SIRP alpha, SIRP beta 1, and SIRP gamma antibodies, and their use

Abstract

Provided herein are antibodies that bind to signal-regulatory protein gamma (SIRPγ) and SIRPα and / or SIRPβ1, and methods of using such antibodies (referred to as SIRP antibodies). In some embodiments, the SIRP antibodies are human monoclonal antibodies that bind to human SIRPγ and SIRPα and / or SIRPβ1. In some embodiments, the SIRP antibodies provided herein are useful for treating diseases or conditions associated with hyperactivation and / or hyperproliferation of lymphocytes, myeloid cells, or a combination thereof, or diseases or conditions associated with SIRPα, SIRPβ1, and / or SIRPγ activity.

Description

[Technical Field]

[0001] Cross-references to related applications This application claims priority under U.S. Provisional Patent Application No. 63 / 022,309, filed on 8 May 2020, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Signal-regulating proteins (SIRPs) are a family of cell surface immunoreceptors that possess an Ig-like extracellular domain. The SIRP family comprises three inhibitory, activating, and non-signaling members, which have closely related extracellular domains but differ in their cytoplasmic domains. Members of the SIRP family play roles in immunomodulation. Signal-regulating protein alpha (SIRPα, SIRP alpha, also known as CD172a, BIT, MFR, MYD-1, P84, PTPNS1, and SHPS1) is a transmembrane glycoprotein and one of the members of the signal-regulating SIRP family of cell surface receptors. SIRPα delivers inhibitory signals via an immunoreceptor tyrosine-based inhibitory motif (ITIM) located in the cytoplasmic domain of the protein, which downregulates myeloid cell phagocytic and pro-inflammatory activity. On phagocytic cells, SIRPα, also known as an integrin-associated protein (IAP), interacts with CD47, a universally expressed cell surface protein that functions, among other things, as a "self" marker on viable cells. Therefore, CD47 / SIRPα signaling acts as a "self-anti-self-eating" immune checkpoint to negatively regulate innate immune cell phagocytosis. SIRPβ1 (also known as SIRPβ, SIRPB1, and CD172b) delivers activation signals via association with the 12kDa DNA polymerase III subunit tau (DNAX) activating protein (DAP12, also known as transmembrane immune signaling adapter TYROBP, or TYROBP), a transmembrane adapter protein with an immune receptor tyrosine-based activation motif (ITAM). SIRPα and SIRPβ1 are expressed on myeloid cells of the immune system, as well as on other cell types. SIRPγ (also known as CD172 antigen-like family member B, CD172g, and SIRP-beta-2) is expressed by lymphocytes such as T cells and also binds to CD47. Drugs that bind to SIRPα, SIRPβ1, and SIRPγ-expressing cells are needed to treat various diseases and conditions. [Overview of the project]

[0003] overview This disclosure provides an Fc-containing antibody that is specific to one or more of SIRPα and SIRPβ1, and also specific to SIRPγ, wherein binding of the antibody to one or more of SIRPα, SIRPβ1, and SIRPγ on cells induces cell depletion.

[0004] This disclosure provides antibodies specific to one or more of SIRPα and SIRPβ1, as well as antibodies specific to SIRPγ, wherein the antibodies comprise a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising (i) a complementation-determining region 1 (CDR-H1) sequence selected from the group consisting of SEQ ID NOs. 54, 56, and 59-65; (ii) a CDR-H2 sequence selected from the group consisting of SEQ ID NOs. 70, 72, and 75-81; and (iii) a CDR-H3 sequence selected from the group consisting of SEQ ID NOs. 86, 88-89, and 92-99; and / or the light chain variable region comprising (i) a light chain CDR1 (CDR-L1) sequence selected from the group consisting of SEQ ID NOs. 5, 7-8, and 11-18; (ii) a CDR-L2 sequence selected from the group consisting of SEQ ID NOs. 23-24, and 27-33; and (iii) a CDR-H3 sequence selected from the group consisting of SEQ ID NOs. 36, 38-39, and 42-49.

[0005] In some embodiments of the antibodies of this disclosure, the antibodies are (a) SEQ ID NO: 5, SEQ ID NO: 23, SEQ ID NO: 36, SEQ ID NO: 54, SEQ ID NO: 70, and SEQ ID NO: 86; (b) SEQ ID NO: 7, SEQ ID NO: 24, SEQ ID NO: 38, SEQ ID NO: 54, SEQ ID NO: 72, and SEQ ID NO: 88; (c) SEQ ID NO: 8, SEQ ID NO: 24, SEQ ID NO: 39, SEQ ID NO: 56, SEQ ID NO: 72, and SEQ ID NO: 89; (d) SEQ ID NO: 11, SEQ ID NO: 27, SEQ ID NO: 42, SEQ ID NO: 59, SEQ ID NO: 75, and SEQ ID NO: 92; (e) SEQ ID NO: 12, SEQ ID NO: 28, SEQ ID NO: 43, SEQ ID NO: 60, SEQ ID NO: 76, and SEQ ID NO: 93; (f) SEQ ID NO: 13, SEQ ID NO: 29, SEQ ID NO: 44, SEQ ID NO: 61, SEQ ID NO: 76, and SEQ ID NO: 94; (g) SEQ ID NO: 13, (h)Sequence IDs 30, 45, 62, 77, and 95; (i)Sequence IDs 15, 31, 47, 62, 79, and 97; (j)Sequence IDs 16, 31, 47, 62, 79, and 97; (k)Sequence IDs 17, 32, 48, 64, 80, and 98; and (l)Sequence IDs 18, 33, 49, 65, 81, and 99, which include combinations of heavy-chain and light-chain variable CDR sequences selected from the group. In some embodiments, the heavy-chain variable region includes sequences selected from the group consisting of Sequence IDs 104, 106-107, and 110-118. In some embodiments, the light chain variable region includes sequences selected from the group consisting of sequence numbers 123, 125-126, and 129-137.

[0006] In some embodiments of the antibodies of this disclosure, the heavy chain variable region sequence and the light chain variable region sequence are selected from the group consisting of (a) SEQ ID NOs: 104 and 123; (b) SEQ ID NOs: 106 and 125; (c) SEQ ID NOs: 107 and 126; (d) SEQ ID NOs: 110 and 129; (e) SEQ ID NOs: 111 and 130; (f) SEQ ID NOs: 112 and 131; (g) SEQ ID NOs: 113 and 132; (h) SEQ ID NOs: 114 and 133; (i) SEQ ID NOs: 115 and 134; (j) SEQ ID NOs: 116 and 135; (k) SEQ ID NOs: 117 and 136; and (l) SEQ ID NOs: 118 and 137.

[0007] In some embodiments of the antibodies of this disclosure, the heavy chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 104 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 123 or an amino acid sequence having at least 80% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 106 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 125 or an amino acid sequence having at least 80% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 107 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 126 or an amino acid sequence having at least 80% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 110 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 129 or an amino acid sequence having at least 80% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 111 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 130 or an amino acid sequence having at least 80% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 112 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 131 or an amino acid sequence having at least 80% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 113 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 132 or an amino acid sequence having at least 80% sequence identity thereto.In some embodiments, the heavy chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 114 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 133 or an amino acid sequence having at least 80% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 115 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 134 or an amino acid sequence having at least 80% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 116 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 135 or an amino acid sequence having at least 80% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 117 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 136 or an amino acid sequence having at least 80% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 118 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 137 or an amino acid sequence having at least 80% sequence identity thereto. In some embodiments, the antibody includes an Fc domain.

[0008] In some embodiments of the antibodies of this disclosure, the antibody is an Fc-containing antibody, and binding of the antibody to one or more of SIRPα, SIRPβ1, and SIRPγ on cells induces cell depletion. In some embodiments, cell depletion is accompanied by antibody-dependent cytophagocytosis (ADCP). In some embodiments, cell depletion is accompanied by antibody-dependent cell-mediated cytotoxicity (ADCC). In some embodiments, cell depletion is accompanied by depletion of SIRPγ-positive cells. In some embodiments, SIRPγ cells are lymphocytes. In some embodiments, lymphocytes are T cells or NK cells. In some embodiments, T cells are cytotoxic T cells, helper T cells, memory T cells, regulatory T cells, natural killer T cells, mucosa-associated invariant T cells, gamma delta T cells, or a combination thereof. In some embodiments, cell depletion is accompanied by depletion of SIRPγ-positive cells as well as SIRPα and / or SIRPβ1-positive cells. In some embodiments, SIRPα and / or SIRPβ1 cells are myeloid cells or myeloid progenitor cells. In some embodiments, SIRPα and / or SIRPβ1 cells are selected from the group consisting of monocytes, macrophages, dendritic cells, basophils, eosinophils, neutrophils, and mast cells.

[0009] In some embodiments of the antibodies described herein, the antibody is a monoclonal antibody. In some embodiments, the antibody is an antibody fragment. In some embodiments, the antibody is a human antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a full-length antibody.

[0010] In some embodiments of the antibodies of this disclosure, the Fc domain is selected from the group consisting of human IgG1, IgG2, IgG3, and IgG4. In some embodiments, the Fc domain includes SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 26. In some embodiments, the Fc domain includes one or more amino acid substitutions for SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 26. In some embodiments, the Fc domain of the antibody is human IgG1, and includes 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, 292, 296, 297, 298 The amino acid substitution includes at least one amino acid substitution at a position selected from the group consisting of 299, 300, 305, 313, 324, 325, 326, 327, 328, 329, 330, 332, 333, 334, 345, 356, 358, 396, 428, 430, 433, 434, and 440, and the positional numbers of the amino acid residues are in accordance with the EU numbering scheme. In some embodiments, IgG1 Fc includes a sequence selected from the group consisting of (a) SEQ ID NO: 19; (b) SEQ ID NO: 20, where X1 is V or A; (c) SEQ ID NO: 21, where X1 is V or A; X2 is G or A, X3 is S or D; X4 is I or E; (d) SEQ ID NO: 22, where X1 is V or A; (e) SEQ ID NO: 25, where X1 is V or A; X2 is M or L; X3 is N or S; and (f) SEQ ID NO: 26, where X1 is K or R; X2 is D or E; X3 is L or M. In some embodiments, IgG4 Fc includes the sequence of SEQ ID NO: 34, 35, or 37, where X1 in SEQ ID NO: 37 is S or P; and X2 in SEQ ID NO: 37 is L or E.

[0011] In some embodiments of the antibodies of this disclosure, antibody binding does not interfere with the interaction between CD47 and SIRPα, and / or the interaction between CD47 and SIRPγ. In some embodiments, antibody binding disrupts the interaction between CD47 and SIRPα, and / or the interaction between CD47 and SIRPγ. In some embodiments, the antibody binds to SIRPα, SIRPβ1, and SIRPγ. In some embodiments, the antibody binds to SIRPα and SIRPγ, showing little to no binding to SIRPβ1. In some embodiments, the antibody binds to SIRPβ1 and SIRPγ, showing little to no binding to SIRPα.

[0012] In some embodiments of the antibodies of this disclosure, the antibodies contain binding affinity to SIRPα of about 100 pm, about 1 nM, about 5 nM, about 10 nM, about 50 nM, about 100 nM, about 500 nM, or about 1 μM. In some embodiments, the antibodies contain binding affinity to SIRPβ1 of about 0.5 nM, about 0.1 nM, about 5 nM, about 10 nM, about 50 nM, about 100 nM, about 500 nM, about 1 μM, about 5 μM, or about 10 μM. In some embodiments, the antibody contains binding affinity to SIRPγ of approximately 0.0001 nM, approximately 0.0005 nM, approximately 0.001 nM, approximately 0.005 nM, approximately 0.1 nM, approximately 0.05 nM, approximately 0.1 nM, approximately 0.5 nM, approximately 1 nM, approximately 5 nM, approximately 10 nM, approximately 50 nM, approximately 100 nM, approximately 500 nM, approximately 1 μM, approximately 2 μM, or approximately 3 μM.

[0013] This disclosure provides pharmaceutical compositions comprising the antibody and, as appropriate, a pharmaceutically acceptable carrier.

[0014] This disclosure provides nucleic acids encoding the antibodies of this disclosure. In some embodiments, the nucleic acid comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 142, 144-145, 148-156, 161, 163-164, and 167-175. In some embodiments, the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 142 or a nucleic acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 161 or a nucleic acid sequence having at least 80% sequence identity thereto. In some embodiments, the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 144 or a nucleic acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 163 or a nucleic acid sequence having at least 80% sequence identity thereto. In some embodiments, the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 145 or a nucleic acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 164 or a nucleic acid sequence having at least 80% sequence identity thereto. In some embodiments, the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 148 or a nucleic acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 167 or a nucleic acid sequence having at least 80% sequence identity thereto. In some embodiments, the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 149 or a nucleic acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 168 or a nucleic acid sequence having at least 80% sequence identity thereto. In some embodiments, the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 150 or a nucleic acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 169 or a nucleic acid sequence having at least 80% sequence identity thereto.In some embodiments, the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 151 or a nucleic acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 170 or a nucleic acid sequence having at least 80% sequence identity thereto. In some embodiments, the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 152 or a nucleic acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 171 or a nucleic acid sequence having at least 80% sequence identity thereto. In some embodiments, the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 153 or a nucleic acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 172 or a nucleic acid sequence having at least 80% sequence identity thereto. In some embodiments, the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 154 or a nucleic acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 173 or a nucleic acid sequence having at least 80% sequence identity thereto. In some embodiments, the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 155 or a nucleic acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 174 or a nucleic acid sequence having at least 80% sequence identity thereto. In some embodiments, the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 156 or a nucleic acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 175 or a nucleic acid sequence having at least 80% sequence identity thereto.

[0015] This disclosure provides vectors comprising the nucleic acids of this disclosure.

[0016] This disclosure provides a method for inducing depletion of a cell population, the method comprising contacting the cell population with the antibody of this disclosure.

[0017] In some embodiments of the methods of this disclosure, at least a portion of the cell population expresses SIRPγ. In some embodiments, the cell population expressing SIRPγ includes lymphocytes. In some embodiments, the lymphocytes include T cells or NK cells. In some embodiments, at least a portion of the cell population expresses SIRPα and / or SIRPβ1. In some embodiments, the cell population expressing SIRPα and / or SIRPβ1 includes myeloid cells or myeloid progenitor cells. In some embodiments, the cell population expressing SIRPα and / or SIRPβ1 includes monocytes, macrophages, dendritic cells, basophils, eosinophils, neutrophils, or mast cells. In some embodiments, the method is in vitro. In some embodiments, the method is in vivo. In some embodiments, the cell population includes tissue resident cells. In some embodiments, the cell population includes circulating cells.

[0018] In some embodiments of the methods of this disclosure, cell depletion includes ADCC. In some embodiments, cell depletion is accompanied by ADCP. In some embodiments, cell depletion is accompanied by ADCC and ADCP.

[0019] This disclosure provides a method for treating a disease or condition in a subject that requires it, and includes administering a therapeutically effective amount of the antibody or pharmaceutical composition of this disclosure to the subject.

[0020] In some embodiments of the methods for treating diseases or conditions of the present disclosure, the disease or condition is characterized by hyperactivation and / or hyperproliferation of lymphocytes, and antibodies induce lymphocyte depletion. In some embodiments, the lymphocytes are T cells. In some embodiments, the disease or condition includes aplastic anemia, cell-mediated rejection of solid organ transplantation, graft failure after HSCT (hematopoietic stem cell transplantation), lymphocyte variant eosinophilia, atopic dermatitis, lymphocytic myocarditis, axial spondyloarthritis, celiac disease, or Rasmussen encephalitis.

[0021] In some embodiments of the methods for treating a disease or condition of the present disclosure, the disease or condition is characterized by hyperactivation and / or hyperproliferation of myeloid cells, and the antibody induces myeloid cell depletion. In some embodiments, myeloid cells include monocytes, macrophages, dendritic cells, basophils, eosinophils, neutrophils, or mast cells. In some embodiments, myeloid cells include eosinophils, and the disease or condition includes acute eosinophilic pneumonia, chronic eosinophilic pneumonia, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic enteritis, eosinophilic colitis, lymphocyte variant eosinophilia, eosinophilic cardiomyopathy / Loeffler endocarditis, Loeffler syndrome, or episodic angioedema / Gleich syndrome with eosinophilia. In some embodiments, myeloid cells include mast cells, and the disease or condition includes cutaneous mastocytosis, mastocellular colitis, systemic mastocytosis, mast cell activation syndrome, hereditary alpha-tryptemia syndrome, chronic urticaria, or severe allergic conjunctivitis. In some embodiments, myeloid cells include neutrophils, and the disease or condition includes neutrophilic dermatosis, psoriatic arthritis, generalized pustular psoriasis, pyoderma gangrenosum, Sweet's syndrome, subcorneal pustular dermatosis, neutrophilic eccrine hidradenitis, gut-associated dermatopathies-arthritis syndrome (BADAS), rheumatic neutrophilic dermatitis, or Behçet's disease.

[0022] In some embodiments of the methods of treating a disease or condition of the present disclosure, the disease or condition includes a disease or disorder associated with both lymphocytes and myeloid cells. In some embodiments, the disease or disorder includes histiocytosis. In some embodiments, the histiocytosis includes hemophagocytic lymphohistiocytosis (HLH) (including primary and secondary HLH), macrophage activation syndrome, Langerhans cell histiocytosis (LCH), indeterminate cell histiocytosis, Erdheim-Chester disease (ECD), mixed LCH / ECD, Rosai-Dorfman disease, malignant histiocytosis, cutaneous non-LCH histiocytosis, juvenile xanthogranuloma, infection-related HLH, or malignancy-induced HLH. In some embodiments, malignancy-induced HLH includes HLH induced by a hematologic malignancy or a solid tumor. In some embodiments, the disease or disorder includes non-Mendelian secondary HLH (secondary HLH, or sHLH). In some embodiments, secondary HLH includes infection-related HLH. In some embodiments, infection-related HLH includes virus-related HLH, bacteria-related HLH, parasite-related HLH, or fungus-related (fungus-induced) HLH. In some embodiments, sHLH is associated with rheumatologic conditions. In some embodiments, sHLH is associated with kidney transplantation or hematopoietic stem cell transplantation.

[0023] In some embodiments of the methods of treating a disease or condition of the present disclosure, the disease or condition includes sHLH or cytokine release syndrome (CRS). In some embodiments, sHLH or CRS is associated with iatrogenic immune activation, infection, T cell therapy, chimeric antigen receptor-T cell therapy (CAR-T), T cell receptor T cell therapy (TCR-T), T cell-activating bispecific antibody therapy, or iatrogenic immunosuppression.

[0024] In some embodiments of the methods for treating a disease or condition of the present disclosure, the disease or condition includes a granulomatous disease or condition, or a disease characterized by the presence of multinucleated giant cells. In some embodiments, the disease or condition includes sarcoidosis, Crohn's disease, Takayasu arteritis, giant cell arteritis, psoriatic arthritis, granulomatosis with polyangiitis (Wegener's granulomatosis), giant cell myocarditis, chronic granulomatous disease, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), or chronic beryllium disease (berylliosis).

[0025] In some embodiments of the methods for treating a disease or condition of the present disclosure, the disease or condition includes an autoimmune disorder or an inflammatory disorder. In some embodiments, an autoimmune disease includes the presentation of self-antigens by antigen-presenting myeloid cells (e.g., dendritic cells) in the germinal centers of the secondary lymphoid tissues of a subject.

[0026] In some embodiments, the disease or condition includes Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), Lambert-Eaton myasthenic syndrome (LEMS), myasthenia gravis (MG), neuromyelitis optica (NMO), bullous pemphigoid, acquired epidermolysis bullosa, pemphigus foliaceus, pemphigus vulgaris, anti-glomerular basement membrane disease (Goodpasture syndrome), membranous nephropathy, ankylosing spondylitis, rheumatoid arthritis, rheumatoid vasculitis, lupus nephritis, lupus vasculitis, systemic lupus erythematosus (SLE), scleroderma (systemic sclerosis), Behçet's disease, granulomatosis with polyangiitis (Wegener's granulomatosis), eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), microscopic polyangiitis (MPA), Kawasaki disease, anti-glomerular basement membrane disease (Goodpasture syndrome), antiphospholipid syndrome and catastrophic antiphospholipid syndrome, Graves' ophthalmopathy, Castleman disease, and antibody-mediated rejection (AMR), Sjögren's syndrome, multiple sclerosis, Hashimoto's thyroiditis, primary sclerosing cholangitis, primary biliary cirrhosis, autoimmune neutropenia, systemic juvenile idiopathic arthritis, axial spondyloarthritis, celiac disease, autoimmune hepatitis, or psoriatic arthritis.

[0027] In some embodiments, the disease or condition is disseminated encephalomyelitis, acute respiratory distress syndrome, Addison's disease, adult-onset Still's disease, ankylosing spondylitis, antibody-mediated rejection (AMR), anti-glomerular basement membrane disease (Goodpasture syndrome), antiphospholipid syndrome, aplastic anemia, atopic dermatitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune lymphoproliferative syndrome, axial spondyloarthritis, Behçet's disease, bullous pemphigoid, Castleman disease, catastrophic antiphospholipid syndrome, celiac disease, solid organ transplantation. Cellular rejection, Chediak-Higashi syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic neutrophilic leukemia, chronic urticaria, coronary artery disease (CAD) / peripheral artery disease (PAD), COVID-19, cutaneous mastocytosis, eosinophilic cardiomyopathy / Loeffler endocarditis, acquired epidermolysis bullosa, Evans syndrome, Felty's disease syndrome, general pustular psoriasis, giant cell myocarditis, graft failure after HSCT (hematopoietic stem cell transplantation), graft-versus-host disease, Graves' disease, Graves' ophthalmopathy, Guillain-Barré syndrome, Hashimoto's thyroiditis, Hereditary alpha-tryptosis syndrome, hyper-IgE syndrome, idiopathic interstitial pneumonia, idiopathic pulmonary fibrosis, IgA nephropathy, immune / idiopathic thrombocytopenic purpura, inclusion body myositis, inflammatory bowel disease, Kawasaki disease, Lambert-Eaton myasthenia purpura (LEMS), linear IgA disease, Loeffler syndrome, lupus nephritis, lupus vasculitis, mast cell activation syndrome, mast cell enteritis, membranous nephropathy, microscopic polyangiitis (MPA), multiple sclerosis, myasthenia gravis, myelodysplastic syndrome, myelofibrosis, myocarditis, neuromyelitis optica (NMO) ), including neutrophilic dermatosis, paraneoplastic syndromes, pemphigus phyllodes, pemphigus vulgaris, primary biliary cholangitis, primary sclerosing cholangitis, pyoderma gangrenosum, Rasmussen's encephalitis, rheumatoid arthritis, vasculitis rheumatoidioids, Schmidt syndrome, scleroderma (systemic scleroderma), severe allergic conjunctivitis, Sjögren's syndrome, Suzak syndrome, systemic inflammatory response syndrome, systemic juvenile idiopathic arthritis, systemic lupus erythematosus, systemic mastocytosis, type 1 diabetes mellitus, ulcerative colitis, uveitis, vitiligo, or X-linked lymphoproliferative disorder.

[0028] In some embodiments of the methods for treating a disease or condition of the present disclosure, the disease or disorder includes hematological malignancies. In some embodiments, hematological malignancies include acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, chronic neutrophilic leukemia, juvenile myelomonocytic leukemia, chronic eosinophilic leukemia, macrogranulomylmyocyteic leukemia, T-cell prelymphocytic leukemia, hepatosplenic lymphoma, Hodgkin lymphoma, T-cell lymphoblastic lymphoma or leukemia, T-cell nonlymphoblastic lymphoma, NK-cell lymphoma / leukemia, myeloid neoplasm, or chronic neutrophilic leukemia.

[0029] In some embodiments of the methods for treating diseases or conditions of the present disclosure, the disease or disorder is hemophagocytic lymphohistiocytosis (HLH) (including primary and secondary HLH), macrophage activation syndrome, Langerhans cell histiocytosis (LCH), somatic cell histiocytosis, Erdheim-Chester disease (ECD), mixed LCH / ECD, Rosei-Dorfmann disease, malignant histiocytosis, cutaneous non-LCH histiocytosis, juvenile xanthogranuloma, virus-associated HLH, bacteria-associated HLH, parasite-associated HLH, fungal-associated / fungal-induced HLH, malignant tumor-induced HLH, or during chemotherapy. HLH associated with onset, HLH associated with systemic onset juvenile idiopathic arthritis (SoJIA), HLH associated with adult-onset Still's disease, HLH associated with systemic lupus erythematosus (SLE), HLH associated with vasculitis, HLH associated with autoimmune diseases, HLH associated with kidney transplantation, HLH associated with hematopoietic stem cell transplantation, sHLH or CRS associated with checkpoint inhibitors to treat malignancies, sHLH or CRS associated with T-cell therapy, sHLH or CRS associated with chimeric antigen receptor (CAR) T-cell therapy, and T-cell activating bispecific monoclonal antibodies. Therapy-related sHLH or CRS, cytokine release syndrome (CRS), systemic mastocytosis, eosinophilic syndrome (including primary, secondary, and idiopathic), hyper-IgE syndrome, X-linked lymphoproliferative disorder, graft-versus-host disease, type 1 diabetes, systemic lupus erythematosus, lupus nephritis, systemic inflammatory response syndrome, acute respiratory distress syndrome, autoimmune lymphoproliferative syndrome, X-linked hyper-IgM syndrome, paraneoplastic syndrome, Suzac syndrome, linear IgA disease, autoimmune neutropenia, idiopathic pulmonary fibrosis, inclusion body myositis, vitiligo, Addison's disease, Graves' disease, Hashimoto's thyroiditis, Schmidt's syndrome Group, acute disseminated encephalomyelitis, sarcoidosis, ankylosing spondylitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, eosinophilic granulomatosis with polyangiitis, pyoderma gangrenosum, giant cell arteritis, rheumatoid arthritis, systemic juvenile idiopathic arthritis, Sjögren's syndrome, primary sclerosing cholangitis, primary biliary cholangitis, myasthenia gravis, multiple sclerosis, Guillain-Barré syndrome, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, chronic eosinophilic leukemia, macrogranulomylphocytic leukemia, T-cell prelymphocytic leukemia, hepatosplenic lymphoma,Hodgkin lymphoma, T-cell lymphoblastic leukemia / leukemia, T-cell non-lymphoblastic lymphoma, B-cell leukemia, B-cell lymphoma (non-Hodgkin), NK-cell lymphoma or leukemia, myeloid neoplasm, autoimmune hemolytic anemia, immune / idiopathic thrombocytopenic purpura, Evans syndrome, Felty syndrome, chronic inflammatory demyelinating porin eurypathy (CIDP), Lambert-Eaton myasthenic syndrome (LEMS), neuromyelitis optica (NMO), bullous pemphigoid, acquired epidermolysis bullosa, pemphigus phyllodes, pemphigus vulgaris, membranous Nephropathy, rheumatic vasculitis, lupus vasculitis, scleroderma (systemic sclerosis), Behçet's disease, granulomatosis with polyangiitis (Wegener's granulomatosis), eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), microscopic polyangiitis (MPA), Kawasaki disease, anti-glomerular basement membrane disease (Goodpasture syndrome), antiphospholipid syndrome, catastrophic antiphospholipid syndrome, Graves' ophthalmopathy, Castleman disease, antibody-mediated rejection (AMR), acute eosinophilic pneumonia, chronic eosinophilic pneumonia, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic Acidophilic gastroenteritis, eosinophilic enteritis, eosinophilic colitis, uveitis, giant cell myocarditis, cutaneous mastocytosis, mastocellular enteritis, mastocell activation syndrome, IgA nephropathy, Chediak-Higashi syndrome, eosinophilic cardiomyopathy / Loeffler endocarditis, acute kidney injury, chronic kidney disease, coronary artery disease (CAD) / peripheral artery disease (PAD), myelofibrosis, IgG4-related disease, Loeffler syndrome, chronic neutrophilic leukemia, myocarditis, episodic angioedema with eosinophilia / Gleich syndrome, idiopathic interstitial pneumonia, hereditary alpha-tryptemia syndrome This includes conditions such as chronic urticaria, severe allergic conjunctivitis, adult-onset Still's disease, aplastic anemia, cell-mediated rejection of solid organ transplants, graft failure after hematopoietic stem cell transplantation (HSCT), lymphocyte variant eosinophilia, myelodysplastic syndrome, atopic dermatitis, axial spondyloarthritis, celiac disease, hyperthyroidism, Rasmussen's encephalitis, chronic beryllium disease (berylliosis), Takayasu's arteritis, autoimmune hepatitis, neutrophilic dermatitis, psoriatic arthritis, coronavirus disease 2019 (COVID-19), or general pustular psoriasis.

[0030] In some embodiments of the methods for treating diseases or conditions described herein, the subject is human.

[0031] In some embodiments of the methods for treating the diseases or conditions of this disclosure, the antibody or pharmaceutical composition is administered intravenously. In some embodiments, the antibody or pharmaceutical composition is administered subcutaneously.

[0032] This disclosure provides cells that express SIRPγ, the cells bind to the antibody of this disclosure, and the antibody binds to SIRPγ.

[0033] This disclosure provides a kit or product comprising the antibody or pharmaceutical composition of this disclosure.

[0034] This disclosure provides the use of the antibodies or pharmaceutical compositions herein for treating diseases or disorders in subjects where such treatment is required.

[0035] This disclosure provides the use of the antibodies or pharmaceutical compositions of this disclosure for the manufacture of pharmaceuticals for treating diseases or disorders in subjects that require them. Further aspects of the present invention are described below: [Section 1] An Fc-containing antibody that is specific to one or more of SIRPα and SIRPβ1, and also specific to SIRPγ, wherein the binding of the antibody to one or more of SIRPα, SIRPβ1, and SIRPγ on a cell induces cell depletion. [Section 2] An antibody that is specific to one or more of SIRPα and SIRPβ1, and is specific to SIRPγ, wherein the antibody comprises a heavy chain variable region and a light chain variable region. The heavy chain variable region is, i. A complementarity determination region 1 (CDR-H1) sequence selected from the group consisting of sequence numbers 54, 56, and 59-65; ii. CDR-H2 sequences selected from the group consisting of sequence numbers 70, 72, and 75-81; and iii. CDR-H3 sequences selected from the group consisting of sequence numbers 86, 88-89, and 92-99. Including; and / or The light chain variable region is, i. A light chain CDR1 (CDR-L1) sequence selected from the group consisting of sequence numbers 5, 7-8, and 11-18; ii. CDR-L2 sequences selected from the group consisting of sequence numbers 23-24 and 27-33; and iii. CDR-H3 sequences selected from the group consisting of sequence numbers 36, 38-39, and 42-49. Antibodies containing antibodies. [Section 3] a. Sequence IDs 5, 23, 36, 54, 70, and 86; b. Sequence IDs 7, 24, 38, 54, 72, and 88; c. Sequence IDs 8, 24, 39, 56, 72, and 89; d. Sequence IDs 11, 27, 42, 59, 75, and 92; e. Sequence IDs 12, 28, 43, 60, 76, and 93; f. Sequence IDs 13, 29, 44, 61, 76, and 94; g. Sequence IDs 13, 30, 45, 62, 77, and 95; h. Sequence IDs 14, 31, 46, 63, 78, and 96; i. Sequence IDs 15, 31, 47, 62, 79, and 97; j. Sequence IDs 16, 31, 47, 62, 79, and 97; k. Sequence IDs 17, 32, 48, 64, 80, and 98; and l. Sequence IDs 18, 33, 49, 65, 81, and 99 The antibody according to item 1 or 2, comprising a combination of heavy chain and light chain variable CDR sequences selected from the group consisting of the following. [Section 4] An antibody according to any one of items 1 to 3, wherein the heavy chain variable region contains a sequence selected from the group consisting of SEQ ID NOs: 104, 106-107, and 110-118. [Section 5] The antibody according to any one of items 1 to 4, wherein the light chain variable region contains a sequence selected from the group consisting of SEQ ID NOs: 123, 125-126, and 129-137. [Section 6] The heavy chain variable region sequence and the light chain variable region sequence are a. Sequence IDs 104 and 123; b. Sequence IDs 106 and 125; c. Sequence IDs 107 and 126; d. Sequence IDs 110 and 129; e. Sequence IDs 111 and 130; f. Sequence IDs 112 and 131; g. Sequence IDs 113 and 132; h. Sequence IDs 114 and 133; i. Sequence IDs 115 and 134; j. Sequence IDs 116 and 135; k. Sequence IDs 117 and 136; and l. Sequence IDs 118 and 137 An antibody selected from the group consisting of items 1 to 5, as described in any one of items 1 to 5. [Section 7] The antibody according to any one of claims 1 to 5, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 104 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 123 or an amino acid sequence having at least 80% sequence identity thereto. [Section 8] The antibody according to any one of claims 1 to 5, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 106 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 125 or an amino acid sequence having at least 80% sequence identity thereto. [Section 9] The antibody according to any one of claims 1 to 5, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 107 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 126 or an amino acid sequence having at least 80% sequence identity thereto. [Section 10] The antibody according to any one of claims 1 to 5, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 110 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 129 or an amino acid sequence having at least 80% sequence identity thereto. [Section 11] The antibody according to any one of claims 1 to 5, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 111 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 130 or an amino acid sequence having at least 80% sequence identity thereto. [Section 12] The antibody according to any one of claims 1 to 5, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 112 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 131 or an amino acid sequence having at least 80% sequence identity thereto. [Section 13] The antibody according to any one of claims 1 to 5, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 113 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 132 or an amino acid sequence having at least 80% sequence identity thereto. [Section 14] The antibody according to any one of claims 1 to 5, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 114 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 133 or an amino acid sequence having at least 80% sequence identity thereto. [Section 15] The antibody according to any one of claims 1 to 5, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 115 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 134 or an amino acid sequence having at least 80% sequence identity thereto. [Section 16] The antibody according to any one of claims 1 to 5, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 116 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 135 or an amino acid sequence having at least 80% sequence identity thereto. [Section 17] The antibody according to any one of claims 1 to 5, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 117 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 136 or an amino acid sequence having at least 80% sequence identity thereto. [Section 18] The antibody according to any one of claims 1 to 5, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 118 or an amino acid sequence having at least 80% sequence identity thereto; and / or the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 137 or an amino acid sequence having at least 80% sequence identity thereto. [Section 19] An antibody according to any one of items 2 to 18, comprising an Fc domain. [Section 20] An antibody according to any one of items 1 to 19, wherein the antibody is an Fc-containing antibody, and the binding of the antibody to one or more of SIRPα, SIRPβ1, and SIRPγ on a cell induces cell depletion. [Section 21] An antibody described in any one of items 1 to 20, wherein cell depletion is accompanied by antibody-dependent phagocytosis (ADCP). [Section 22] An antibody as described in any one of items 1 to 21, wherein cell depletion is accompanied by antibody-dependent cytotoxicity (ADCC). [Section 23] The method according to any one of items 1 to 22, wherein cell depletion is accompanied by depletion of SIRPγ-positive cells. [Section 24] The antibody described in any one of items 1 to 23, wherein SIRPγ cells are lymphocytes. [Section 25] The antibody described in item 24, wherein the lymphocytes are T cells or NK cells. [Section 26] The antibody described in item 25, wherein the T cells are cytotoxic T cells, helper T cells, memory T cells, regulatory T cells, natural killer T cells, mucosa-associated invariant T cells, gamma delta T cells, or a combination thereof. [Section 27] The antibody according to any one of items 1 to 22, wherein cell depletion is accompanied by depletion of SIRPγ-positive cells and / or SIRPα and / or SIRPβ1-positive cells. [Section 28] The antibody described in item 27, wherein SIRPα and / or SIRPβ1 cells are myeloid cells or myeloid progenitor cells. [Section 29] The antibody described in section 27 or 28, wherein SIRPα and / or SIRPβ1 cells are selected from the group consisting of myeloid progenitor cells, monocytes, macrophages, dendritic cells, basophils, eosinophils, neutrophils, and mast cells. [Section 30] A monoclonal antibody, as described in any one of items 1 to 29. [Section 31] An antibody fragment, which is an antibody as described in any one of items 1 to 29. [Section 32] A human antibody, as described in any one of items 1 to 29. [Section 33] A humanized antibody, as described in any one of items 1 to 29. [Section 34] An antibody that is a chimeric antibody, as described in any one of items 1 to 29. [Section 35] A full-length antibody, as described in any one of items 1 to 29. [Section 36] An antibody according to any one of items 1 and 19 to 35, wherein the Fc domain is selected from the group consisting of human IgG1, IgG2, IgG3, and IgG4. [Section 37] The antibody according to item 36, wherein the Fc domain comprises SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 26. [Section 38] The antibody according to item 36, wherein the Fc domain comprises one or more amino acid substitutions relative to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 26. [Section 39] The antibody's Fc domain is human IgG1, and the following samples were found: 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, 292, 296, 297, 298, 299, 300, 3 The antibody described in item 36, comprising at least one amino acid substitution at a position selected from the group consisting of 05, 313, 324, 325, 326, 327, 328, 329, 330, 332, 333, 334, 345, 356, 358, 396, 428, 430, 433, 434, and 440, wherein the positional numbers of the amino acid residues are in accordance with the EU numbering scheme. [Section 40] IgG1 Fc, a. Sequence ID 19; bX 1 Sequence ID 20, where is V or A; cX 1 is V or A; X 2 is G or A; X 3 is S or D; X 4 Sequence ID 21, where is I or E; dX 1 Sequence ID 22, where is V or A; eX 1 is V or A; X 2 is M or L; X 3 Sequence ID 25, where is N or S; and fX 1 is K or R; X 2 is D or E; X 3 Sequence ID 26, where L or M The antibody according to item 36, comprising a sequence selected from the group consisting of the following. [Section 41] IgG4 Fc contains the sequence of SEQ ID NO: 34, 35, or 37, and X in SEQ ID NO: 37 1 is S or P, and X in sequence number 37 2 The antibody described in item 36, wherein L is or E. [Section 42] An antibody according to any one of items 1 to 41, wherein the binding of the antibody does not interfere with the interaction between CD47 and SIRPα, and / or the interaction between CD47 and SIRPγ. [Section 43] An antibody according to any one of items 1 to 41, wherein the binding of the antibody disrupts the interaction between CD47 and SIRPα, and / or between CD47 and SIRP. [Section 44] An antibody according to any one of items 1 to 43, which binds to SIRPα, SIRPβ1, and SIRPγ. [Section 45] An antibody according to any one of items 1 to 43, which binds to SIRPα and SIRP and shows little or no binding to SIRPβ1. [Section 46] An antibody according to any one of items 1 to 43, which binds to SIRPβ1 and SIRPγ and shows little or no binding to SIRPα. [Section 47] An antibody according to any one of items 1 to 45, comprising a binding affinity for SIRPα of approximately 100 pm, approximately 1 nM, approximately 5 nM, approximately 10 nM, approximately 50 nM, approximately 100 nM, approximately 500 nM, or approximately 1 μM. [Section 48] An antibody according to any one of items 1 to 47, comprising a binding affinity for SIRPβ1 of approximately 0.05 nM, approximately 0.1 nM, approximately 5 nM, approximately 10 nM, approximately 50 nM, approximately 100 nM, approximately 500 nM, approximately 1 μM, approximately 5 μM, or approximately 10 μM. [Section 49] An antibody according to any one of items 1 to 47, comprising a binding affinity for SIRPγ of approximately 0.0001 nM, approximately 0.0005 nM, approximately 0.001 nM, approximately 0.005 nM, approximately 0.1 nM, approximately 0.05 nM, approximately 0.1 nM, approximately 0.5 nM, approximately 1 nM, approximately 5 nM, approximately 10 nM, approximately 50 nM, approximately 100 nM, approximately 500 nM, approximately 1 μM, approximately 2 μM, or approximately 3 μM. [Section 50] A pharmaceutical composition comprising one of the antibodies described in any one of items 1 to 49 and a pharmaceutically acceptable carrier as appropriate. [Section 51] A nucleic acid encoding an antibody as described in any one of items 1 to 49. [Section 52] The nucleic acid described in item 51, comprising a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 142, 144-145, 148-156, 161, 163-164, and 167-175. [Section 53] The nucleic acid according to claim 51 or 52, wherein the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 142 or a nucleic acid sequence having at least 80% sequence identity thereto, and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 161 or a nucleic acid sequence having at least 80% sequence identity thereto. [Section 54] The nucleic acid according to claim 51 or 52, wherein the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 144 or a nucleic acid sequence having at least 80% sequence identity thereto, and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 163 or a nucleic acid sequence having at least 80% sequence identity thereto. [Section 55] The nucleic acid according to claim 51 or 52, wherein the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 145 or a nucleic acid sequence having at least 80% sequence identity thereto, and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 164 or a nucleic acid sequence having at least 80% sequence identity thereto. [Section 56] The nucleic acid according to claim 51 or 52, wherein the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 148 or a nucleic acid sequence having at least 80% sequence identity thereto, and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 167 or a nucleic acid sequence having at least 80% sequence identity thereto. [Section 57] The nucleic acid according to item 51 or 52, wherein the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 149 or a nucleic acid sequence having at least 80% sequence identity thereto, and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 168 or a nucleic acid sequence having at least 80% sequence identity thereto. [Section 58] The nucleic acid according to claim 51 or 52, wherein the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 150 or a nucleic acid sequence having at least 80% sequence identity thereto, and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 169 or a nucleic acid sequence having at least 80% sequence identity thereto. [Section 59] The nucleic acid according to claim 51 or 52, wherein the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 151 or a nucleic acid sequence having at least 80% sequence identity thereto, and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 170 or a nucleic acid sequence having at least 80% sequence identity thereto. [Section 60] The nucleic acid according to item 51 or 52, wherein the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 152 or a nucleic acid sequence having at least 80% sequence identity thereto, and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 171 or a nucleic acid sequence having at least 80% sequence identity thereto. [Section 61] The nucleic acid according to item 51 or 52, wherein the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 153 or a nucleic acid sequence having at least 80% sequence identity thereto, and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 172 or a nucleic acid sequence having at least 80% sequence identity thereto. [Section 62] The nucleic acid according to claim 51 or 52, wherein the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 154 or a nucleic acid sequence having at least 80% sequence identity thereto, and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 173 or a nucleic acid sequence having at least 80% sequence identity thereto. [Section 63] The nucleic acid according to claim 51 or 52, wherein the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 155 or a nucleic acid sequence having at least 80% sequence identity thereto, and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 174 or a nucleic acid sequence having at least 80% sequence identity thereto. [Section 64] The nucleic acid according to claim 51 or 52, wherein the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 156 or a nucleic acid sequence having at least 80% sequence identity thereto, and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 175 or a nucleic acid sequence having at least 80% sequence identity thereto. [Section 65] A vector comprising a nucleic acid as described in any one of items 51 to 64. [Section 66] A method for inducing depletion of a cell population, comprising contacting the cell population with an antibody described in any one of items 1 to 49. [Section 67] The method according to item 66, wherein at least a portion of the cell population expresses SIRPγ. [Section 68] The method according to item 66, wherein the cell population expressing SIRPγ includes lymphocytes. [Section 69] The method according to item 68, wherein the lymphocytes include T cells or NK cells. [Section 70] The method according to any one of items 66 to 69, wherein at least a portion of the cell population expresses SIRPα and / or SIRPβ1. [Section 71] The method according to item 70, wherein the cell population expressing SIRPα and / or SIRPβ1 includes myeloid cells or myeloid progenitor cells. [Section 72] The method according to item 70, wherein the cell population expressing SIRPα and / or SIRPβ1 includes monocytes, macrophages, dendritic cells, basophils, eosinophils, neutrophils, or mast cells. [Section 73] The method according to any one of items 66 to 72, in vitro. [Section 74] The method according to any one of claims 66 to 72, in vivo. [Section 75] The method according to any one of claims 66 to 74, wherein the cell population includes tissue resident cells. [Section 76] The method according to any one of items 66 to 75, wherein the cell population includes circulating cells. [Section 77] The method according to any one of items 66 to 76, wherein cell depletion is accompanied by ADCC. [Section 78] The method according to any one of items 66 to 77, wherein cell depletion is accompanied by ADCP. [Section 79] The method according to any one of claims 66 to 78, wherein cell depletion is accompanied by ADCC and ADCP. [Section 80] A method for treating a disease or condition in a subject requiring such treatment, comprising administering a therapeutically effective amount of an antibody described in any one of items 1 to 49 or a pharmaceutical composition described in item 50 to the subject. [Section 81] The method according to paragraph 80, wherein the disease or condition is characterized by hyperactivation and / or hyperproliferation of lymphocytes, and the antibody induces lymphocyte depletion. [Section 82] The method described in item 81, wherein the lymphocytes are T cells. [Section 83] The method according to item 82 or 83, wherein the disease or condition includes aplastic anemia, cell-mediated rejection of solid organ transplants, graft failure after HSCT (hematopoietic stem cell transplantation), lymphocyte variant eosinophilia, atopic dermatitis, lymphocytic myocarditis, axial spondyloarthritis, celiac disease, or Rasmussen encephalitis. [Section 84] The method according to paragraph 80, wherein the disease or condition is characterized by hyperactivation and / or hyperproliferation of myeloid cells, and the antibody induces myeloid cell depletion. [Section 85] The method according to item 84, wherein the myeloid cells include monocytes, macrophages, dendritic cells, basophils, eosinophils, neutrophils, or mast cells. [Section 86] The method according to item 85, wherein the myeloid cells include eosinophils, and the disease or condition includes acute eosinophilic pneumonia, chronic eosinophilic pneumonia, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic enteritis, eosinophilic colitis, lymphocyte variant eosinophilia, eosinophilic cardiomyopathy / Loeffler endocarditis, Loeffler syndrome, or episodic angioedema / Gleich syndrome with eosinophilia. [Section 87] The method according to item 85, wherein the myeloid cells include mast cells, and the disease or condition includes cutaneous mastocytosis, mastocellular enteritis, systemic mastocytosis, mastocell activation syndrome, hereditary alpha-tryptemia syndrome, chronic urticaria, or severe allergic conjunctivitis. [Section 88] The method according to item 85, wherein the myeloid cells include neutrophils, and the disease or condition includes neutrophilic dermatosis, psoriatic arthritis, generalized pustular psoriasis, pyoderma gangrenosum, Sweet's syndrome, subcorneal pustular dermatosis, neutrophilic eccrine hidradenitis, gut-associated dermatopathies-arthritis syndrome (BADAS), rheumatic neutrophilic dermatitis, or Behçet's disease. [Section 89] The method according to paragraph 80, wherein the disease or condition includes a disease or disorder in which both lymphocytes and myeloid cells are involved. [Section 90] The method according to item 89, wherein the disease or disorder includes histiocytosis. [Section 91] The method according to item 90, wherein histiocytosis includes hemophagocytic lymphohistiocytosis (HLH) (including primary and secondary HLH), macrophage activation syndrome, Langerhans cell histiocytosis (LCH), uncertain cell histiocytosis, Erdheim-Chester disease (ECD), mixed LCH / ECD, Rosei-Dorfmann disease, malignant histiocytosis, cutaneous non-LCH histiocytosis, juvenile xanthogranuloma, virus-associated HLH, bacteria-associated HLH, parasite-associated HLH, fungal-associated (fungus-induced) HLH, autoimmune disease-mediated HLH, or malignant tumor-induced HLH. [Section 92] The method according to item 91, wherein malignant tumor-induced HLH includes HLH induced by hematological malignancies or solid tumors. [Section 93] The method according to paragraph 89, wherein the disease or disorder includes non-Mendelian secondary HLH (secondary HLH, or sHLH). [Section 94] The method according to paragraph 93, wherein secondary HLH includes infection-associated HLH. [Section 95] The method described in paragraph 93, wherein sHLH is associated with a rheumatic condition. [Section 96] The method according to paragraph 93, wherein sHLH is associated with kidney transplantation or hematological stem cell transplantation. [Section 97] The method according to item 80, wherein the disease or condition includes cytokine release syndrome (CRS). [Section 98] The method according to paragraph 97, wherein the CRS is associated with iatrogenic immune activation, infection, T-cell therapy, or T-cell activating bispecific antibody therapy. [Section 99] The method according to item 80, wherein the disease or condition includes sHLH or CRS associated with iatrogenic immune activation, infection, T-cell therapy, chimeric antigen receptor T-cell (CAR-T) therapy, T-cell receptor T-cell therapy (TCR-T), T-cell activating bispecific antibody therapy, or iatrogenic immunosuppression. [Section 100] The method according to paragraph 80, wherein the disease or disorder is a granulomatous disease or condition, or a disease characterized by the presence of multinucleated giant cells. [Section 101] The method according to item 100, wherein the disease or condition includes sarcoidosis, Crohn's disease, Takayasu's arteritis, giant cell arteritis, psoriatic arthritis, granulomatosis with polyangiitis (Wegener's granulomatosis), giant cell myocarditis, chronic granulomatous disease, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), or chronic beryllium disease (berylliosis). [Section 102] The method according to paragraph 80, wherein the disease or condition includes an autoimmune disorder or an inflammatory disorder. [Section 103] The method according to item 102, wherein the autoimmune disease involves the presentation of autoantigens by antigen-presenting dendritic cells in the germinal centers of the secondary lymphoid tissue of the subject. [Section 104] The method according to item 80, wherein the disease or condition is associated with pathological alloantibodies or autoantibodies. [Section 105] The method according to paragraph 80, wherein the disease or disorder includes hematological malignancies. [Section 106] The method described in any one of items 80 to 105, wherein the subject is a human. [Section 107] The method according to any one of claims 80 to 106, wherein the antibody or pharmaceutical composition is administered intravenously. [Section 108] The method according to any one of claims 80 to 106, wherein the antibody or pharmaceutical composition is administered subcutaneously. [Section 109] A cell expressing SIRPγ, wherein the cell binds to an antibody described in any one of items 1 to 49, and the antibody binds to SIRPγ. [Section 110] A kit or product comprising an antibody as described in any one of items 1 to 49, or a pharmaceutical composition as described in item 50. [Section 111] Use of an antibody according to any one of items 1 to 49, or a pharmaceutical composition according to item 50, for treating a disease or disorder in a subject that requires it. [Section 112] Use of an antibody according to any one of claims 1 to 49, or a pharmaceutical composition according to claim 50, in the manufacture of a pharmaceutical for treating a disease or disorder in a subject that requires it. [Brief explanation of the drawing]

[0036] [Figure 1A] The binding of selected antibodies of this disclosure to human SIRPα and cynomolgus monkey (cyno) SIRPα is shown by enzyme-linked immunosorbent assay (ELISA). [Figure 1B] This shows the binding of selected antibodies of this disclosure to human SIRPα, SIRPβ1, and SIRPγ by ELISA. [Figure 2A-2B] The binding curves of selected antibodies against human and cynomolgus monkey SIRPα, obtained by ELISA, are shown. [Figure 2C] The binding curves of selected antibodies against human and cynomolgus monkey SIRPα (top row) and SIRPβ1 (bottom row) obtained by ELISA are shown. [Figure 2D] The binding curves of selected antibodies against human and cynomolgus monkey SIRPγ, obtained by ELISA, are shown. [Figure 2E] The binding curves of selected antibodies against human and cynomolgus monkey SIRPα (top row) and SIRPβ1 (bottom row) obtained by ELISA are shown. [Figure 2F] The binding curves of selected antibodies against human and cynomolgus monkey SIRPγ, obtained by ELISA, are shown. [Figure 2G] The binding curves of 15 antibodies against human and cynomolgus monkey SIRPα (top row) and SIRPβ1 (bottom row) obtained by ELISA are shown. [Figure 2H] The binding curves of 15 antibodies against human and cynomolgus monkey SIRPγ, obtained by ELISA, are shown. [Figure 3A] The binding curves of selected antibodies of this disclosure to human SIRPα and cynomolgus monkey SIRPα, obtained by ELISA, are shown. [Figure 3B] The binding curves of selected antibodies of this disclosure to human SIRPβ1 and human SIRPγ, obtained by ELISA, are shown. [Figure 3C] The binding curves of antibody 29 against human SIRPα, SIRPβ1, and human SIRPγ, obtained by ELISA, are shown. [Figure 3D] The binding curves of selected antibodies of this disclosure to human and cynomolgus monkey SIRPα (top row) and SIRPβ1 (bottom row) are shown by ELISA. [Figure 3E] The binding curves of selected antibodies of this disclosure to human and cynomolgus monkey SIRPγ, obtained by ELISA, are shown. [Figure 4A] The binding curves of selected antibodies of this disclosure to monocytes, neutrophils, T lymphocytes, and B lymphocytes in human whole blood, as determined by flow cytometry, are shown. [Figure 4B] The binding curves of selected antibodies of this disclosure to monocytes, granulocytes, and T lymphocytes in cynomolgus monkey (cyno) whole blood, obtained by flow cytometry, are shown. [Figure 4C]The binding curves of selected antibodies from this disclosure to human SIRPα-expressing CHO cells, obtained by flow cytometry, are shown. [Figure 4D] The binding curves of selected antibodies from this disclosure to human SIRPβ1 / DAP12-expressing CHO cells, obtained by flow cytometry, are shown. [Figure 4E] The binding curves of selected antibodies from this disclosure to human SIRPγ-expressing CHO cells, obtained by flow cytometry, are shown. [Figure 4F] The binding curves of selected antibodies from this disclosure to human SIRPα, SIRPβ1 / DAP12, or SIRPγ-expressing CHO cells, as determined by flow cytometry, are shown. [Figure 5] This disclosure demonstrates the efficacy of selected antibodies against antibody-dependent cell-mediated cytotoxicity (ADCC) of THP-1 cells in vitro. [Figure 6A] This document demonstrates the efficacy of selected antibodies of this disclosure against human monocyte ADCC in vitro. [Figure 6B] This disclosure demonstrates the efficacy of selected antibodies against ADCC in human and cynomolgus monkey (cyno) monocytes in vitro. [Figure 6C] This disclosure demonstrates the efficacy of selected antibodies against ADCC in human and cynomolgus monkey (cyno) CD4+ T cells in vitro. [Figure 6D] This disclosure demonstrates the efficacy of selected antibodies against ADCC in human and cynomolgus monkey (cyno) CD8+ T cells in vitro. [Figure 7] This exhibits the effect of selected antibodies of this disclosure on antibody-dependent cell phagocytosis (ADCP) of MOLM-13 cells by THP-1 cells in vitro. [Figure 8] This document demonstrates the in vitro efficacy of human monocytes against human monocyte-mediated ADCP of selected antibodies according to this disclosure. [Figure 9A-9B] This document demonstrates the efficacy of the selected antibodies of this disclosure against monocyte depletion in vivo. [Figure 10A-10B] This document demonstrates the efficacy of the selected antibodies of this disclosure against neutrophil depletion in vivo. [Figure 11A-11B] This document demonstrates the efficacy of the selected antibodies of this disclosure against lymphocyte depletion in vivo. [Figures 12A-12B] This document demonstrates the efficacy of the selected antibodies of this disclosure against eosinophil depletion in vivo. [Figures 13A-13B] This document demonstrates the efficacy of the selected antibodies of this disclosure against basophil depletion in vivo. [Figure 14] This graph displays the results of ELISA experiments evaluating the ability of various antibodies to compete with CD47 for binding to human SIRPα. [Modes for carrying out the invention]

[0037] Detailed explanation This specification provides antibodies that bind to (a) SIRPγ and (b) SIRPα and / or SIRPβ1. Methods for producing and using such antibodies are also provided. Antibodies may be useful for treating diseases or conditions involving cells expressing SIRPγ, SIRPα and / or SIRPβ1. For example, in some embodiments, antibodies may be used as part of a pathology to treat diseases or conditions involving hyperactivation and / or hyperproliferation of SIRPα, SIRPβ1 (e.g., myeloid cells), or SIRPγ-expressing cells (e.g., lymphocytes).

[0038] When elements are presented in list format (e.g., Markush groups), it should be understood that each possible subgroup of the elements is also disclosed, and any one or more elements may be removed from the list or group.

[0039] Unless otherwise expressly indicated, in any method described or disclosed herein that involves more than one act, the order of the acts is not necessarily limited to the order in which the acts of the method are described, and it should be understood that this disclosure includes exemplary embodiments in which the order of the acts is thus limited.

[0040] Terms used throughout this specification are defined as follows, unless otherwise specified in particular: Where used in this specification and in the claims, unless the context explicitly indicates otherwise, the singular forms “a,” “an,” and “the” refer to multiple subjects. All technical and scientific terms, acronyms, and abbreviations used throughout this specification and in the claims have the same meanings as commonly understood by those skilled in the art to whom this disclosure relates, unless otherwise defined and stated. All numerical ranges include the value defining the range, as well as all integer values ​​between them, unless otherwise indicated or defined.

[0041] The terms “individual,” “subject,” and “patient” are used interchangeably herein and refer to any subject for which treatment or therapy is desired. A subject may be a mammalian subject. Mammalian subjects may include humans, non-human primates, rodents (e.g., rats, mice), lagomorphs (e.g., rabbits), ungulates (e.g., cattle, sheep, pigs, horses, goats, etc.). In some embodiments, the subject is human. In some embodiments, the subject is a non-human primate, e.g., a cynomolgus macaque. In some embodiments, the subject is a companion animal (e.g., a cat, a dog).

[0042] All publications, patents, and patent applications described herein are specific in such a way that each individual publication, patent, or patent application is incorporated by reference, and is incorporated herein by reference to the same extent as each individual publication, patent, or patent application is incorporated by reference.

[0043] I. Antibodies A.SIRP antibody This specification provides antibodies that bind to SIRPγ, SIRPα, SIRPβ1, or a combination of SIRPα and SIRPβ1. Therefore, antibodies that bind to (a) SIRPγ and SIRPα, (b) SIRPγ and SIRPβ1, or (c) SIRPγ, SIRPα and SIRPβ1 are considered to be within the scope of this disclosure and are collectively referred to herein as "SIRP antibodies," "SIRP antibodies," or "anti-SIRP antibodies." The binding specificity of the SIRP antibodies of this disclosure is, as a whole, such that the SIRP antibody exhibits binding to SIRPγ and one or more SIRPα and / or SIRPβ1 (i.e., the antibody exhibits binding to SIRP and SIRPα and / or SIRPβ1).

[0044] Those skilled in the art will understand, depending on the context, that SIRP antibodies of the disclosure having the ability to bind to SIRPγ and SIRPα and / or SIRPβ1 may encounter binding surfaces (e.g., cells) that may express only some of the targets to which the antibody can bind. For example, an antibody capable of binding to SIRPγ and SIRPα may bind to cells that express only SIRPγ or cells that express only SIRPα. Alternatively, a binding surface such as a cell may express one or more, or all, of the targets to which the antibody can bind. In such situations, the antibody is also expected to bind to that surface. For example, an antibody capable of binding to SIRPβ1 and SIRPγ may bind to cells that express both SIRPβ1 and SIRPγ. Thus, the SIRP antibodies of the disclosure bind to SIRPγ and SIRPα and / or SIRPβ1, but binding to all targets is not required for activity.

[0045] As used herein, the term “antibody” is used in its broadest sense and includes monoclonal antibodies, polyclonal antibodies, human antibodies, humanized antibodies, non-human antibodies, chimeric antibodies, monovalent antibodies, and antibody fragments.

[0046] In exemplary embodiments, the SIRP antibody provided herein is a monoclonal antibody (mAb). In exemplary embodiments, the SIRP antibody provided herein is a human antibody. In exemplary embodiments, the SIRP antibody provided herein is a humanized antibody. In exemplary embodiments, the SIRP antibody provided herein is a monoclonal human antibody. In exemplary embodiments, the SIRP antibody provided herein is a chimeric antibody. In exemplary embodiments, the SIRP antibody provided herein is a monoclonal chimeric antibody.

[0047] In some embodiments, the SIRP antibodies provided herein are antibody fragments that retain SIRPγ and SIRPβ1 and / or SIRPα antigen-binding specificity. In some embodiments, the antibody fragment is an antigen-binding fragment (Fab), a variable fragment (Fv) containing VH and VL sequences, a single-stranded variable fragment (scFv) containing VH and VL sequences linked together in a single chain, a single-stranded antibody fragment (scAb), or other antibody variable region fragments such as Fab', F(ab')2, dsFv diabody, and Fd polypeptide fragment.

[0048] Furthermore, this specification provides SIRP antibody-drug conjugates, bispecific antibodies comprising at least one arm specific to SIRPγ and SIRPα and / or SIRPβ1, and polyspecific antibodies exhibiting binding to SIRPγ and SIRPα and / or SIRPβ1.

[0049] The SIRPα protein is characterized by its high polymorphism, but this does not appear to affect its ligand-binding properties. At least 13 variants (polymorphisms) are characterized by variants 1-13, with V1 and V2 being the most common in humans (Hatherley et al., JBC 289: pp. 10024-10028, 2014). SIRPα also has at least three isoforms. Therefore, the term "SIRPα" as used herein encompasses all variants and isoforms of SIRPα.

[0050] The amino acid sequence of human SIRPα (hSIRPα) isoform 1, variant 1 (V1) is provided in SEQ ID NO: 1, and is referred to herein as hSIRPαV1. 1 MEPAGPAPGR LGPLLCLLLA ASCAWSGVAG EEELQVIQPD KSVLVAAGET ATLRCTATSL 61 IPVGPIQWFR GAGPGRELIY NQKEGHFPRV TTVSDLTKRN NMDFSIRIGN ITPADAGTYY 121 CVKFRKGSPD DVEFKSGAGT ELSVRAKPSA PVVSGPAARA TPQHTVSFTC ESHGFSPRDI 181 TLKWFKNGNE LSDFQTNVDP VGESVSYSIH STAKVVLTRE DVHSQVICEV AHVTLQGDPL 241 RGTANLSETI RVPPTLEVTQ QPVRAENQVN VTCQVRKFYP QRLQLTWLEN GNVSRTETAS 301 TVTENKDGTY NWMSWLLVNV SAHRDDVKLT CQVEHDGQPA VSKSHDLKVS AHPKEQGSNT 361 AAENTGSNER NIYIVVGVVC TLLVALLMAA LYLVRIRQKK AQGSTSSTRL HEPEKNAREI 421 TQDTNDITYA DLNLPKGKKP APQAAEPNNH TEYASIQTSP QPASEDTLTY ADLDMVHLNR 481 TPKQPAPKPE PSFSEYASVQ VPRK (Sequence ID 1)

[0051] The amino acid sequences of hSIRPα isoform 1 and variant 2 (V2) are provided in Sequence ID No. 2 and are referred to herein as hSIRPαV2. 1 MEPAGPAPGR LGPLLCLLLA ASCAWSGVAG EEELQVIQPD KSVSVAAGES AILHCTVTSL 61 IPVGPIQWFR GAGPARELIY NQKEGHFPRV TTVSESTKRE NMDFSISISN ITPADAGTYY 121 CVKFRKGSPD TEFKSGAGTE LSVRAKPSAP VVSGPARAT PQHTVSFTCE SHGFSPRDIT 181 LKWFKNGNEL SDFQTNVDPV GESVSYSIHS TAKVVLTRED VHSQVICEVA HVTLQGDPLR 241 GTANLSETIR VPPTLEVTQQ PVRAENQVNV TCQVRKFYPQ RLQLTWLENG NVSRTETAST 301 VTENKDGTYN WMSWLLVNVS AHRDDVKLTC QVEHDGQPAV SKSHDLKVSA HPKEQGSNTA 361 AENTGSNERN IYIVVGVVCT LLVALLMAAL YLVRIRQKKA QGSTSSTRLH EPEKNAREIT 421 QVQSLDTNDI TYADLNLPKG KKPAPQAAEP NNHTEYASIQ TSPQPASEDT LTYADLDMVH 481 LNRTPKQPAP KPEPSFSEYA SVQVPRK (Sequence ID 2)

[0052] The amino acid sequence of hSIRPα isoform 2 is provided herein as SEQ ID NO: 6. 1 MEPAGPAPGR LGPLLCLLLA ASCAWSGVAG EEELQVIQPD KSVLVAAGET ATLRCTATSL 61 IPVGPIQWFR GAGPGRELIY NQKEGHFPRV TTVSDLTKRN NMDFSIRIGN ITPADAGTYY 121 CVKFRKGSPD DVEFKSGAGT ELSVRAKPSA PVVSGPAARA TPQHTVSFTC ESHGFSPRDI 181 TLKWFKNGNE LSDFQTNVDP VGESVSYSIH STAKVVLTRE DVHSQVICEV AHVTLQGDPL 241 RGTANLSETI RVPPTLEVTQ QPVRAENQVN VTCQVRKFYP QRLQLTWLEN GNVSRTETAS 301 TVTENKDGTY NWMSWLLVNV SAHRDDVKLT CQVEHDGQPA VSKSHDLKVS AHPKEQGSNT 361 AAENTGSNER NIYIVVGVVC TLLVALLMAA LYLVRIRQKK AQGSTSSTRL HEPEKNAREI 421 TQVQSLDTND ITYADLNLPK GKKPAPQAAE PNNHTEYASI QTSPQPASED TLTYADLDMV 481 HLNRTPKQPA PKPEPSFSEY ASVQVPRK (Sequence ID 6)

[0053] The amino acid sequence of human SIRPα isoform 4 is provided in SEQ ID NO: 40. 1 MEPAGPAPGR LGPLLCLLLA ASCAWSGVAG EEELQVIQPD KSVLVAAGET ATLRCTATSL 61 IPVGPIQWFR GAGPGRELIY NQKEGHFPRV TTVSDLTKRN NMDFSIRIGN ITPADAGTYY 121 CVKFRKGSPD VEFKSGAGTE LSVRAKPSAP VVSGPAARAT PQHTVSFTCE SHGFSPRDIT 181 LKWFKNGNEL SDFQTNVDPV GESVSYSIHS TAKVVLTRED VHSQVICEVA HVTLQGDPLR 241 GTANLSETIR VPPTLEVTQQ PVRAENQVNV TCQVRKFYPQ RLQLTWLENG NVSRTETAST 301 VTENKDGTYN WMSWLLVNVS AHRDDVKLTC QVEHDGQPAV SKSHDLKVSA HPKEQGSNTA 361 AENTGSNERN IYIVVGVVCT LLVALLMAAL YLVRIRQKKA QGSTSSTRLH EPEKNAREIT 421 QDTNDITYAD LNLPKGKKPA PQAAEPNNHT EYASIQTSPQ PASEDTLTYA DLDMVHLNRT 481 PKQPAPKPEP SFSEYASVQV PRK (Sequence ID 40)

[0054] In some embodiments, the SIRP antibody also binds to one or more variants or isoforms of a single species of SIRPα. In some embodiments, the SIRP antibody also binds to one or more variants or isoforms of SIRPα from one or more species. In some embodiments, the SIRP antibody binds to one or more variants or isoforms of human SIRPα. In some embodiments, the SIRP antibody also binds to one or more variants or isoforms of non-human primate SIRPα, such as cynomolgus monkey SIRPα.

[0055] In some embodiments, the SIRP antibody also binds to multiple SIRPα variants found in a particular species, for example, the SIRP antibody binds to one or more of SIRPα human variants 1-13. In some embodiments, the SIRP antibody also binds to hSIRPαV1. In some embodiments, the SIRP antibody also binds to hSIRPαV2. In some embodiments, the SIRP antibody also binds to both hSIRPαV1 and V2. In some embodiments, the SIRP antibody also binds to the extracellular domain of SIRPα, for example, hSIRPαV1 (e.g., Met1-Arg370 of V1, Gly27-Arg370 of V1, or Glu31-Arg370 of V1), or for example, hSIRPαV2 (Met1-Arg369).

[0056] In some embodiments, the SIRP antibody of this disclosure binds to multiple SIRPα isoforms. For example, the SIRP antibody of this disclosure can bind to two or more SIRPα isoforms, or to all SIRPα isoforms. In some embodiments, the SIRP antibody binds to SIRPα isoforms 1, 2, and 4.

[0057] In some embodiments, the SIRP antibody also specifically binds to hSIRPαV1. In some embodiments, the SIRP antibody also specifically binds to hSIRPαV2. In some embodiments, the SIRP antibody also specifically binds to both hSIRPαV1 and hSIRPαV2. In some embodiments, the SIRP antibody also specifically binds to one or more variants of SIRPα, but shows little to no binding to SIRPβ1.

[0058] Human SIRPβ1 (hSIRPβ1) has at least three isoforms. The amino acid sequence of hSIRPβ1 isoform 1 is: 9 It will be provided to. 1 MPVPASWPHL PSPFLLMTLL LGRLTGVAGE DELQVIQPEK SVSVAAGESA TLRCAMTSLI 61 PVGPIMWFRG AGAGRELIYN QKEGHFPRVT TVSELTKRNN LDFSISISNI TPADAGTYYC 121 VKFRKGSPDD VEFKSGAGTE LSVRAKPSAP VVSGPAVRAT PEHTVSFTCE SHGFSPRDIT 181 LKWFKNGNEL SDFQTNVDPA GDSVSYSIHS TARVVLTRGD VHSQVICEIA HITLQGDPLR 241 GTANLSEAIR VPPTLEVTQQ PMRAENQANV TCQVSNFYPR GLQLTWLENG NVSRTETAST 301 LIENKDGTYN WMSWLLVNTC AHRDDVVLTC QVEHDGQQAV SKSYALEISA HQKEHGSDIT 361 HEAALAPTAP LLVALLLGPK LLLVVGVSAI YICWKQKA (Sequence ID) 9 )

[0059] In some embodiments, the SIRP antibody also binds to one or more variants or isoforms of a single species of SIRPβ1. In some embodiments, the SIRP antibody also binds to one or more variants or isoforms of SIRPβ1 from more than one species. In some embodiments, the SIRP antibody binds to one or more variants or isoforms of human SIRPβ1. In some embodiments, the SIRP antibody also binds to one or more variants or isoforms of non-human primate SIRPβ1, such as cynomolgus monkey SIRPβ.

[0060] In some embodiments, the SIRP antibody also binds to multiple SIRPβ1 variants or isoforms found in a particular species. For example, the SIRP antibody binds to one or more of the SIRPβ1 human isoforms 1-3. In some embodiments, the SIRP antibody also binds to the extracellular domain of SIRPβ1 (e.g., SEQ ID NO: 9 It binds to amino acids 1-371 of SIRPα. In some embodiments, the SIRP antibody also specifically binds to one or more variants or isoforms of SIRPα, in addition to binding to SIRPγ and SIRPβ1.

[0061] Human SIRPγ has at least four isoforms. The amino acids of hSIRPγ isoform 1 are as follows: 10 It will be offered as such. 1 MPVPASWPHP PGPFLLLTLL LGLTEVAGEE ELQMIQPEKL LLVTVGKTAT LHCTVTSLLP 61 VGPVLWFRGV GPGRELIYNQ KEGHFPRVTT VSDLTKRNNM DFSIRISSIT PADVGTYYCV 121 KFRKGSPENV EFKSGPGTEM ALGAKPSAPV VLGPAARTTP EHTVSFTCES HGFSPRDITL 181 KWFKNGNELS DFQTNVDPTG QSVAYSIRST ARVVLDPWDV RSQVICEVAH VTLQGDPLRG 241 TANLSEAIRV PPTLEVTQQP MRVGNQVNVT CQVRKFYPQS LQLTWSENGN VCQRETASTL 301 TENKDGTYNW TSWFLVNISD QRDDVVLTCQ VKHDGQLAVS KRLALEVTVH QKDQSSDATP 361 GPASSLTALL LIAVLLGPIY VPWKQKT(Sequence ID) 10 )

[0062] In some embodiments, the SIRP antibody binds to one or more variants or isoforms of a single species of SIRPγ. In some embodiments, the SIRP antibody binds to one or more variants or isoforms of SIRPγ from more than one species. In some embodiments, the SIRP antibody binds to one or more variants or isoforms of human SIRPγ. In some embodiments, the SIRP antibody binds to one or more variants or isoforms of non-human primate SIRPγ, such as cynomolgus monkey SIRPγ.

[0063] In some embodiments, the SIRP antibody binds to multiple SIRPγ variants or isoforms found in a particular species. For example, the SIRP antibody binds to one or more of the SIRPγ human isoforms 1-3. In some embodiments, the SIRP antibody binds to the extracellular domain of SIRPγ (e.g., SEQ ID NO: 10 It binds to amino acids 1-360.

[0064] Antibodies that show little or no binding to the target antigen can be described as having low affinity for the target antigen and a high equilibrium dissociation constant (KD), e.g., a KD of about 10 μM or greater, about 100 μM or greater, about 1 mM or greater, or about 10 mM or greater. Those skilled in the art will recognize that, for example, SIRP antibodies that bind to SIRPγ and SIRPα can bind to SIRPβ1 with low affinity. The SIRP antibodies of the present disclosure that have low affinity for SIRPβ1 can bind to SIRPβ1 having a KD of about 10 μM or greater, about 100 μM or greater, about 1 mM or greater, or about 10 mM or greater, while retaining a higher binding affinity for SIRPγ and SIRPα. As a further example, SIRP antibodies that bind to SIRPγ and SIRPβ1 can bind to SIRPα with low affinity.

[0065] In some embodiments, provided herein are SIRP antibodies having a binding affinity (KD) for SIRPα of 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, or about 1 μM.

[0066] In some embodiments, provided herein are SIRP antibodies having a binding affinity (KD) for SIRPα of about 0.05 nM to 1 μM, about 0.5 nM to 1 μM, about 1 nM to 1 μM, about 5 nM to 1 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 0.05 nM to 50 nM, about 0.5 nM to 50 nM, about 1 nM to 50 nM, or about 5 nM to 50 nM.

[0067] In some embodiments, provided herein are SIRP antibodies having a binding affinity (KD) for SIRPβ1 of 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, about 3 μM, about 5 μM, or about 10 μM.

[0068] In some embodiments, provided herein are SIRP antibodies having a binding affinity (KD) for SIRPβ1 between about 0.05 nM and 10 μM, about 0.5 nM and 10 μM, about 1 nM and 10 μM, about 5 nM and 10 μM, about 10 nM and 10 μM, about 50 nM and 10 μM, about 100 nM and 10 μM, about 0.05 nM and 1 μM, about 0.5 nM and 1 μM, about 1 nM and 1 μM, about 5 nM and 1 μM, about 10 nM and 1 μM, 50 nM and 1 μM, about 0.05 nM and 500 nM, about 0.5 nM and 500 nM, about 1 nM and 500 nM, about 5 nM and 500 nM, 10 nM and 500 nM, about 0.001 nM and 50 nM, about 0.005 nM and 50 nM, about 0.05 nM and 50 nM, about 0.5 nM and 50 nM, about 1 nM and 50 nM, or about 5 nM and 50 nM.

[0069] In some embodiments, provided herein are SIRP antibodies having a binding affinity (KD) for SIRPγ of about 0.0001 nM, about 0.0005 nM, about 0.0 01 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.

[0070] In some embodiments, provided herein are SIRP antibodies having a binding affinity (KD) for SIRPγ between about 0.00 01 nM and 5 μM, about 0.0005 nM and 5 μM, about 0.05 nM and 5 μM, about 0.5 nM and 5 μM, about 1 nM and 5 μM, about 5 nM and 5 μM, 0.0001 nM and 2 μM, about 0.0005 nM and 2 μM, about 0.05 nM and 2 μM, about 0.5 nM and 2 μM, about 1 nM and 2 μM, about 5 nM and 2 μM, 0.0001 nM and 1 μM, about 0.0005 nM and 1 μM, about 0.05 nM and 1 μM, about 0.5 nM and 1 μM, about 1 nM and 1 μM, about 5 nM and 1 μM, about 0.0001 nM and 500 nM, about 0.0005 nM and 500 nM, about 0.05 nM and 500 nM, about 0.5 nM and 500 nM, about 1 nM and 500 nM, about 5 nM and 500 nM, about 0.0001 nM and 50 nM, about 0.0005 nM and 50 nM, about 0.05 nM and 50 nM, about 0.5 nM and 50 nM, about ɪ nM and 50 nM, or about 5 nM and 50 nM.

[0071] In some embodiments, the SIRP antibodies of this disclosure compete with CD47 for binding to SIRPα or SIRPγ on cells or other surfaces. In some embodiments, the SIRP antibodies of this disclosure partially compete with CD47 for binding to SIRPα or SIRPγ on cells or other surfaces. In other embodiments, the SIRP antibodies of this disclosure do not compete with CD47 for binding to surfaces, such as cells. Exemplary antibodies of this disclosure that do not compete with CD47 binding to SIRPα include antibodies 1 and 13, refer to Table 11. Exemplary antibodies of this disclosure that partially inhibit the binding of CD47 to SIRPα include antibodies 3 and 7, refer to Table 11.

[0072] In some embodiments, the constant region of the SIRP antibody (interchangeably referred to as the Fc domain, Fc sequence, or simply Fc) is a human Fc domain. In some embodiments, the Fc domain of the SIRP antibody is human IgG1, human IgG2, human IgG3, or human IgG4. In some embodiments, the Fc domain of the SIRP antibody is mouse. In some embodiments, the Fc domain of the SIRP antibody is mouse IgG1 or mouse IgG2a. In some embodiments, the Fc domain of the SIRP antibody is rat. In some embodiments, the Fc domain of the SIRP antibody is rat IgG1 or rat IgG2b. In some embodiments, the Fc domain of the SIRP antibody is rat IgG2b. In some embodiments, the Fc domain of the SIRP antibody is from a non-human primate, for example, it is a cynomolgus monkey Fc domain.

[0073] In some embodiments, the SIRP antibody provided herein is a full-length antibody. In some embodiments, the constant region of the full-length antibody (referred interchangeably as the Fc domain, Fc sequence, or simply Fc) is a human Fc domain. In some embodiments, the Fc domain of the full-length SIRP antibody is human IgG1, human IgG2, human IgG3, or human IgG4. In some embodiments, the Fc domain of the full-length SIRP antibody is from a mouse. In some embodiments, the Fc domain of the full-length SIRP antibody is mouse IgG1 or mouse IgG2a. In some embodiments, the Fc domain of the full-length SIRP antibody is from a rat. In some embodiments, the Fc domain of the full-length SIRP antibody is rat IgG1 or rat IgG2b. In embodiments, the Fc domain of the full-length SIRP antibody is from a non-human primate, for example, it is a cynomolgus monkey Fc domain.

[0074] In some embodiments, the SIRP antibody includes an Fc domain, and the Fc domain of the SIRP antibody is human IgG1 Fc. Exemplary but non-limiting human IgG1 Fc domain sequences are provided as SEQ ID NOs: 3-4, 19-22, 25-26, 41, 50-53, 55, 57-58, 66-69, 71, and 73-74. 1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (Sequence ID 3) 1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKAEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (Sequence ID 4) 1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKAEP KSCDKTHTCP PCPAPELLAG 121 PDVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPEEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (Sequence ID 19) 1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLAG 121 PDVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPEEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (Sequence ID 41) 1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG 121 PDVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPEEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (Sequence ID 50) 1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPEEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (Sequence ID 51) 1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG 121 PDVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (Sequence ID 52) 1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKAEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK(SEQ ID NO: 53) 1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV LHEALHNHYT QKSLSLSPGK(SEQ ID NO: 55) 1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHSHYT QKSLSLSPGK (Sequence ID 57) 1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKAEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV LHEALHNHYT QKSLSLSPGK (Sequence ID 58) 1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKAEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHSHYT QKSLSLSPGK (Sequence ID 66) 1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (Sequence ID 67) 1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPSREE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (Sequence ID 68) 1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPSREE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (Sequence ID 69) 1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (Sequence ID 71) 1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKAEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (Sequence ID 73) 1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKAEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPEEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (Sequence ID 74)

[0075] In some embodiments, the human IgG1 Fc domain sequence is sequence number 20, and X1 is V or A. 1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKX1EP KSCDKTHTCP PCPAPELLAG 121 PDVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPEEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (Sequence ID 20)

[0076] In some embodiments, the human IgG1 Fc domain sequence is sequence number 21, where X1 is V or A; X2 is G or A; X3 is S or D; and X4 is I or E. 1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKX1EP KSCDKTHTCP PCPAPELLX2G 121 PX3VFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPX4EKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (Sequence ID 21)

[0077] In some embodiments, the human IgG1 Fc domain sequence is sequence number 22, and X1 is V or A. 1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKX1EP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV LHEALHSHYT QKSLSLSPGK (Sequence ID 22)

[0078] In some embodiments, the human IgG1 Fc domain sequence is sequence number 25, where X1 is V or A; X2 is M or L; and X3 is N or S. 1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKX1EP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV X2HEALHX3HYT QKSLSLSPGK (Sequence ID 25)

[0079] In some embodiments, the human IgG1 Fc domain sequence is sequence number 26, where X1 is K or R; X2 is D or E; and X3 is L or M. 1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKX1VEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPSRX2E 241 X3TKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (Sequence ID 26)

[0080] In some embodiments, the SIRP antibody includes an Fc domain, and the Fc domain of the SIRP antibody is human IgG4 Fc. Exemplary human IgG4 heavy chain Fc domain sequences are provided as SEQ ID NOs: 34-35, 37, 82-85, and 87. ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(Sequence ID 34) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(Sequence ID 35) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(Sequence ID 82) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(Sequence ID 83) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEALGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(Sequence ID 84) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(Sequence ID 85) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(Sequence ID 87)

[0081] In some embodiments, the human IgG4 Fc domain sequence is sequence number 37, where X1 is S or P; and X2 is L or E. ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPX1CPAPEFX2GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(Sequence ID 37)

[0082] In some embodiments, the SIRP antibody provided herein is a chimeric antibody comprising a variable region from one species and a constant region from another species, for example, a human variable region and a rat constant region. In some embodiments, the rat constant region is rat IgG1 or IgG2b. In some embodiments, the rat constant region is 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 IgG2a. In some embodiments, the antibody comprises a human variable region and a human constant region. In exemplary embodiments, the human constant region is human IgG1 or human IgG4.

[0083] The EU numbering scheme is one of many available antibody numbering schemes based on residue numbers assigned to canonical antibody sequences. Therefore, those skilled in the art will understand that a reference to a particular residue using the EU numbering scheme may or may not be accurate to one of the residues in the SIRP antibody of this disclosure. For example, if the SIRP antibody of this disclosure contains a V215A substitution in Fc (where the amino acid residue position number is according to the EU numbering scheme), the residue may not be the actual residue 215 in that particular SIRP antibody. It could be the actual residue number 213, or 214, or 215, or 216, or any other. Therefore, those skilled in the art will understand how to correspond the residues enumerated using the EU numbering scheme to the actual residues in the SIRP antibody of this disclosure. The EU numbering scheme for antibodies is known in the art and can be found, for example, at imgt.org / IMGTScientificChart / Numbering / Hu_IGHGnber.html.

[0084] In some embodiments, the Fc domain of the SIRP antibody is an IgG1 Fc domain (e.g., SEQ ID NOs: 3-4, 19-22, or 25-26) or an IgG4 human Fc domain (e.g., SEQ ID NOs: 34, 35, or 37), and is represented by 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, 26 The amino acid substitution includes at least one amino acid substitution at a position selected from the group consisting of 9, 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, the position number of this amino acid residue being in the EU numbering scheme.

[0085] In some embodiments, the Fc domain of the SIRP antibody includes, for example, SEQ ID NOs: 3-4, 19-22, or 25-26, and optionally one or more Fc amino acid substitutions, 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 The amino acid residue includes at least one amino acid substitution at a position selected from the group consisting of 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, the position number of which amino acid residue is in accordance with the EU numbering scheme. Examples of substitutions include one or more of K214R, V215A, G236A, S239D, I332E, D356E, L358M, M428L, and N434S, the position number of which amino acid residue is in accordance with the EU numbering scheme.

[0086] In some embodiments, the Fc domain of the SIRP antibody is human IgG1 (e.g., SEQ ID NOs: 3-4, 19-22, or 25-26), and includes V215A, G236A, S239D, I332E, G236A / S239D, G236A / I332E, S239D / I332E, G236A / S239D / I332E, K326W / E333S, S267E / H268F / S324T, and E345R / E430G / S440Y, F24 Substitutions selected from the group consisting of 3L / R292P / Y300L / V305I / P396L, S239D / I332E, S298A / E333A / K334A, L234Y / L235Q / G236W / S239M / H268D / D270E / S298A, and D270E / K326D / A330M / K334E are introduced to enhance effector function, and the positional numbers of these amino acid residues are in accordance with the EU numbering scheme.

[0087] In some embodiments, the Fc domain of the SIRP antibody is human IgG4 (e.g., SEQ ID NOs: 3-4, 19-22, or 25-26), and substitutions including one or more of N297A, N297Q, N297G, L235E, L234A, L235A, K214R, D356E, and L358M are introduced to reduce effector function, with the positional numbers of these amino acid residues being those of the EU numbering scheme.

[0088] In some embodiments, the Fc domain of the SIRP antibody is human IgG4 (e.g., SEQ ID NOs: 34, 35, or 37), and substitutions including L235E and one or more of F234A / L235A are introduced to reduce effector function, with the positional numbering of these amino acid residues being in the EU numbering scheme.

[0089] In some embodiments, the Fc domain of the SIRP antibody is human IgG2, and substitutions including H268Q / V309L / A330S / P331S and V234A / G237A / P238S / H268A / V309L / A330S / P331S are introduced to reduce effector function, and the positional numbers of these amino acid residues are according to the EU numbering scheme.

[0090] In some embodiments, the Fc domain of the SIRP antibody is the IgG4 human Fc domain (e.g., SEQ ID NO: 34, 35, or 37), and the antibody is susceptible to the dynamic process of Fab-arm exchange. Therefore, in some embodiments, the IgG4 Fc domain includes an S228P substitution that reduces this process, and the position number of this amino acid residue is according to the EU numbering scheme.

[0091] In some embodiments, the Fc domain of the SIRP antibody is human IgG4 (e.g., SEQ ID NOs: 34, 35, or 37), and one or more of the following substitutions are introduced: L235A, L235E, S228P, L235E / S228P, S228P / F234A, S228P / F234A / L235A, where the positional numbering of the amino acid residues is in accordance with the EU numbering scheme.

[0092] In other embodiments, the Fc domain of the SIRP antibody is modified to increase its serum half-life. Such modifications include substitutions of human IgG1, IgG2, IgG3, or IgG4, such as M428L, N343S, T250Q / M428L, M252Y / S254T / T256E, M428L / N434S, S267E / L328F, N325S / L328F, and H433K / N434F, where the positional numbers of these amino acid residues are those of the EU numbering scheme.

[0093] i. SIRP antibody-mediated cell depletion The SIRP antibodies containing the Fc domain provided herein can target various cell types and induce depletion of these cells. An exemplary, non-limiting list of antibodies of this disclosure that exhibit cell depletion includes antibodies 23, 25, and 28-31, provided in Table 11.

[0094] In some embodiments, the SIRP antibody containing the Fc domain provided herein can deplete SIRPγ-expressing cells. In some embodiments, the SIRP antibody provided herein can induce lymphocyte depletion. In some embodiments, the SIRP antibody provided herein can induce depletion of SIRPα-expressing cells and / or SIRPβ1-expressing cells, such as myeloid cells and myeloid progenitor cells, including but not limited to monocytes, macrophages, dendritic cells, mast cells, eosinophils, basophils, and neutrophils. For example, in some embodiments where the SIRP antibody binds to SIRPγ and SIRPα, the SIRP antibody can induce depletion of SIRPα-expressing cells and SIRPγ-expressing cells. For example, in some embodiments where the SIRP antibody binds to SIRPβ1, the SIRP antibody can induce depletion of SIRPβ1-expressing cells and SIRPγ-expressing cells. For example, in some embodiments in which the SIRP antibody binds to SIRPγ, SIRPα, and SIRPβ1, the SIRP antibody can induce depletion of SIRPα-expressing cells, SIRPβ1-expressing cells, and SIRPγ-expressing cells.

[0095] While not bound by any particular theory, it is assumed that the SIRP antigen-binding domain enables the antigen-binding fragment (Fab) of the antibody to bind to SIRP-expressing cells, and that the Fc portion of the antibody induces depletion. Therefore, in some embodiments, cell depletion is accompanied by antibody-dependent cytotoxicity (ADCC). In some embodiments, cell depletion is accompanied by antibody-dependent cytophagocytosis (ADCP). In some embodiments, cell depletion is accompanied by both ADCC and ADCP. The Fc-containing SIRP antibodies of this disclosure include full-length antibodies or antibody fragments that bind to the Fc domain, such as a VH-VL-Fc single-chain antibody.

[0096] ii. Exemplary SIRP antibody-complementarity-determining region (CDR) sequences Sequences for exemplary SIRP antibodies of this disclosure are provided herein. Exemplary CDR-L1, L2, L3, H1, H2, and H3 sequences constituting the SIRP antigen-binding domain are presented in Tables 1-6 below. As referred to below, the light chain variable (VL) domain CDR1 region is referred to as CDR-L1, the VL CDR2 region as CDR-L2, the VL CDR3 region as CDR-L3, the heavy chain variable (VH) domain CDR1 region as CDR-H1, the VH CDR2 region as CDR-H2, and the VH CDR3 region as CDR-H3. Tables 7 and 8 provide exemplary CDR triplets for the light and heavy chains of the SIRPα antibodies of this disclosure. Table 9 provides exemplary CDR combinations of the antibodies of this disclosure.

[0097] [Table 1]

[0098] [Table 2]

[0099] [Table 3]

[0100] [Table 4]

[0101] [Table 5]

[0102] [Table 6]

[0103] [Table 7]

[0104] [Table 8]

[0105] [Table 9]

[0106] In some embodiments, the SIRP antibodies provided herein include one or more amino acid sequences of the CDR sequences provided in Tables 1-6.

[0107] In some embodiments, a SIRP antibody is provided herein, which comprises the following: (a) One of the CDR-L1 amino acid sequences listed in Table 1, sequence numbers 5, 7-8, or 11-18; (b) One of the CDR-L2 amino acid sequences listed in Table 2, either sequence numbers 23-24 or 27-33; (c) One of the CDR-L3 amino acid sequences listed in Table 3, such as sequence numbers 36, 38-39, or 42-49; (d) One of the CDR-H1 amino acid sequences listed in Table 4, sequence numbers 54, 56, or 59-65; (e) Any one of the CDR-H2 amino acid sequences of SEQ ID NOs. 70, 72, or 75-81 listed in Table 5; and / or (f) One of the CDR-H3 amino acid sequences listed in Table 6, number 86, 88-89, or 92-99.

[0108] In some embodiments, a SIRP antibody is provided herein, and the light chain variable domain of the antibody includes the following: (g) CDR-L1 containing any one of the amino acid sequences of SEQ ID NOs. 5, 7-8, or 11-18; (h) CDR-L2 containing any one of the amino acid sequences of SEQ ID NOs. 23-24 or 27-33; and (i) CDR-L3 containing any one of the amino acid sequences of sequence numbers 36, 38-39, or 42-49.

[0109] In some embodiments, a SIRP antibody is provided herein, and the heavy chain variable domain of the antibody includes: (j) CDR-H1 containing any one of the amino acid sequences of SEQ ID NOs. 54, 56, or 59-65; (k) CDR-H2 containing any one of the amino acid sequences of SEQ ID NOs. 70, 72, or 75-81; and (l) CDR-H3 containing any one of the amino acid sequences of sequence numbers 86, 88-89, or 92-99.

[0110] In some embodiments, a SIRP antibody is provided herein, the light chain variable domain of the antibody comprises one of the sequences provided in Tables 1-3, and the heavy chain variable domain of the antibody comprises the following: (m) CDR-H1 containing any one of the amino acid sequences of SEQ ID NOs. 54, 56, or 59-65; (n) CDR-H2 containing any one of the amino acid sequences of SEQ ID NOs. 70, 72, or 75-81; and (o) CDR-H3 containing any one of the amino acid sequences of sequence numbers 86, 88-89, or 92-99.

[0111] In some embodiments, a SIRP antibody is provided herein, the heavy chain variable domain of the antibody comprises one of the sequences provided in Tables 4-6, and the light chain variable domain of the antibody comprises the following: (p) CDR-L1 containing any one of the amino acid sequences of SEQ ID NOs. 5, 7-8, or 11-18; (q) CDR-L2 containing any one of the amino acid sequences of SEQ ID NOs. 23-24 or 27-33; and (r) CDR-L3 containing any one of the amino acid sequences of SEQ ID NOs. 36, 38-39, or 42-49.

[0112] In some embodiments, a SIRP antibody is provided herein, and the light chain of the antibody comprises the following amino acid sequence: a. Sequence ID 5, Sequence ID 23, and Sequence ID 36; b. Sequence IDs 7, 24, and 38; c. Sequence ID 8, Sequence ID 24, and Sequence ID 39; d. Sequence IDs 11, 27, and 42; e. Sequence IDs 12, 28, and 43; f. Sequence IDs 13, 29, and 44; g. Sequence IDs 13, 30, and 45; h. Sequence ID 14, Sequence ID 31, and Sequence ID 46; i. Sequence IDs 15, 31, and 47; j. Sequence IDs 16, 31, and 47; k. Sequence ID 17, Sequence ID 32, and Sequence ID 48, or l. Sequence IDs 18, 33, and 49.

[0113] In some embodiments, a SIRP antibody is provided herein, and the heavy chain of the antibody comprises the following amino acid sequence: a. Sequence IDs 54, 70, and 86; b. Sequence IDs 54, 72, and 88; c. Sequence IDs 56, 72, and 89; d. Sequence IDs 59, 75, and 92; e. Sequence IDs 60, 76, and 93; f. Sequence IDs 61, 76, and 94; g. Sequence IDs 62, 77, and 95; h. Sequence ID 63, Sequence ID 78, and Sequence ID 96; i. Sequence IDs 62, 79, and 97; j. Sequence IDs 62, 79, and 97; k. Sequence ID 64, Sequence ID 80, and Sequence ID 98, or l. Sequence IDs 65, 81, and 99. In some embodiments, a SIRP antibody is provided herein, and the antibody comprises the following amino acid sequence: a. Sequence IDs 5, 23, 36, 54, 70, and 86; b. Sequence IDs 7, 24, 38, 54, 72, and 88; c. Sequence IDs 8, 24, 39, 56, 72, and 89; d. Sequence IDs 11, 27, 42, 59, 75, and 92; e. Sequence IDs 12, 28, 43, 60, 76, and 93; f. Sequence IDs 13, 29, 44, 61, 76, and 94; g. Sequence IDs 13, 30, 45, 62, 77, and 95; h. Sequence IDs 14, 31, 46, 63, 78, and 96; i. Sequence IDs 15, 31, 47, 62, 79, and 97; j. Sequence IDs 16, 31, 47, 62, 79, and 97; k. Sequence ID 17, Sequence ID 32, Sequence ID 48, Sequence ID 64, Sequence ID 80, and Sequence ID 98, or l. Sequence IDs 18, 33, 49; 65, 81, and 99.

[0114] iv. Exemplary SIRP antibody-variable region sequence The terms variable region and variable domain are used interchangeably and refer to the light and heavy chain portions of an antibody, including the complementarity-determining region and the framework region (FR).

[0115] Table 10 provides amino acid sequences for the variable domains of exemplary SIRP antibodies of the present disclosure. Accordingly, in some embodiments, the SIRP antibodies of the present disclosure include a variable heavy chain comprising an amino acid sequence selected from SEQ ID NOs. 104, 106-107, and 110-118, or having at least 80% identity thereto. In some embodiments, the SIRP antibodies of the present disclosure include a variable light chain comprising an amino acid sequence selected from SEQ ID NOs. 123, 125-126, and 129-137, or having at least 80% identity thereto. In some embodiments, the SIRP antibodies of the present disclosure include a variable heavy chain comprising an amino acid sequence selected from SEQ ID NOs. 104, 106-107, and 110-118, or having at least 80% identity thereto, and a variable light chain comprising an amino acid sequence selected from SEQ ID NOs. 123, 125-126, and 129-137, or having at least 80% identity thereto.

[0116] In some embodiments, the SIRP antibody of this disclosure comprises one combination of VH / VL variable chain sequences from antibodies 1, 3-4, and 7-15 presented in Table 10.

[0117] [Table 10-1] [Table 10-2]

[0118] In some embodiments, a SIRP antibody is disclosed herein, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 104 or an amino acid sequence having at least 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 the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 123 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 104, and the light chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 123. In some embodiments, the light chain variable domain includes the CDR sequences of SEQ ID NOs: 5, 23, and 36, and the heavy chain variable domain includes the CDR sequences of SEQ ID NOs: 54, 70, and 86.

[0119] In some embodiments, a SIRP antibody is disclosed herein, the heavy chain variable domain of the antibody comprising the amino acid sequence of SEQ ID NO: 106 or an amino acid sequence having at least 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 the light chain variable domain of the antibody comprising the amino acid sequence of SEQ ID NO: 125 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 106, and the light chain variable domain of the antibody includes SEQ ID NO: 125. In some embodiments, the light chain variable domain includes the CDR sequences of SEQ ID NOs: 7, 24, and 38, and the heavy chain variable domain includes the CDR sequences of SEQ ID NOs: 54, 72, and 88.

[0120] In some embodiments, a SIRP antibody is disclosed herein, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 107 or an amino acid sequence having at least 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 the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 126 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 107, and the light chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 126. In some embodiments, the light chain variable domain includes the CDR sequences of SEQ ID NOs: 8, 24, and 39, and the heavy chain variable domain includes the CDR sequences of SEQ ID NOs: 56, 72, and 89.

[0121] In some embodiments, a SIRP antibody is disclosed herein, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 110 or an amino acid sequence having at least 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 the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 129 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 110, and the light chain variable domain of the antibody includes SEQ ID NO: 129. In some embodiments, the light chain variable domain includes the CDR sequences of SEQ ID NOs: 11, 27, and 42, and the heavy chain variable domain includes the CDR sequences of SEQ ID NOs: 59, 75, and 92.

[0122] In some embodiments, a SIRP antibody is disclosed herein, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 111 or an amino acid sequence having at least 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 the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 130 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 111, and the light chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 130. In some embodiments, the light chain variable domain includes the CDR sequences of SEQ ID NOs: 12, 28, and 43, and the heavy chain variable domain includes the CDR sequences of SEQ ID NOs: 501, 56, 76, and 93.

[0123] In some embodiments, a SIRP antibody is disclosed herein, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 112 or an amino acid sequence having at least 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 the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 131 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 112, and the light chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 131. In some embodiments, the light chain variable domain includes the CDR sequences of SEQ ID NOs: 13, 29, and 44, and the heavy chain variable domain includes the CDR sequences of SEQ ID NOs: 61, 76, and 94.

[0124] In some embodiments, a SIRP antibody is disclosed herein, the heavy chain variable domain of the antibody comprising the amino acid sequence of SEQ ID NO: 113 or an amino acid sequence having at least 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 the light chain variable domain of the antibody comprising the amino acid sequence of SEQ ID NO: 132 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 113, and the light chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 132. In some embodiments, the light chain variable domain includes the CDR sequences of SEQ ID NOs: 13, 30, and 45, and the heavy chain variable domain includes the CDR sequences of SEQ ID NOs: 62, 77, and 95.

[0125] In some embodiments, a SIRP antibody is disclosed herein, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 114 or an amino acid sequence having at least 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 the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 133 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 114, and the light chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 133. In some embodiments, the light chain variable domain includes the CDR sequences of SEQ ID NOs: 14, 31, and 46, and the heavy chain variable domain includes the CDR sequences of SEQ ID NOs: 63, 78, and 96.

[0126] In some embodiments, a SIRP antibody is disclosed herein, the heavy chain variable domain of the antibody comprising the amino acid sequence of SEQ ID NO: 115 or an amino acid sequence having at least 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 the light chain variable domain of the antibody comprising the amino acid sequence of SEQ ID NO: 134 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 115, and the light chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 134. In some embodiments, the light chain variable domain includes the CDR sequences of SEQ ID NOs: 15, 31, and 47, and the heavy chain variable domain includes the CDR sequences of SEQ ID NOs: 62, 79, and 97.

[0127] In some embodiments, a SIRP antibody is disclosed herein, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 116 or an amino acid sequence having at least 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 the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 135 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 116, and the light chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 135. In some embodiments, the light chain variable domain includes the CDR sequences of SEQ ID NOs: 16, 31, and 47, and the heavy chain variable domain includes the CDR sequences of SEQ ID NOs: 62, 79, and 97.

[0128] In some embodiments, a SIRP antibody is disclosed herein, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 117 or an amino acid sequence having at least 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 the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 136 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 117, and the light chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 136. In some embodiments, the light chain variable domain includes the CDR sequences of SEQ ID NOs: 17, 32, and 48, and the heavy chain variable domain includes the CDR sequences of SEQ ID NOs: 64, 80, and 98.

[0129] In some embodiments, a SIRP antibody is disclosed herein, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 118 or an amino acid sequence having at least 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 the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 137 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 118, and the light chain variable domain of the antibody includes the amino acid sequence of SEQ ID NO: 137. In some embodiments, the light chain variable domain includes the CDR sequences of SEQ ID NOs: 18, 33, and 49, and the heavy chain variable domain includes the CDR sequences of SEQ ID NOs: 65, 81, and 99.

[0130] Table 11 provides exemplary full-length SIRP antibodies of this disclosure.

[0131] [Table 11]

[0132] B. Generation of SIRP antibody The production of antibodies provided herein is obtained by using any method known to those skilled in the art. In some embodiments, the antibodies are produced by hybridomas. In some embodiments, the antibodies are encoded by nucleic acids and expressed, purified, and isolated.

[0133] The terms polynucleotide and nucleic acid are used interchangeably herein and refer to polymeric forms of nucleotides of any length, which may be ribonucleotides or deoxyribonucleotides. This term includes, but is not limited to, single-stranded, double-stranded, or multi-strand DNA or RNA, genomic DNA, cDNA, DNA-RNA hybrids, or polymers containing purine and pyrimidine bases or other natural, chemically or biochemically modified, unnatural, or derivative nucleotide bases. Unless otherwise specified, this term encompasses nucleic acids containing known analogues of natural nucleotides, possessing similar binding properties, and being metabolized in a similar manner to natural nucleotides.

[0134] Accordingly, nucleic acids encoding any of the antibodies disclosed herein, vectors comprising any of the nucleic acids encoding such antibodies, and host cells comprising any such vector are provided herein. Exemplary nucleic acid sequences encoding the variable heavy chain and variable light chain of the SIRP antibodies disclosed herein are also provided herein.

[0135] Table 12 provides exemplary nucleic acid sequences for the SIRP antibody of the present disclosure. Accordingly, in some embodiments, the nucleic acid sequence encoding the SIRP antibody of the present disclosure includes a variable heavy chain nucleic acid sequence selected from SEQ ID NOs. 142, 144-145, and 148-156, or having at least 80% identity thereto. In some embodiments, the nucleic acid sequence encoding the SIRP antibody of the present disclosure includes a variable light chain nucleic acid sequence selected from SEQ ID NOs. 161, 163-164, and 167-175, or having at least 80% identity thereto. In some embodiments, the nucleic acid sequence encoding the SIRP antibody of the present disclosure includes a variable heavy chain nucleic acid sequence selected from SEQ ID NOs. 142, 144-145, and 148-156, or having at least 80% identity thereto, and a variable light chain nucleic acid sequence selected from SEQ ID NOs. 161, 163-164, and 167-175, or having at least 80% identity thereto. Those skilled in the art will understand that, due to redundancy in triplet coding, multiple nucleic acids may encode the same amino acid sequence. Therefore, nucleic acid sequences that are not identical to those listed in Table 12 may still encode the amino acid sequences listed in Table 10.

[0136] [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4]

[0137] In some embodiments, nucleic acids encoding any of the SIRP antibodies disclosed herein are provided herein. In some embodiments, nucleic acids comprising one or more of the nucleic acid sequences in Table 12 are provided herein. In some embodiments, the heavy chain variable domain and light chain variable domain of the SIRP antibodies disclosed herein are encoded by nucleic acids comprising one or more of the nucleic acid sequences in Table 12.

[0138] In some embodiments, the heavy chain variable domain of the SIRP antibody of the Disclosure is encoded by the nucleic acid sequence of SEQ ID NO: 142 or a nucleic acid sequence having at least 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 the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 161 or a nucleic acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 142, or a nucleic acid sequence having at least 97% sequence identity thereto, and / or the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 161, or a nucleic acid sequence having at least 97% sequence identity thereto.

[0139] In some embodiments, the heavy chain variable domain of the SIRP antibody of the Disclosure is encoded by the nucleic acid sequence of SEQ ID NO: 144 or a nucleic acid sequence having at least 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 the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 163 or a nucleic acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 144, or a nucleic acid sequence having at least 97% sequence identity thereto, and / or the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 163, or a nucleic acid sequence having at least 97% sequence identity thereto.

[0140] In some embodiments, the heavy chain variable domain of the SIRP antibody of the Disclosure is encoded by the nucleic acid sequence of SEQ ID NO: 145 or a nucleic acid sequence having at least 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 the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 164 or a nucleic acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 145, or a nucleic acid sequence having at least 97% sequence identity thereto, and / or the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 164, or a nucleic acid sequence having at least 97% sequence identity thereto.

[0141] In some embodiments, the heavy chain variable domain of the SIRP antibody of the Disclosure is encoded by the nucleic acid sequence of SEQ ID NO: 148 or a nucleic acid sequence having at least 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 the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 167 or a nucleic acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 148, or a nucleic acid sequence having at least 97% sequence identity thereto, and / or the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 167, or a nucleic acid sequence having at least 97% sequence identity thereto.

[0142] In some embodiments, the heavy chain variable domain of the SIRP antibody of this disclosure is encoded by the nucleic acid sequence of SEQ ID NO: 149 or a nucleic acid sequence having at least 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 the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 168 or a nucleic acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 149, or a nucleic acid sequence having at least 97% sequence identity thereto, and / or the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 168, or a nucleic acid sequence having at least 97% sequence identity thereto.

[0143] In some embodiments, the heavy chain variable domain of the SIRP antibody of the Disclosure is encoded by the nucleic acid sequence of SEQ ID NO: 150 or a nucleic acid sequence having at least 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 the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 169 or a nucleic acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 150, or a nucleic acid sequence having at least 97% sequence identity thereto, and / or the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 169, or a nucleic acid sequence having at least 97% sequence identity thereto.

[0144] In some embodiments, the heavy chain variable domain of the SIRP antibody of the Disclosure is encoded by the nucleic acid sequence of SEQ ID NO: 151 or a nucleic acid sequence having at least 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 the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 170 or a nucleic acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 151, or a nucleic acid sequence having at least 97% sequence identity thereto, and / or the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 170, or a nucleic acid sequence having at least 97% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 151, and the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 170.

[0145] In some embodiments, the heavy chain variable domain of the SIRP antibody of the Disclosure is encoded by the nucleic acid sequence of SEQ ID NO: 152 or a nucleic acid sequence having at least 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 the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 171 or a nucleic acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 152, or a nucleic acid sequence having at least 97% sequence identity thereto, and / or the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 171, or a nucleic acid sequence having at least 97% sequence identity thereto.

[0146] In some embodiments, the heavy chain variable domain of the SIRP antibody of the Disclosure is encoded by the nucleic acid sequence of SEQ ID NO: 1532 or a nucleic acid sequence having at least 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 the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 172 or a nucleic acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 153, or a nucleic acid sequence having at least 97% sequence identity thereto, and / or the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 1721, or a nucleic acid sequence having at least 97% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 153, and the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 172.

[0147] In some embodiments, the heavy chain variable domain of the SIRP antibody of the Disclosure is encoded by the nucleic acid sequence of SEQ ID NO: 154 or a nucleic acid sequence having at least 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 the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 173 or a nucleic acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 154, or a nucleic acid sequence having at least 97% sequence identity thereto, and / or the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 173, or a nucleic acid sequence having at least 97% sequence identity thereto.

[0148] In some embodiments, the heavy chain variable domain of the SIRP antibody of the Disclosure is encoded by the nucleic acid sequence of SEQ ID NO: 155 or a nucleic acid sequence having at least 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 the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 174 or a nucleic acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 155, or a nucleic acid sequence having at least 97% sequence identity thereto, and / or the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 174, or a nucleic acid sequence having at least 97% sequence identity thereto.

[0149] In some embodiments, the heavy chain variable domain of the SIRP antibody of the present disclosure is encoded by the nucleic acid sequence of SEQ ID NO: 156 or a nucleic acid sequence having at least 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 the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 175 or a nucleic acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 156, or a nucleic acid sequence having at least 97% sequence identity thereto, and / or the light chain variable domain of the antibody is encoded by the nucleic acid sequence of SEQ ID NO: 175, or a nucleic acid sequence having at least 97% sequence identity thereto.

[0150] This disclosure also provides vectors comprising any nucleic acid of this disclosure. In some embodiments, the nucleic acid of the vector comprises one or more nucleic acid sequences selected from Table 12. In some embodiments, the vector is an expression vector or expression construct. In some embodiments, the vector is a mammalian vector. In some embodiments, the vector is a viral vector.

[0151] In some embodiments, the SIRP antibody provided herein is produced by culturing cells under conditions suitable for inducing SIRP antibody expression, and these cells contain a vector.

[0152] II. Use of SIRP antibodies A. SIRP antibody-mediated cell depletion A method for inducing cell depletion is provided herein, comprising contacting cells with one of the Fc-containing SIRP antibodies of this disclosure. The method can be performed in vitro or in vivo. In some embodiments, cell depletion is accompanied by ADCC. In some embodiments, cell depletion is accompanied by ADCP. In some embodiments, cell depletion is accompanied by both ADCC and ADCP.

[0153] In some embodiments, the cells are SIRPγ-expressing cells. In some embodiments, the cells include a first population of SIRPγ-expressing cells and a second population of SIRPα-expressing cells and / or SIRPβ1-expressing cells. In some embodiments, the cells include a first population of SIRPγ-expressing cells, a second population of SIRPα-expressing cells, and a third population of SIRPβ1-expressing cells.

[0154] In some embodiments, SIRPγ-expressing cells include lymphocytes. In some embodiments, lymphocytes include B cells, T cells, or natural killer (NK) cells. In some embodiments, SIRPγ-expressing cells are T cells. In some embodiments, T cells are cytotoxic T cells, helper T cells, memory T cells, regulatory T cells, natural killer T cells, mucosa-associated invariant T cells, or gamma delta T cells. In some embodiments, SIRPγ-expressing cells are NK cells. In some embodiments, SIRPγ-expressing cells are activated T cells or activated NK cells. In some embodiments, SIRPγ-expressing cells are fibroblasts. In some embodiments, SIRPγ-expressing cells are not myeloid cells. Markers for identifying T cells, NK cells, and B cells, as well as specific populations of T cells, will be known to those skilled in the art. For example, cytotoxic T cells express CD8, helper T cells express CD4, regulatory T cells express CD4 as well as additional markers, such as CTLA-4, CCR4, or CXCR4, and memory T cells express CD8 as well as CD95. B cells express IgM and CD19, and activated B cells express CD19, CD25, and CD30. NK cells can be identified based on high CD56 expression.

[0155] In some embodiments, SIRPα-expressing cells are myeloid cells. Myeloid, or myeloid cells, are blood cells arising from progenitor cells for granulocytes or monocytes. In some embodiments, SIRPα-expressing cells are monocytes, macrophages, dendritic cells, mast cells, eosinophils, basophils, and neutrophils. In some embodiments, SIRPα-expressing cells are myeloid progenitor cells.

[0156] In some embodiments, SIRPβ1-expressing cells are myeloid cells. In some embodiments, SIRPβ1-expressing cells are granulocytes, such as eosinophils or neutrophils. In some embodiments, SIRPβ1-expressing cells are monocytes. In some embodiments, monocytes are classical, intermediate, non-classical, or a combination thereof. In some embodiments, SIRPβ1-expressing cells are macrophages. In some embodiments, SIRPβ1-expressing cells are Kupffer cells or Hofbauer cells. In some embodiments, SIRPβ1-expressing cells are dendritic cells. In some embodiments, SIRPβ1-expressing cells are alveolar cells.

[0157] In some embodiments, depleted cells include lymphocytes. In some embodiments, for example, those embodiments in which the antibody is specific to SIRPγ and SIRPα and / or SIRPβ1, depleted cells include lymphocytes and at least one other cell type. In some embodiments, depleted cells include lymphocytes and myeloid cells. In some embodiments, depleted cells include lymphocytes and granulocytes, monocytes and / or dendritic cells. In some embodiments, cell depletion is antibody dose-dependent. Exemplary antibodies of the disclosure that induce cell depletion include antibodies 23, 25, and 28-31, which are referred to in Table 11.

[0158] Methods for depleting a population of cells in a subject, comprising administering the subject one of the Fc-containing SIRP antibodies of this disclosure, are also disclosed herein. Exemplary antibodies of this disclosure that exhibit such effects include antibodies 23 and 28-31, as referred to in Table 11. In some embodiments, cell depletion is accompanied by ADCC. In some embodiments, cell depletion is accompanied by ADCP. In some embodiments, cell depletion is accompanied by ADCC and ADCP. In some embodiments, the cells include SIRPγ-expressing cells. In some embodiments, the SIRPγ-expressing cells include lymphocytes. In some embodiments, the lymphocytes include B cells, T cells, or NK cells. In some embodiments, the cells further include SIRPα-expressing cells. In some embodiments, the SIRPα-expressing cells are myeloid cells. In some embodiments, the SIRPα-expressing myeloid cells are monocytes, macrophages, dendritic cells, mast cells, eosinophils, basophils, or neutrophils. In some embodiments, the SIRPα-expressing cells are myeloid progenitor cells. In some embodiments, the cells are not SIRPα-expressing cells, such as lymphocytes, but are depleted by the SIRP antibody of this disclosure. In some embodiments, the cells include SIRPβ1-expressing cells. In some embodiments, the SIRPβ1-expressing cells include myeloid cells. In some embodiments, the SIRPβ1-expressing cells include granulocytes, monocytes, macrophages, or dendritic cells. In some embodiments, the granulocytes are eosinophils, basophils, or neutrophils. In some embodiments, the SIRPβ1-expressing cells include macrophages. In some embodiments, the SIRPβ1-expressing cells include Kupffer cells or Hofbauer cells. In some embodiments, the cells are tissue-resident cells. In some embodiments, the cells are circulating cells. In some embodiments, cell depletion is antibody dose-dependent.

[0159] In some embodiments, the method induces ADCC in vitro, and the SIRP 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%. Exemplary antibodies of the disclosure that exhibit such effects include antibodies 23, 28, and 31-32, which are referenced in Table 11.

[0160] In some embodiments, the method induces ADCP in vitro, and the SIRP 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%. Exemplary antibodies of the disclosure that exhibit such effects include antibodies 23, 25, and 28-31, which are referenced in Table 11.

[0161] In some embodiments, the method yields ADCC and / or ADCP in vitro, and the SIRP antibody increases ADCC and / or 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%. Exemplary antibodies of the disclosure that exhibit such effects include antibodies 23, 25, and 28-32, which are referenced in Table 11.

[0162] In some embodiments, the SIRP antibody of the present disclosure induces ADCC in SIRPγ-expressing lymphocytes in vitro. In some embodiments, ADCC increases 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%.

[0163] In some embodiments, the SIRP antibody of the Disclosure induces ADCP in SIRPγ-expressing lymphocytes in vitro. In some embodiments, ADCP increases 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%.

[0164] In some embodiments, the SIRP antibody of this disclosure induces ADCC and ADCP in SIRPγ-expressing lymphocytes in vitro. In some embodiments, ADCC and / or ADCP are increased 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%.

[0165] In some embodiments, the SIRP antibody of this disclosure induces ADCC in SIRPγ-expressing T cells in vitro. In some embodiments, ADCC increases 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%.

[0166] In some embodiments, the SIRP antibody of the present disclosure induces ADCP in SIRPγ-expressing T cells in vitro. In some embodiments, ADCP increases 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%.

[0167] In some embodiments, the SIRP antibody of this disclosure induces ADCC and / or ADCP in SIRPγ-expressing T cells in vitro. In some embodiments, ADCC and / or ADCP are increased 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%.

[0168] In some embodiments, the SIRP antibody of this disclosure induces ADCC in SIRPγ-expressing NK cells in vitro. In some embodiments, ADCC increases 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%.

[0169] In some embodiments, the SIRP antibody of the present disclosure induces ADCP in SIRPγ-expressing NK cells in vitro. In some embodiments, ADCP increases 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%.

[0170] In some embodiments, the SIRP antibody of this disclosure induces ADCC and / or ADCP in SIRPγ-expressing NK cells in vitro. In some embodiments, ADCC and ADCP are increased 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%.

[0171] In some embodiments, the SIRP antibody binds to SIRPα and also induces ADCC in SIRPα-expressing cells in vitro. In some embodiments, ADCC increases 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%.

[0172] In some embodiments, the SIRP antibodies of this disclosure are also specific to SIRPα and induce ADCC in SIRPα-expressing myeloid cells in vitro. Exemplary antibodies of the disclosure that exhibit such effects include antibodies 23, 28, and 31-32, which are referenced in Table 11. In some embodiments, ADCC increases 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%.

[0173] In some embodiments, the SIRP antibodies of this disclosure are also specific to SIRPα and induce ADCP in SIRPα-expressing myeloid cells in vitro. Exemplary antibodies of the disclosure that exhibit such effects include antibodies 23, 25, and 28-31, which are referenced in Table 11. In some embodiments, ADCP increases 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%.

[0174] In some embodiments, the SIRP antibodies of this disclosure are also specific to SIRPα and induce ADCP and ADCC in SIRPα-expressing myeloid cells in vitro. Exemplary antibodies of the disclosure that exhibit such effects include antibodies 23, 25, and 28-32, which are referenced in Table 11. In some embodiments, ADCC and / or ADCP are increased 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%.

[0175] In some embodiments, the SIRP antibodies of this disclosure are also specific to SIRPα and induce ADCC in SIRPα-expressing monocytes in vitro. Exemplary antibodies of the disclosure that exhibit such effects include antibodies 23, 28, 31-32, which are referenced in Table 11. In some embodiments, ADCC increases 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%.

[0176] In some embodiments, the SIRP antibodies of this disclosure are also specific to SIRPα and induce ADCP in SIRPα-expressing monocytes in vitro. Exemplary antibodies of the disclosure that exhibit such effects include antibodies 23, 25, and 28-31, which are referenced in Table 11. In some embodiments, ADCP increases 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%.

[0177] In some embodiments, the SIRP antibodies of this disclosure are also specific to SIRPα and induce ADCC and ADCP in SIRPα-expressing monocytes in vitro. Exemplary antibodies of the disclosure that exhibit such effects include antibodies 23, 25, and 28-32, which are referenced in Table 11. In some embodiments, ADCC and / or ADCP are increased 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%.

[0178] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPα and induces ADCC in SIRPα-expressing myeloid progenitor cells in vitro. In some embodiments, ADCC is increased 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%.

[0179] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPα and also induces ADCP in SIRPα-expressing myeloid progenitor cells in vitro. In some embodiments, ADCP is increased 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%.

[0180] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPα and also induces ADCC and ADCP in SIRPα-expressing myeloid progenitor cells in vitro. In some embodiments, ADCC and / or ADCP are increased 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%.

[0181] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPα and also induces ADCC in SIRPα-expressing macrophages in vitro. In some embodiments, ADCC is increased 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%.

[0182] In some embodiments, the SIRP antibody of the Disclosure induces ADCP in SIRPα-expressing macrophages in vitro. In some embodiments, ADCP is increased 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%.

[0183] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPα and also induces ADCC and ADCP in SIRPα-expressing macrophages in vitro. In some embodiments, ADCC and / or ADCP are increased 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%.

[0184] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPα and also induces ADCC in SIRPα-expressing dendritic cells in vitro. In some embodiments, ADCC is increased 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%.

[0185] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPα and also induces ADCP in SIRPα-expressing dendritic cells in vitro. In some embodiments, ADCP is increased 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%.

[0186] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPα and also induces ADCC and ADCP in SIRPα-expressing dendritic cells in vitro. In some embodiments, ADCC and / or ADCP are increased 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%.

[0187] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPα and also induces ADCC of SIRPα-expressing basophils in vitro. In some embodiments, ADCC is increased 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%.

[0188] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPα and also induces ADCP in SIRPα-expressing basophils in vitro. In some embodiments, ADCP is increased 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%.

[0189] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPα and also induces ADCC and ADCP in SIRPα-expressing basophils in vitro. In some embodiments, ADCC and / or ADCP are increased 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%.

[0190] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPα and also induces ADCC in SIRPα-expressing neutrophils in vitro. In some embodiments, ADCC is increased 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%.

[0191] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPα and also induces ADCP in SIRPα-expressing neutrophils in vitro. In some embodiments, ADCP is increased 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%.

[0192] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPα and also induces ADCC and ADCP in SIRPα-expressing neutrophils in vitro. In some embodiments, ADCC and / or ADCP are increased 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%.

[0193] In some embodiments, the SIRP antibody of the present disclosure is also specific to SIRPα and also induces ADCC in SIRPα-expressing eosinophils in vitro. In some embodiments, ADCC increases 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%.

[0194] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPα and also induces ADCP in SIRPα-expressing eosinophils in vitro. In some embodiments, ADCP increases 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%.

[0195] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPα and also induces ADCC and ADCP in SIRPα-expressing eosinophils in vitro. In some embodiments, ADCC and / or ADCP are increased 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%.

[0196] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPα and also induces ADCC in SIRPα-expressing mast cells in vitro. In some embodiments, ADCC is increased 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%.

[0197] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPα and also induces ADCP in SIRPα-expressing mast cells in vitro. In some embodiments, ADCP is increased 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%.

[0198] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPα and also induces ADCC and ADCP in SIRPα-expressing mast cells in vitro. In some embodiments, ADCC and / or ADCP are increased 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%.

[0199] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPβ1 and also induces ADCC and / or ADCP in SIRPβ1-expressing cells in vitro. In some embodiments, ADCC and / or ADCP are increased 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%.

[0200] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPβ1 and also induces ADCC and / or ADCP in SIRPβ1-expressing myeloid cells in vitro. In some embodiments, ADCC and / or ADCP are increased 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%.

[0201] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPβ1 and also induces ADCC and / or ADCP in SIRPβ1-expressing granulocytes in vitro. In some embodiments, ADCC and / or ADCP are increased 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%. In some embodiments, the granulocytes are eosinophils, neutrophils, or a combination thereof.

[0202] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPβ1 and also induces ADCC and / or ADCP in SIRPβ1-expressing monocytes in vitro. In some embodiments, ADCC and / or ADCP are increased 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%. In some embodiments, the monocytes are classical, intermediate, non-classical, or a combination thereof.

[0203] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPβ1 and also induces ADCC and / or ADCP in SIRPβ1-expressing dendritic cells in vitro. In some embodiments, ADCC and / or ADCP are increased 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%.

[0204] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPβ1 and also induces ADCC and / or ADCP in SIRPβ1-expressing macrophages in vitro. In some embodiments, ADCC and / or ADCP are increased 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%.

[0205] In some embodiments, the SIRP antibody of this disclosure induces antibody-mediated depletion of cells, causing these cells to either not express SIRPα or to express SIRPα only under specific physiological conditions, such as when activated (e.g., activated lymphocytes). In some embodiments, the SIRP antibody of this disclosure induces antibody-mediated depletion of cells, causing these cells to either not express SIRPβ1 or to express SIRPβ1 only under specific physiological conditions. In some embodiments, the SIRP antibody of this disclosure induces ADCC in lymphocytes in vitro. In some embodiments, the SIRP antibody of this disclosure induces ADCP in lymphocytes in vitro. In some embodiments, the SIRP antibody of this disclosure induces both ADCC and ADCP in lymphocytes in vitro. In some embodiments, ADCC and / or ADCP increase 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%.

[0206] In some embodiments, the method results in in vivo ADCC, and the SIRP 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%.

[0207] In some embodiments, the method results in in vivo ADCP, and the SIRP 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%.

[0208] In some embodiments, the method results in ADCC and / or ADCP in vivo, and the SIRP antibody increases ADCC and / or 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%.

[0209] In some embodiments, the method results in in vivo cell depletion, and the SIRP 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%. Exemplary antibodies of this disclosure that exhibit such effects include antibodies 23 and 28-31, as referred to in Table 11.

[0210] In some embodiments, the SIRP antibody of this disclosure induces cell depletion (e.g., ADCC and / or ADCP) of SIRPγ-expressing cells in vivo. In some embodiments, the cell depletion increases 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%.

[0211] In some embodiments, the SIRP antibody of this disclosure induces in vivo cell depletion of SIRPγ-expressing lymphocytes (e.g., ADCC and / or ADCP). In some embodiments, the cell depletion increases 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%.

[0212] In some embodiments, the SIRP antibody of this disclosure induces in vivo cell depletion of SIRPγ-expressing T cells (e.g., ADCC and / or ADCP). In some embodiments, the cell depletion increases 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%.

[0213] In some embodiments, the SIRP antibody of this disclosure induces in vivo cell depletion of SIRPγ-expressing NK cells (e.g., ADCC and / or ADCP). In some embodiments, the cell depletion increases 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%.

[0214] In some embodiments, the SIRP antibodies of this disclosure are also specific to SIRPα and induce cell depletion of SIRPα-expressing myeloid cells in vivo (e.g., ADCC and / or ADCP). Exemplary antibodies of this disclosure that exhibit such effects include antibodies 23 and 28-31, as referred to in Table 11. In some embodiments, cell depletion increases 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%.

[0215] In some embodiments, the SIRP antibodies of this disclosure are also specific to SIRPα and induce cell depletion of SIRPα-expressing monocytes in vivo (e.g., ADCC and / or ADCP). Exemplary antibodies of this disclosure that exhibit such effects include antibodies 23 and 28-31, which are referenced in Table 11. In some embodiments, cell depletion increases 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%.

[0216] In some embodiments, the SIRP antibodies of this disclosure are also specific to SIRPα and induce in vivo cell depletion of SIRPα-expressing neutrophils (e.g., ADCC and / or ADCP). Exemplary antibodies of this disclosure that exhibit such effects include antibodies 23 and 28-31, which are referenced in Table 11. In some embodiments, cell depletion increases 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%.

[0217] In some embodiments, the SIRP antibodies of this disclosure are also specific to SIRPα and induce in vivo cell depletion of SIRPα-expressing eosinophils (e.g., ADCC and / or ADCP). Exemplary antibodies of this disclosure that exhibit such effects include antibodies 23 and 28-31, as mentioned in Table 11. In some embodiments, cell depletion increases 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%.

[0218] In some embodiments, the SIRP antibodies of this disclosure are also specific to SIRPα and induce in vivo cell depletion of SIRPα-expressing basophils (e.g., ADCC and / or ADCP). Exemplary antibodies of this disclosure that exhibit such effects include antibodies 23 and 28-31, as mentioned in Table 11. In some embodiments, cell depletion increases 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%.

[0219] In some embodiments, the SIRP antibodies of the Disclosure are also specific to SIRPα and induce antibody-mediated depletion of cells that do not express SIRPα or express SIRPα only under certain physiological conditions, such as when activated (e.g., activated lymphocytes). Thus, in some embodiments, the SIRP antibodies of the Disclosure induce lymphocyte depletion (e.g., ADCC and / or ADCP) in vivo. Exemplary antibodies of the Disclosure exhibiting such effects include antibodies 23 and 28-31, referenced in Table 11. In some embodiments, cell depletion increases 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%.

[0220] In some embodiments, the SIRP antibody of the present disclosure is also specific to SIRPα and induces cell depletion (e.g., ADCC and / or ADCP) of SIRPα-expressing myeloid progenitor cells in vivo. In some embodiments, the cell depletion increases 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%.

[0221] In some embodiments, the SIRP antibody of the present disclosure is also specific to SIRPα and induces cell depletion of SIRPα-expressing macrophages (e.g., ADCC and / or ADCP) in vivo. In some embodiments, the cell depletion increases 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%.

[0222] In some embodiments, the SIRP antibody of the present disclosure is also specific to SIRPα and induces cell depletion (e.g., ADCC and / or ADCP) of SIRPα-expressing dendritic cells in vivo. In some embodiments, the cell depletion increases 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%.

[0223] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPα and induces cell depletion (e.g., ADCC and / or ADCP) of SIRPα-expressing mast cells in vivo. In some embodiments, the cell depletion increases 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%.

[0224] In some embodiments, the SIRP antibody of the present disclosure is also specific to SIRPβ1 and induces cell depletion (e.g., ADCC and / or ADCP) of SIRPβ1-expressing cells in vivo. In some embodiments, the cell depletion increases 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%.

[0225] In some embodiments, the SIRP antibody of the present disclosure is also specific to SIRPβ1 and induces cell depletion (e.g., ADCC and / or ADCP) of SIRPβ1-expressing myeloid cells in vivo. In some embodiments, the cell depletion increases 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%.

[0226] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPβ1 and induces cell depletion (e.g., ADCC and / or ADCP) of SIRPβ1-expressing granulocytes in vivo. In some embodiments, the cell depletion is increased 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%. In some embodiments, the granulocytes include eosinophils, neutrophils, or a combination thereof.

[0227] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPβ1 and induces cell depletion (e.g., ADCC and / or ADCP) of SIRPβ1-expressing monocytes in vivo. In some embodiments, the cell depletion increases 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%.

[0228] In some embodiments, the SIRP antibody of the present disclosure is also specific to SIRPβ1 and induces cell depletion of SIRPβ1-expressing macrophages (e.g., ADCC and / or ADCP) in vivo. In some embodiments, the cell depletion increases 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%.

[0229] In some embodiments, the SIRP antibody of this disclosure is also specific to SIRPβ1 and induces cell depletion (e.g., ADCC and / or ADCP) of SIRPβ1-expressing dendritic cells in vivo. In some embodiments, the cell depletion increases 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%.

[0230] B. Therapeutic SIRP antibodies As discussed in Section IA above, antibodies that recognize and bind to SIRPα and / or SIRPβ1 in combination with SIRPγ are provided herein. The antibodies disclosed herein may be used as therapeutic agents in subjects.

[0231] Accordingly, in subjects requiring treatment of a disease or condition, methods for treating the disease or condition are provided herein, the methods comprising administering a therapeutically effective amount of the SIRP antibody or its pharmaceutical composition to the subject. 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 subject, such as a cynomolgus monkey.

[0232] i. Treatment of disease / condition In some embodiments, the SIRP antibodies provided herein are useful for depleting a target cell population to treat a disease or condition of interest. In some embodiments, the therapeutic SIRP antibodies provided herein may be used to treat diseases or conditions involving the hyperactivation or hyperproliferation of certain cells, such as SIRPγ-expressing cells (e.g., lymphocytes), as part of the pathology, although they may be used in combination as appropriate with SIRPα and / or SIRPβ1-expressing cells (e.g., myeloid cells).

[0233] In some embodiments, the therapeutically effective dose of the antibody or pharmaceutical composition is sufficient to deplete the target cell population, for example, by ADCC and / or ADCP. In some embodiments, the cells are hyperactivated or hyperproliferating. In some embodiments, the cells are SIRPγ-expressing cells. In some embodiments, the SIRPγ-expressing cells are lymphocytes. In some embodiments, the SIRPγ-expressing lymphocytes are selected from the group consisting of B cells, T cells, and NK cells. In some embodiments, the cells are tissue-resident cells. In other embodiments, the cells are circulating cells. In some embodiments, cell depletion is antibody dose-dependent.

[0234] In some embodiments, the therapeutically effective amount of the antibody or pharmaceutical composition is sufficient to deplete the target SIRPα and / or SIRPβ1 expression population. In some embodiments, the cells are hyperactivated or overproliferating. In some embodiments, the SIRPα and / or SIRPβ1 expressing cells include myeloid cells. In some embodiments, the SIRPα and / or SIRPβ1 expressing cells include monocytes, macrophages, dendritic cells, mast cells, eosinophils, basophils, and neutrophils.

[0235] In some embodiments, the disease or condition is characterized by hyperactivation and / or hyperproliferation of lymphocytes (including lymphoblasts). In some embodiments, the disease or condition is characterized by hyperactivation and / or hyperproliferation of myeloid cells (including myeloid progenitor cells) and other SIRPα and / or SIRPβ1 expressing cells. Exemplary diseases associated with hyperactivation and / or hyperproliferation include, but are not limited to, histiocytic disorders, cytokine release syndromes (CRS), granulomatous diseases, autoimmune disorders, and hematological malignancies.

[0236] In some embodiments, the disease or disorder includes a disease or disorder associated with lymphocytes. In some embodiments, the disease or disorder includes a disease or disorder associated with myeloid cells. In some embodiments, the disease or disorder includes a disease or disorder associated with both lymphocytes and myeloid cells.

[0237] In some embodiments, the disease or disorder includes diseases or disorders related to both lymphocytes and myeloid cells. In some embodiments, the disease or condition is a type of histiocytosis, such as hemophagocytic lymphohistiocytosis (HLH) (including primary and secondary HLH), macrophage activation syndrome, Langerhans cell histiocytosis (LCH), somatic cell histiocytosis, Erdheim-Chester disease (ECD), mixed LCH / ECD, Rosei-Dorfmann disease, malignant histiocytosis, cutaneous non-LCH histiocytosis, juvenile xanthogranuloma, virus-associated HLH, bacteria-associated HLH, parasite-associated HLH, fungal-associated (fungal-inducible) HLH, autoimmune disease-associated HLH, or malignant tumor-induced HLH.

[0238] In some embodiments, the disease or condition is associated with non-Mendelian secondary HLH (sHLH). In some embodiments, such sHLH is infection-related HLH, such as virus-related HLH, bacterial-related HLH, parasite-related HLH, or fungal-related HLH. Examples of virus-related HLH include, but are not limited to, EBV-related HLH, CMV-related HLH, HLH associated with other defined herpesvirus infections, HIV-related HLH, influenza-related HLH, and HLH associated with other viral infections. In exemplary embodiments, infection-related sHLH is associated with coronavirus [e.g., COVID-19, SARS (SARS-CoV), MERS], or Ebola infection. Examples of bacterial-related HLH include Mycobacterium-related HLH. Examples of parasite-related HLH include Leishmania-related or Plasmodium-related HLH. Examples of fungal-induced HLH include Histoplasma-related HLH.

[0239] In other embodiments, such sHLH is malignancy-associated HLH, such as malignancy-induced HLH (HLH at the time of malignancy onset), and includes hematological malignancies [e.g., T-cell lymphoblastic lymphoma / leukemia, T-cell non-lymphoblastic lymphoma, B-cell leukemia, B-cell lymphoma (non-Hodgkin), Hodgkin lymphoma, NK-cell lymphoma / leukemia, myeloid neoplasms, and other hematological malignancies], and solid tumors. In other embodiments, such sHLH is HLH that occurs during chemotherapy (not related to the initial diagnosis of malignancy).

[0240] In other embodiments, such sHLH is associated with a defined rheumatic condition (e.g., macrophage activation syndrome-HLH, or MAS-HLH). These include, but are not limited to, HLH associated with systemic-onset juvenile idiopathic arthritis (SoJIA), HLH associated with adult-onset Still's disease, HLH associated with systemic lupus erythematosus (SLE), HLH associated with vasculitis, HLH associated with rheumatoid arthritis, and HLH associated with other defined autoimmune conditions and HLH associated with undefined autoimmune conditions.

[0241] In other embodiments, such sHLHs are transplant-related HLHs, such as HLHs associated with kidney transplantation or hematological stem cell transplantation.

[0242] In some embodiments, the disease or condition includes sHLH or cytokine release syndrome (CRS). In some embodiments, the disease or condition includes CRS. In some embodiments, sHLH or CRS is associated with iatrogenic immune activation, for example, with checkpoint inhibitors for the treatment of malignant tumors, with T-cell therapy, for example, chimeric antigen receptor T-cell therapy (CAR-T) or T-cell receptor T-cell therapy (TCR-T), with NK cell activation bispecific monoclonal antibody therapy, or with T-cell activation bispecific monoclonal antibody therapy. In other embodiments, such sHLH or CRS is associated with iatrogenic immunosuppression. In other embodiments, sHLH or CRS is associated with viral infection, for example, infection such as COVID-19.

[0243] In other embodiments, the therapeutic SIRP antibodies provided herein are useful for treating granulomatous diseases or conditions, or diseases characterized by the presence of multinucleated giant cells. In some embodiments, granulomatous diseases or conditions, or giant cell diseases or conditions, include sarcoidosis, inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, Takayasu's arteritis, giant cell arteritis, psoriatic arthritis, granulomatosis with polyangiitis (Wegener's granulomatosis), giant cell myocarditis, chronic granulomatous disease, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), or chronic berylliumosis (berylliosis).

[0244] In some embodiments, the disease or condition includes, but is not limited to, T-cell-mediated disorders such as aplastic anemia, cell-mediated rejection of solid organ transplants, graft failure after HSCT (hematopoietic stem cell transplantation), lymphocyte variant eosinophilia, atopic dermatitis, lymphocytic myocarditis, axial spondyloarthritis, celiac disease, or Rasmussen encephalitis.

[0245] In some embodiments, the disease or condition includes a disease or condition characterized by abnormal activity and / or proliferation of granule cells. In some embodiments, granule cells include eosinophils, basophils, mast cells, or neutrophils.

[0246] In some embodiments, the disease or condition includes a disease or condition characterized by abnormal activity and / or proliferation of eosinophils. In some embodiments, the disease or condition includes eosinophilic syndromes (including primary, secondary, and idiopathic), acute eosinophilic pneumonia, chronic eosinophilic pneumonia, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic enteritis, eosinophilic colitis, lymphocyte variant eosinophilia, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), eosinophilic cardiomyopathy / Loeffler endocarditis, Loeffler syndrome, or episodic angioedema / Gleich syndrome with eosinophilia, or lymphocyte variant eosinophilia.

[0247] In some embodiments, the disease or condition includes a disease or condition characterized by abnormal activity and / or proliferation of mast cells. In some embodiments, the disease or condition includes cutaneous mastocytosis, mastocellular colitis, systemic mastocytosis, mast cell activation syndrome, hereditary alpha-tryptemia syndrome, chronic urticaria, or severe allergic conjunctivitis.

[0248] In some embodiments, the disease or condition includes a disease or condition characterized by abnormal activity and / or proliferation of neutrophils. In some embodiments, the disease or condition includes neutrophilic dermatopathies, psoriatic arthritis, generalized pustular psoriasis, pyoderma gangrenosum, Sweet's syndrome, subcorneal pustular dermatopathies, neutrophilic eccrine hidradenitis, gut-associated dermatopathies-arthritis syndrome (BADAS), rheumatic neutrophilic dermatitis, or Behçet's disease.

[0249] In some embodiments, the disease or condition includes autoimmune disorders. In some embodiments, autoimmune disorders involve the presentation of autoantigens by antigen-presenting cells occurring in germinal centers of secondary lymphoid tissue, triggering the activation of autoreactive T and B cells, which then produce autoantibodies that mediate cytokine release and sometimes IgG-induced phagocytosis. By targeting and depleting these antigen-presenting dendritic cells and autoreactive lymphocytes, the antibodies described herein can treat these diseases by halting this process of autoantigen presentation.

[0250] In some embodiments, the therapeutic SIRP antibodies provided herein are used to treat acute disseminated encephalomyelitis, acute respiratory distress syndrome, Addison's disease, adult-onset Still's disease, ankylosing spondylitis, antibody-mediated rejection (AMR), anti-glomerular basement membrane disease (Goodpasture syndrome), catastrophic antiphospholipid syndrome, antiphospholipid syndrome, aplastic anemia, allograft rejection, atopic dermatitis, atherosclerosis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, axial spondyloarthritis, Behçet's disease, bullous pemphigoid, Castleman disease, Catastrophic antiphospholipid syndrome, celiac disease, cell-mediated rejection of solid organ transplants, chronic obstructive pulmonary disease (COPD), Chediak-Higashi syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic neutrophilic leukemia, chronic urticaria, coronary artery disease (CAD) / peripheral artery disease (PAD), COVID-19, cutaneous mastocytosis, eosinophilic cardiomyopathy / Loeffler endocarditis, Crohn's disease, acquired epidermolysis bullosa, Evans syndrome, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), Felty syndrome, generalized pustular psoriasis, giant cell myocarditis, graft failure after HSCT ( Hematopoietic stem cell transplantation, graft-versus-host disease, Graves' disease, Graves' ophthalmopathy, granulomatosis with polyangiitis (Wegener's granulomatosis), Guillain-Barré syndrome, Hashimoto's thyroiditis, hereditary alpha-tryptemia syndrome, hyper-IgE syndrome, idiopathic interstitial pneumonia, idiopathic pulmonary fibrosis, IgA nephropathy, immunopathological / idiopathic thrombocytopenic purpura, inclusion body myositis, inflammatory bowel disease, Kawasaki disease, Lambert-Eaton myasthenic syndrome (LEMS), myasthenia gravis (MG), linear IgA disease, Loeffler's syndrome, lupus nephritis, lupus vasculitis, systemic lupus erythematosus (SLE), mast cell activation syndrome, obesity Cholecellular colitis, membranous nephropathy, microscopic polyangiitis (MPA), multiple sclerosis, myelodysplastic syndrome, myelofibrosis, myocarditis, neuromyelitis optica (NMO), neutrophilic dermatosis, paraneoplastic syndromes, pemphigus foliaceus, pemphigus vulgaris, primary biliary cholangitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriatic arthritis, pyoderma gangrenosum, Rasmussen's encephalitis, rheumatoid arthritis, rheumatic vasculitis, Schmidt syndrome, scleroderma (systemic sclerosis), Sjögren's syndrome, severe allergic conjunctivitis, Sjögren's syndrome, Suzak syndrome, systemic inflammatory response syndrome, systemic juvenile idiopathic arthritis,It is useful in the treatment of autoimmune or inflammatory (chronic or acute) disorders such as systemic lupus erythematosus, systemic mastocytosis, type 1 diabetes, ulcerative colitis, uveitis, vitiligo, or X-linked lymphoproliferative disorders.

[0251] In some embodiments, the therapeutic SIRP antibodies provided herein are useful for treating hematological malignancies. In some embodiments, the hematological malignancies are selected from the group consisting of acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, chronic neutrophilic leukemia, juvenile myelomonocytic leukemia, chronic eosinophilic leukemia, macrogranular lymphocytic leukemia, T-cell prelymphocytic leukemia, hepatosplenic lymphoma, Hodgkin lymphoma, T-cell lymphoblastic lymphoma or leukemia, T-cell nonlymphoblastic lymphoma, NK-cell lymphoma / leukemia, myeloid neoplasms, chronic neutrophilic leukemia, and other hematological malignancies.

[0252] In other embodiments, the therapeutic SIRP antibodies provided herein are useful for treating diseases or conditions associated with pathological alloantibodies or autoantibodies, including myasthenia gravis, Guillain-Barré syndrome, autoimmune hemolytic anemia, immune / idiopathic thrombocytopenic purpura, Evans syndrome, Felty syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), Lambert-Eaton myasthenia optica syndrome (LEMS), neuromyelitis optica (NMO), bullous pemphigoid, acquired epidermolysis bullosa, pemphigus foliaceus, pemphigus vulgaris, anti-glomerular basement membrane disease (Goodpasture syndrome), membranous nephropathy, rheumatic vasculitis, lupus vasculitis, scleroderma (systemic sclerosis), Behçet's disease, microscopic polyangiitis (MPA), Kawasaki disease, antiphospholipid syndrome, catastrophic antiphospholipid syndrome, Graves' ophthalmopathy, Castleman disease, and antibody-mediated rejection (AMR).

[0253] In some embodiments, the disease or condition is hemophagocytic lymphohistiocytosis (HLH) (including primary and secondary HLH), macrophage activation syndrome, Langerhans cell histiocytosis (LCH), somatic cell histiocytosis, Erdheim-Chester disease (ECD), mixed LCH / ECD, Rosei-Dorfmann disease, malignant histiocytosis, cutaneous non-LCH histiocytosis, juvenile xanthogranuloma, virus-associated HLH, bacteria-associated HLH, parasite-associated HLH, fungal-associated / fungal-induced HLH, malignant tumor-induced HLH, HLH occurring during chemotherapy, systemic juvenile HLH associated with sexually idiopathic arthritis (SoJIA), HLH associated with adult-onset Still's disease, HLH associated with systemic lupus erythematosus (SLE), HLH associated with vasculitis, HLH associated with autoimmune conditions, HLH associated with kidney transplantation, HLH associated with hematological stem cell transplantation, sHLH or CRS associated with checkpoint inhibitors for the treatment of malignancies, sHLH or CRS associated with T-cell therapy, sHLH or CRS associated with chimeric antigen receptor (CAR) T-cell therapy, and sHLH associated with T-cell activating bispecific monoclonal antibody therapy. Alternatively, CRS, cytokine release syndrome (CRS), systemic mastocytosis, eosinophilia syndrome (including primary, secondary, and idiopathic), hyper-IgE syndrome, X-linked lymphoproliferative disorder, graft-versus-host disease, type 1 diabetes, systemic lupus erythematosus, lupus nephritis, systemic inflammatory response syndrome, acute respiratory distress syndrome, autoimmune lymphoproliferative syndrome, X-linked hyper-IgM syndrome, paraneoplastic syndrome, Suzak syndrome, linear IgA disease, autoimmune neutropenia, idiopathic pulmonary fibrosis, inclusion body myositis, vitiligo, Addison's disease, Graves' disease, Hashimoto's thyroiditis, Schmidt syndrome, acute disseminated cerebrospinal fluid syndrome Inflammation, sarcoidosis, ankylosing spondylitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, eosinophilic granulomatosis with polyangiitis, pyoderma gangrenosum, giant cell arteritis, rheumatoid arthritis, systemic juvenile idiopathic arthritis, Sjögren's syndrome, primary sclerosing cholangitis, primary biliary cholangitis, myasthenia gravis, multiple sclerosis, Guillain-Barré syndrome, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, chronic eosinophilic leukemia, macrogranulomylphocytic leukemia, T-cell prolymphocytic leukemia, hepatosplenic lymphoma, Hodgkin's lymphoma,T-cell lymphoblastic lymphoma / leukemia, T-cell non-lymphoblastic lymphoma, B-cell leukemia, B-cell lymphoma (non-Hodgkin), NK-cell lymphoma or leukemia, myeloid neoplasms, autoimmune hemolytic anemia, immune / idiopathic thrombocytopenic purpura, Evans syndrome, Felty syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), Lambert-Eaton myasthenia pallidus syndrome (LEMS), neuromyelitis optica (NMO), bullous pemphigoid, acquired epidermolysis bullosa, pemphigus foliaceus, pemphigus vulgaris, anti-glomerular basement membrane disease ( Goodpasture syndrome, membranous nephropathy, rheumatic vasculitis, lupus vasculitis, scleroderma (systemic scleroderma), Behçet's disease, granulomatosis with polyangiitis (Wegener's granulomatosis), eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), microscopic polyangiitis (MPA), Kawasaki disease, antiphospholipid syndrome, catastrophic antiphospholipid syndrome, Graves' ophthalmopathy, Castleman disease, antibody-mediated rejection (AMR), acute eosinophilic pneumonia, chronic eosinophilic pneumonia, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastrointestinal Inflammation, eosinophilic enteritis, eosinophilic colitis, uveitis, giant cell myocarditis, cutaneous mastocytosis, mastocellular enteritis, mastocell activation syndrome, IgA nephropathy, Chediak-Higashi syndrome, eosinophilic cardiomyopathy / Loeffler endocarditis, acute kidney injury, chronic kidney disease, coronary artery disease (CAD) / peripheral artery disease (PAD), myelofibrosis, IgG4-related disease, Loeffler syndrome, chronic neutrophilic leukemia, myocarditis, episodic angioedema with eosinophilia / Gleich syndrome, idiopathic interstitial pneumonia, hereditary alpha-tryptemia syndrome, chronic This includes urticaria, severe allergic conjunctivitis, adult-onset Still's disease, aplastic anemia, cell-mediated rejection of solid organ transplants, graft failure after hematopoietic stem cell transplantation (HSCT), lymphocyte variant eosinophilia, myelodysplastic syndrome, atopic dermatitis, axial spondyloarthritis, celiac disease, hyperthyroidism, Rasmussen's encephalitis, chronic beryllium disease (berylliosis), Takayasu's arteritis, autoimmune hepatitis, neutrophilic dermatitis, psoriatic arthritis, coronavirus disease 2019 (COVID-19), or generalized pustular psoriasis.

[0254] D. Pharmaceutical Compositions This disclosure also provides pharmaceutical compositions comprising one of the SIRP antibodies disclosed herein and a pharmaceutically acceptable excipient or, optionally, a carrier. In some embodiments, the pharmaceutical compositions are sterile. The pharmaceutical compositions can be formulated to suit their intended route of administration. In some embodiments, the pharmaceutical compositions of this disclosure are suitable for administration to human subjects.

[0255] E. Combination Therapy An administration of any one of the therapeutic SIRP antibodies provided herein can be combined with any other known drug or treatment for a disease or condition as described in the IIC. In some embodiments, the disease or condition is associated with the hyperactivation and / or hyperproliferation of myeloid cells, lymphocytes, or other cells expressing SIRPα, SIRPβ1, or SIRPγ. In some embodiments, the disease or condition is an autoimmune disease or condition. In some embodiments, the disease or condition is a neoplasm or malignant tumor. In exemplary embodiments, the disease or condition being treated is an hyperinflammatory syndrome or CRS such as HLH (e.g., autoimmune-related CRS, or adoptive cell therapy-related CRS), and the therapeutic SIRP antibody can be used in combination with a corticosteroid (e.g., dexamethasone).

[0256] In some embodiments, therapeutic SIRP antibodies are provided for treating CRS or sHLH resulting from infection, in combination with an antiviral agent appropriate for treating a viral infection, or in combination with an antibiotic therapy appropriate for treating a bacterial infection. As just one example, therapeutic antibodies of the present disclosure could be administered in combination with antiviral therapy, e.g., antiviral therapy for COVID-19, SARS (SARS-CoV), MERS, Ebola, or Epstein-Barr virus, or in combination with antibiotic therapy, e.g., antibiotic therapy for treating sepsis. In some embodiments, SIRP antibodies are administered in combination with standard treatment for the infection.

[0257] In some embodiments, the therapeutic SIRP antibodies provided herein are used in combination with appropriate chemotherapy agents or malignancy-related treatments for the oncological indication to treat CRS or sHLH resulting from malignant tumors. In some embodiments, the therapeutic SIRP antibodies provided herein are used in combination with appropriate treatments for autoimmune disorders such as rheumatic disorders including systemic lupus erythematosus or rheumatoid arthritis. Examples of appropriate treatments include, but are not limited to, corticosteroids.

[0258] F. Administration of therapeutic SIRP antibodies In vivo administration of the therapeutic SIRP antibodies described herein may be performed intravenously, intramuscularly, subcutaneously, topically, orally, percutaneously, percutaneously, intraperitoneally, intraorbitally, intraarachnoidally, intraventricularly, intranasally, transmucosally, implantably, or by inhalation. Intravenous administration may be performed by injection or infusion. In some embodiments, the SIRP antibodies of this disclosure are administered intravenously. In some embodiments, the SIRP antibodies of this disclosure are administered subcutaneously. Administration of the therapeutic SIRP antibodies may be performed with any suitable excipient, carrier, or other agent to achieve appropriate or improved resistance, mobility, delivery, etc.

[0259] G. Diagnostic antibodies The antibodies provided herein can also be used for diagnostic purposes. For example, in the case of SIRPα-binding SIRPα antibodies, the diagnostic antibodies can be used to detect the presence of SIRPα-mediated disorders or to detect the target SIRPα level before drug administration (e.g., as a companion diagnostic).

[0260] III. Kits and Products This disclosure also provides kits or products comprising any of the antibodies disclosed herein or any of the pharmaceutical compositions disclosed herein. In some embodiments, the kit may further include instructional materials for carrying out any of the methods disclosed herein. In some embodiments, the kit may further include sterile containers or vials for holding the antibodies and / or pharmaceutical compositions disclosed herein. In some embodiments, the kit may further include a sterile delivery device for administering the antibodies and / or pharmaceutical compositions disclosed herein. In some embodiments, the product may include any of the pharmaceutical compositions disclosed. [Examples]

[0261] [Example 1] Hybridoma library screening for identifying anti-human SIRP antibodies Anti-human SIRP monoclonal antibodies (referred interchangeably to as SIRP antibodies in this example) were identified from various immunized rodent models. Rodent strains were immunized with the extracellular domain of human SIRPα (hSIRPα). Hybridoma libraries (six libraries) were generated from spleen cells of immunized animals using standard techniques. Anti-hSIRPα antibody-producing clones were identified by flow cytometry analysis of hSIRPα-expressing cells incubated in the supernatant of each clone. Twelve individual clones were identified (antibodies 1, 3, 4, and 7-15). Antibodies 1, 3-4, and 7-14 possess a human variable region and a rat IgG2b Fc domain. Antibody 15 possesses a mouse variable region and a mouse IgG2a Fc domain.

[0262] [Example 2] Binding of SIRP antibody to SIRPα protein The selected hybridoma supernatants from Example 1 were further tested for binding to human SIRPα V1 and cynomolgus monkey SIRPα by enzyme-linked immunosorbent assay (ELISA). Briefly, the extracellular domain of SIRPα at 1 μg / mL was coated onto high-protein binding plates and blocked. The supernatant was diluted 1:5 and added to the coated plates. Antibodies were detected using anti-rat or anti-mouse IgG antibodies and chemiluminescent substrates. Figure 1A shows the binding results for antibodies 1, 3, 4, 7-15. The data are displayed as relative luminescence units read from a plate reader capable of detecting chemiluminescence.

[0263] The selected hybridoma supernatants from Example 1 were further tested for binding to human SIRPα V1, SIRPβ1, and SIRPγ by enzyme-linked immunosorbent assay (ELISA). Briefly, the extracellular domain of each SIRP at 2 μg / mL was coated onto high-protein binding plates and blocked. The supernatant was added to the coated plates without dilution. Antibodies were detected using anti-rat or anti-mouse IgG antibodies and chemiluminescent substrates. Figure 1B shows the binding results for antibodies 1, 3, 4, 7-15. The data are displayed as relative luminescence units read from a plate reader capable of detecting chemiluminescence.

[0264] Figures 2A-2B show the binding curves of SIRP antibodies to human SIRPα V1 and cynomolgus monkey SIRPα, obtained by ELISA. Selected SIRP antibodies were purified using protein G from hybridoma supernatant and analyzed by ELISA titration. Briefly, 1 μg / mL of extracellular domain SIRPα was coated onto high-protein binding plates and blocked. The purified antibodies were added to the coated plates by titration. Antibodies were detected using anti-rat IgG antibody and chemiluminescent substrate.

[0265] Figures 2C-2H show the binding curves of SIRP antibodies to human SIRPα V1, human SIRPβ1, human SIRPγ, cynomolgus monkey SIRPα, cynomolgus monkey SIRPβ1, and cynomolgus monkey SIRPγ, obtained by ELISA. Selected SIRP antibodies were purified using protein G from hybridoma supernatant and analyzed by ELISA titration. Briefly, the extracellular domains of each SIRP molecule at 2 μg / mL were coated onto high-protein binding plates and blocked. The purified antibodies were added to the coated plates by titration. Antibodies were detected using anti-rat IgG or anti-mouse IgG antibodies and chemiluminescent substrates.

[0266] Figures 3A–3C show the binding curves of SIRP antibodies and two isotype controls containing human Fc to human SIRPα V1, human SIRPβ1, human SIRPγ, and cynomolgus monkey SIRPα, as measured by ELISA. The selected SIRP antibody from Example 1 was fully humanized. Isotype control 1 was an unrelated human IgG1 antibody containing an unrelated CDR. Isotype control 2 was similar to isotype control 1 but contained the same amino acid substitutions in the Fc region as some of the selected SIRP antibodies (referred to in Table 11) due to increased FcγR binding. DNA was transiently transfected into CHO cells for 7 days. Antibodies were purified by protein A from the cell supernatant and analyzed by titration via ELISA using an anti-human IgG antibody as the detection antibody, as previously described in Figures 2A–2B.

[0267] Figures 3D-3E show the binding curves of SIRP antibodies containing human Fc to human SIRPα V1, human SIRPβ1, human SIRPγ, cynomolgus monkey SIRPα, cynomolgus monkey SIRPβ, and cynomolgus monkey SIRPγ, obtained by ELISA. The selected SIRP antibodies from Example 1 were fully humanized. DNA was transiently transfected into CHO cells for 7 days. The antibodies were purified with protein A from the cell supernatant and analyzed by titration via ELISA using anti-human IgG antibody as the detection antibody, as previously described in Figures 2C-2H.

[0268] The selected antibodies were tested for their affinity to two hSIRPα variants (V1 and V2), as well as to cynomolgus monkey (hereinafter referred to as "cyno") SIRPα. The compositions of these antibodies are presented in Tables 10 and 11. The affinity of these SIRP antibodies was determined using surface plasmon resonance. The SIRP antibodies were flowed onto a chip and captured by covalently bound anti-mouse IgG or anti-human IgG on the chip surface. Three-point titration of the extracellular binding domain of hSIRPα was performed according to the manufacturer's recommended protocol. The obtained kinetic data were analyzed and globally fitted using a 1:1 binding model, and the calculated affinities are presented in Tables 13 and 14 below. These tables show the KD (affinity) of the selected antibodies binding to monomeric human SIRPα and monomeric cynomolgus monkey SIRPα as assayed by BIACORE.

[0269] Selected SIRP antibodies were tested for their affinity to human SIRPα, SIRPβ1, and SIRPγ using a biolayer interferometry (BLI) Octet system (Pall ForteBio). The compositions of these antibodies are shown in Tables 10 and 11. Each SIRP antibody containing rat or mouse Fc was immobilized on a biosensor chip by anti-mouse IgG capture (AMC). Antibodies containing human Fc were digested with gingipain K enzyme to obtain monomer F(ab'), biotinylated, and then coated onto a streptavidin biosensor. The biosensor was exposed to SIRP-His monomer protein at three concentrations (100 nM, 33.3 nM, and 11.1 nM), and the on-rate dynamics of the SIRP antibody bound to the SIRP-His protein were measured. The biosensor was then exposed to a washing buffer, and the off-rate dynamics were measured. The obtained dynamic data were analyzed, and using a 1:1 binding model, k at each concentration of SIRP-His protein was determined. on and k disFitted while separately fitting. K D The affinity is k at each concentration of SIRP-His dis versus k on Calculated as a ratio and averaged. K for each antibody D The average of the affinities is presented in Table 15 below. The table shows the K for the binding of selected antibodies to monomeric human SIRPα, SIRPβ1, and SIRPγ assayed by ForteBio Octet D is shown.

[0270]

Table 13

[0271]

Table 14

[0272]

Table 15

[0273] [Example 3] In vitro binding of SIRP antibodies to cells via flow cytometry The selected antibody and two isotype controls were tested for binding to human monocytes, neutrophils, T lymphocytes, and B lymphocytes. Figure 4A shows the results of binding studies of SIRP antibody against monocytes, neutrophils, T lymphocytes, and B lymphocytes in human whole blood compared to the two isotype controls. 50 μg / mL of fluorescent dye-conjugated SIRP antibody or isotype controls were incubated with whole blood from two normal donors. Positive signals were detected in monocytes and neutrophils via flow cytometry. No signals were detected in T lymphocytes and B lymphocytes compared to the isotype controls. Monocytes were identified as CD45+ and CD14+ populations. Neutrophils were identified as CD45+, CD14-, CD19-, and SSC. high The T lymphocytes were identified as CD45+, CD14-, CD19-, and SSC. low The populations were identified as CD3+ and CD16-. B lymphocytes were CD45+, SSC low The populations were identified as CD45+ and CD14+. The graph shows the median fluorescence intensity (MFI) for each population. The selected antibody and two isotype controls were tested for binding to cynomolgus monkey monocytes, granulocytes, and T lymphocytes. The isotype controls used were the same as those used for human binding experiments. Figure 4B shows the results of binding studies performed with SIRP antibody and isotype controls against monocytes, granulocytes, and T lymphocytes in cyno-whole blood. 50 μg / mL of fluorescent dye-conjugated SIRP antibody was incubated with whole blood from three normal donors. Positive signals were detected in monocytes, granulocytes, and T lymphocytes via flow cytometry. The monocytes were identified as CD45+ and CD14+ populations. The granulocytes were identified as CD45+, CD14-, CD19-, and SSC. high The T lymphocyte populations were identified as CD45+, CD14-, CD19-, SSClow, CD3+, and CD16-. The graph shows the median fluorescence intensity (MFI) for each population.

[0274] The selected antibodies were tested for binding to stably transfected human SIRPα, SIRPβ1 (co-transfected with DAP12), or SIRPγ Chinese hamster ovary (CHO) cells via flow cytometry. Titrations of the SIRP antibody were added to the cells and detected using a fluorescently labeled secondary antibody. The graphs show the median fluorescence intensity (MFI) for each concentration. Figures 4C–4E show the binding curves of SIRP antibodies to human SIRPα, SIRPβ, or SIRPγ-expressing CHO cells detected using anti-rat or anti-mouse IgG antibodies. Figure 4F shows the binding curves of SIRP antibodies to human SIRPα, SIRPβ, or SIRPγ-expressing CHO cells detected using anti-human IgG antibodies.

[0275] [Example 4] The effect of SIRP antibodies on ADCC Antibody-dependent cell-mediated cytotoxicity (ADCC) induced by selected SIRP antibodies in SIRPα-expressing human monocyte cell lines was evaluated. Immortalized human monocyte-like cell lines, THP-1, were stained with the intracellular dye [CellTracker®] and exposed to various concentrations of test substances (SIRPα antibody or isotype control). Human NK (effector) cells were then co-incubated with SIRP antibody-opsonized THP-1 (target) cells in a 1:1 effector-to-target cell ratio at 37°C for 4 hours. Dead cells were stained using DAPI, and samples were analyzed via flow cytometry. Figure 5 shows the percentage of dual DAPI+ and CellTracker+ THP-1 cells. The data demonstrate ADCC in THP-1 cells induced by the selected antibodies of this disclosure. The ADCC effect is antibody dose-dependent. These results are presented in comparison to isotype controls of unrelated IgG1 antibodies, including irrelevant CDRs.

[0276] Antibody-dependent cell-mediated cytotoxicity (ADCC) induced by selected SIRP antibodies against primary monocytes was evaluated. SIRPα-expressing human primary monocytes (target) were exposed to various concentrations of the test substance, washed, and then co-incubated with human NK (effector) cells in a 1:1 effector-to-target cell ratio at 37°C for 4 hours. Samples were stained with anti-CD14 antibody, followed by DAPI, and analyzed via flow cytometry. The graph in Figure 6A shows the percentage of dual DAPI+ and CD14+ cells. Figure 6A shows ADCC in human monocytes induced by the selected antibodies of this disclosure. The ADCC effect is antibody dose-dependent. These results are presented in comparison to isotype controls of unrelated IgG1 antibodies, including unrelated CDRs.

[0277] ADCC induced by selected SIRP antibodies against primary human and cynomolgus monkey monocytes and quiescent T lymphocytes was evaluated. SIRP-expressing human and cynomolgus monkey primary monocytes or quiescent T lymphocytes (target cells) were stained with intracellular CellTracker® Green, washed, and then exposed to varying concentrations of SIRP antibody. Target cells were co-incubated with human NK (effector) cells in a 2:1 effector cell-to-target cell ratio at 37°C for 4 hours. Samples were stained with Zombie Violet dye and analyzed via flow cytometry. Graphs in Figures 6B–6D show the percentage of cells positive for Zombie Violet dye (ADCC %) relative to the total number of cells positive for CellTracker® Green. Figure 6B shows ADCC of human and cyno monocytes induced by the selected antibodies of this disclosure. Figure 6C shows ADCC of human and cynoCD4+ T cells induced by the selected antibodies. Figure 6D shows ADCC in human and cynoCD8+ T cells induced by the selected antibody. The ADCC effect is antibody dose-dependent. These results are presented in comparison to isotype controls. Isotype control 1 was an unrelated IgG1 antibody containing irrelevant CDRs. Isotype control 2 was similar to isotype control 1 but contained the same high-affinity substitutions in the Fc region as some of the selected SIRP antibodies.

[0278] [Example 5] The effect of SIRP antibodies on ADCP Antibody-dependent cell phagocytosis (ADCP) of monocyte cell lines induced by selected SIRPα antibodies was evaluated. Two human monocyte cell lines, MOLM-13 and THP-1, were labeled with different colored intracellular dyes [CellTracker® Green and CellTracker® Deep Red]. MOLM-13 (target) cells were opsonized with the indicated concentrations of SIRP antibody and co-incubated at 37°C for 2 hours with a target cell-to-phagocytic cell ratio of 1:1 for THP-1 (phagocytic cells). Cells were analyzed by flow cytometry. The graph shows the percentage of THP-1 cells positive for each color. Figure 7 shows ADCP of MOLM-13 cells by THP-1 cells induced by the selected antibodies of this disclosure.

[0279] Antibody-dependent cell phagocytosis (ADCP) of primary monocytes induced by SIRPα antibodies was evaluated. Primary human CD14+ monocytes were split into two sets and labeled with different colored intracellular dyes [CellTracker® Green and CellTracker® Deep Red]. One set (target cells) was opsonized with the indicated concentrations of SIRP antibody and co-incubated with the other set (phagocytic cells) at a 1:1 target cell-to-phagocytic cell ratio at 37°C for 2 hours. Cells were analyzed by flow cytometry. The graph shows the percentage of phagocytic cells positive for each color. Figure 8 shows ADCP of human monocytes induced by the selected antibodies of this disclosure.

[0280] [Example 6] Efficacy of SIRP antibodies against in vivo depletion of selected cell types The effect of selected SIRP antibodies on monocytes in cynomolgus monkeys administered intravenously was evaluated. Data were generated from whole blood samples collected at different time points after administration and processed according to the laboratory's standard operating procedures (SOPs). Samples were analyzed using an automated blood analyzer. The graph shows the mean absolute monocyte count per microliter of whole blood samples plotted against time (n=3 monkeys). Monocyte depletion was observed. The effect was transient but reversible. Figure 9 shows that intravenous administration of the selected antibodies of this disclosure, at the indicated doses, resulted in transient in vivo monocyte depletion in cynomolgus monkeys.

[0281] The effect of selected SIRP antibodies on neutrophils in cynomolgus monkeys administered intravenously was evaluated. Data were generated from whole blood samples collected at different time points after administration and processed according to the laboratory's standard operating procedures (SOPs). Samples were analyzed using an automated blood analyzer. The graph shows the mean absolute neutrophil count per microliter of whole blood samples plotted against time (n=3 monkeys). Figure 10 shows that intravenous administration of the selected antibodies of this disclosure, at the indicated doses, resulted in transient in vivo neutrophil depletion in cynomolgus monkeys.

[0282] The effect of selected SIRP antibodies on lymphocytes in cynomolgus monkeys administered intravenously was evaluated. Data were generated from whole blood samples collected at different time points after administration and processed according to the laboratory's standard operating procedures (SOPs). Samples were analyzed using an automated blood analyzer. The graph shows the mean absolute lymphocyte count per microliter of whole blood samples plotted against time (n=3 monkeys). Figure 11 shows that intravenous administration of the selected antibodies of this disclosure, at the indicated doses, resulted in transient in vivo lymphocyte depletion in cynomolgus monkeys.

[0283] The effect of selected SIRP antibodies on eosinophils in cynomolgus monkeys administered intravenously was evaluated. Data were generated from whole blood samples collected at different time points after administration and processed according to the laboratory's standard operating procedures (SOPs). Samples were analyzed using an automated blood analyzer. The graph shows the mean absolute eosinophil count per microliter of whole blood samples plotted against time (n=3 monkeys). Figure 12 shows that intravenous administration of the selected antibodies of this disclosure, at the indicated doses, resulted in transient in vivo eosinophil depletion in cynomolgus monkeys.

[0284] The effect of selected SIRP antibodies on basophils in cynomolgus monkeys administered intravenously was evaluated. Data were generated from whole blood samples collected at different time points after administration and processed according to the laboratory's standard operating procedures (SOPs). Samples were analyzed using an automated blood analyzer. The graph shows the mean absolute basophil count per microliter of whole blood samples plotted against time (n=3 monkeys). Figure 13 shows that intravenous administration of the selected antibodies of this disclosure, at the indicated doses, resulted in transient in vivo basophil depletion in cynomolgus monkeys.

[0285] [Example 7] Determination of competition between SIRP antibody and CD47 for binding to SIRPα. ELISA analysis was performed to evaluate whether the SIRP antibodies of this disclosure compete with CD47-Fc for binding to hSIRPα, and whether either SIRP antibody can replace CD47-Fc in binding to hSIRPα. To perform the competition experiment, the extracellular binding domain of SIRPα was coated onto a 384-well plate and incubated overnight. Blocking solution was then added. Next, each SIRP antibody at a concentration of 10 μg / mL was incubated on the plate for 1 hour. Biotinylated CD47-Fc at a concentration of 2.5 μg / mL was then added and equilibrated for 1 hour. After washing, streptavidin-HRP was added, the plate was washed again, and then colorimetric analysis was performed using the substrate according to the standard protocol. The plates were then read on a plate reader and luminescence was evaluated. A non-SIRPα-binding human IgG4 monoclonal antibody was used as a negative binding control. Non-biotinylated CD47-Fc was used as a positive control. A subset of antibodies tested and shown in Figure 14 showed significant interference with CD47-Fc binding to hSIRPα. Another subset of antibodies tested and shown in Figure 14 showed no interference with CD47-Fc binding to hSIRPα, or negligible interference. Antibodies 1 and 13 did not interfere with CD47 binding and did not compete with CD47. Antibodies 3 and 7 at least partially inhibited the binding of CD47 to SIRPα. The competition data shown in Figure 14 demonstrate varying degrees of luminescence for the tested antibodies, suggesting that some antibodies bind to different regions on SIRPα.

[0286] SIRP antibodies were tested for their ability to interfere with SIRP-CD47 binding using a biolayer interferometry (BLI) Octet system (Pall ForteBio). Streptavidin (SA) biosensors were coated with biotinylated recombinant CD47-His. Human SIRPα or SIRPγ conjugated to the Fc region were tested to determine their ability to bind to CD47 immobilized on the biosensor, and response values ​​during association were generated for each. To test for inhibition of SIRP-CD47 binding, selected SIRP antibodies (200 nM) were pre-incubated with SIRP-Fc protein (20 nM) in 10x molecular excess, and then tested for their ability to block the binding of SIRPα-Fc or SIRPγ-Fc to CD47-His-biotin immobilized on the biosensor. Table 16 shows the total response values ​​calculated during association for each antibody-SIRPα-Fc or SIRPγ-Fc complex, measured and compared as the percentage of CD47 binding and response for SIRPα-Fc or SIRPγ-Fc alone. A response of 100% or more indicates no blocking of the antibody:SIRP antigen complex to the CD47 receptor. A response of less than 100% indicates blocking or partial blocking of the antibody:SIRP antigen complex to the CD47 receptor.

[0287] [Table 16]

[0288] [Example 8] The effect of SIRP antibodies on germinal centers Preliminary histological data from non-human primate studies indicate that in vivo administration of SIRP antibodies resulted in a decrease in germinal center cellularity in the spleen, characterized by a reduction in the size of active germinal centers, a decrease in the number of larger lymphocytes or chromatable macrophages, or complete absence of germinal centers. These observations are consistent with the mechanism of action of the antibodies described herein, which can deplete SIRP-expressing cells found in germinal centers, namely dendritic cells (SIRPα and SIRPβ1) and lymphocytes (SIRPγ). These observations suggest that the antibodies described herein may offer therapeutic effects in diseases in which ectopic germinal centers or ectopic lymphoid structures contribute to pathologies, including autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, multiple sclerosis, Hashimoto's thyroiditis, primary sclerosing cholangitis and primary biliary cirrhosis, and myasthenia gravis.

Claims

1. An antibody specific to SIRPα, SIRPβ1, and SIRPγ, wherein the binding of the antibody to SIRPα, SIRPβ1, and SIRPγ does not interfere with the interaction between CD47 and SIRPα, and the interaction between CD47 and SIRPγ, and the antibody comprises the complementarity-determining region (CDR)-L1 sequence of SEQ ID NO: 5, the CDR-L2 sequence of SEQ ID NO: 23, the CDR-L3 sequence of SEQ ID NO: 36, the CDR-H1 sequence of SEQ ID NO: 54, the CDR-H2 sequence of SEQ ID NO: 70, and the CDR-H3 sequence of SEQ ID NO:

86.

2. The antibody according to claim 1, comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 104 or an amino acid sequence having at least 80% sequence identity thereto; and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 123 or an amino acid sequence having at least 80% sequence identity thereto.

3. The antibody according to claim 1 or 2, comprising an Fc domain.

4. The antibody according to claim 3, wherein the Fc domain is human IgG1.

5. Monoclonal antibody, antigen-binding fragment (Fab), variable fragment (Fv), single-stranded variable fragment (scFv), single-stranded antibody fragment (scAb), Fab', F(ab') ２ The antibody according to any one of claims 1 to 4, which is a dsFv diabody, an Fd polypeptide fragment, a human antibody, a humanized antibody, a chimeric antibody, or a full-length antibody.

6. An antibody according to any one of claims 1 to 5, which binds to SIRPα, SIRPβ1, and SIRPγ.

7. A pharmaceutical composition comprising one antibody according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.

8. A nucleic acid encoding an antibody according to any one of claims 1 to 6.

9. The nucleic acid according to claim 8, wherein the heavy chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 142 or a nucleic acid sequence having at least 80% sequence identity thereto, and / or the light chain variable domain is encoded by the nucleic acid sequence of SEQ ID NO: 161 or a nucleic acid sequence having at least 80% sequence identity thereto.

10. A vector comprising the nucleic acid described in claim 9.

11. The pharmaceutical composition according to claim 7 for treating histiocytic proliferative disorders in subjects requiring such treatment.

12. a. Histiocytosis includes hemophagocytic lymphohistiocytosis (HLH) (including primary and secondary HLH), macrophage activation syndrome, Langerhans cell histiocytosis (LCH), uncertain cell histiocytosis, Erdheim-Chester disease (ECD), mixed LCH / ECD, Rosei-Dorfmann disease, malignant histiocytosis, cutaneous non-LCH histiocytosis, juvenile xanthogranuloma, virus-associated HLH, bacteria-associated HLH, parasite-associated HLH, fungal-associated (fungus-induced) HLH, autoimmune disease-mediated HLH, or malignant tumor-induced HLH; or, b. Histiocytic proliferative disorder includes non-Mendelian secondary HLH (secondary HLH, or sHLH), where the secondary HLH is, i. Including infection-related HLH; ii. Associated with a rheumatic condition; or iii. Related to kidney transplantation or hematological stem cell transplantation, The pharmaceutical composition according to claim 11.

13. The pharmaceutical composition according to claim 12, wherein the malignant tumor-induced HLH comprises HLH induced by a hematological malignancy or a solid tumor.

14. The pharmaceutical composition according to claim 11, wherein histiocytosis is associated with iatrogenic immune activation, infection, T-cell therapy, chimeric antigen receptor T-cell (CAR-T) therapy, T-cell receptor T-cell (TCR-T) therapy, T-cell activating bispecific antibody therapy, or iatrogenic immunosuppression, comprising sHLH.

15. A pharmaceutical composition according to any one of claims 11 to 14, wherein the target is a human.

16. A pharmaceutical composition according to any one of claims 11 to 14, for intravenous or subcutaneous administration.

17. Use of an antibody according to any one of claims 1 to 6, or a pharmaceutical composition according to claim 7, in the manufacture of a pharmaceutical for treating histiocytic proliferative disorders in subjects requiring such treatment.

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