, 329, 330, 332, 333, 334, 345, 396, 428, 430, 433, 434, and 440, wherein the amino acid residue position numbers are according to the EU numbering scheme.

9. The antibody of claim 1 or 2, wherein the antibody comprises a light chain constant region derived from the amino acid sequence of any one of SEQ ID NOs: 38 to 42.

10. 3. The antibody of claim 1 or 2, wherein binding of the antibody does not disrupt the interaction between CD47 and SIRPγ.

11. 3. The antibody of claim 1 or 2, wherein binding of the antibody disrupts the interaction between CD47 and SIRPγ.

12. 3. The antibody of claim 1 or 2, wherein binding of the antibody stabilizes or enhances the interaction between CD47 and SIRPγ.

13. The antibody of claim 1 or 2, which binds to human SIRPγ and cynomolgus monkey SIRPγ.

14. 3. The antibody of claim 1 or 2, comprising a binding affinity to SIRPy of less than about 500 nM.

15. 6. The antibody of claim 5, wherein binding of the antibody to a SIRPγ-expressing cell induces effector-mediated depletion of SIRPγ expression.

16. 16. The antibody of claim 15, wherein the SIRPγ-expressing cell is a T cell, a B cell, or an NK cell.

17. 17. The antibody of claim 16, wherein the SIRPγ-expressing cell is a T cell.

18. 16. The antibody of claim 15, wherein the cell depletion involves antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), or complement-dependent cytotoxicity (CDC).

19. 3. The antibody of claim 1 or 2, which has low or no affinity for binding to SIRPα and SIRPβ1.

20. A pharmaceutical composition comprising the antibody of claim 1 or 2, and optionally a pharmaceutically acceptable carrier.

21. A nucleic acid encoding the antibody of claim 1 or 2.

22. A vector comprising the nucleic acid of claim 21.

23. 3. A SIRPγ-expressing cell, wherein the cell binds to the antibody of claim 1 or 2, and the antibody binds to SIRPγ.

24. 10. A kit or article of manufacture comprising an antibody according to claim 1 or 2, or a pharmaceutical composition comprising an antibody according to claim 1 or 2, and optionally a pharmaceutically acceptable carrier.

25. 10. Use of the antibody of claim 1 or 2 or a pharmaceutical composition comprising the antibody of claim 1 or 2, and optionally a pharmaceutically acceptable carrier, for the manufacture of a medicament for the treatment of a disease or condition involving SIRPγ-expressing cells in a subject in need thereof.

26. 26. The use of claim 25, wherein the SIRPγ-expressing cell is a T cell, a B cell, or an NK cell.

27. 26. The use of claim 25, wherein the disease or condition comprises an autoimmune, oncological, or inflammatory disorder.

28. 28. The use of claim 27, wherein the disease or condition comprises a T cell-mediated autoimmune disease, a T cell-mediated inflammatory disease, or a T cell-mediated oncological disease.

29. 26. The use of claim 25, wherein the subject is a human.

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