Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
  • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
  • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/52—Constant or Fc region; Isotype
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
  • C07K2317/565—Complementarity determining region [CDR]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
  • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
  • C07K2317/622—Single chain antibody (scFv)
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
  • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
  • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
  • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
  • C07K2317/734—Complement-dependent cytotoxicity [CDC]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
  • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

• FIG. 4D is a model - upon activation of T-cells, SIRPy expression is increased, and such increased target expression allows for preferential depletion of activated T-cells.
• FIG. 9 shows the results of a mixed lymphocyte reaction (MLR) experiment, assessing the effect of selected antibodies on T-cell proliferation.
• MLR mixed lymphocyte reaction
• FIG. 10 shows the effect of selected antibodies on human CD3+ T-cell depletion in vivo.
• a SIRPy antibody of the disclosure disrupts the binding of CD47 to SIRPy on a cell or other surface. In other embodiments, a SIRPy antibody of the disclosure enhances or promotes the binding of CD47 to SIRPy on a cell or other surface.
• the Fc domain of a Fc-containing SIRPy antibody is a human
• the EU numbering scheme is one of many available antibody numbering schemes based on the residue numbers assigned to a canonical antibody sequence. Accordingly, a skilled artisan would understand that reference to a particular residue using the EU numbering scheme may or may not be exactly the residue in one of the SIRPy antibodies of the disclosure. For example, if a SIRPy antibody of the disclosure comprises a V215A substitution in the Fc region of the heavy chain, wherein the position number of the amino acid residue is of the EU numbering scheme, the residue may not be the actual residue 215 in that particular SIRPy antibody. It may be actual residue number 213, or 214, or 215, or 216 or others.
• RTVAAPSVFI FPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO : 38
• SIRPy antibody-drug conjugates bispecific antibodies comprising at least one arm specific for SIRPy, and multispecific antibodies that exhibit binding for SIRPy.
• a SIRPy antibody comprising the amino acid sequences of the following three VL CDRs: SEQ ID NO: 123, SEQ ID NO: 143, SEQ ID NO: 186; and/or comprises the amino acid sequences of the following three VH CDRs SEQ ID NO: 229, SEQ ID NO: 265, and SEQ ID NO: 302.
• a SIRPy antibody comprising the amino acid sequences of the following three VL CDRs: SEQ ID NO: 129, SEQ ID NO: 155, SEQ ID NO: 205; and/or comprises the amino acid sequences of the following three VH CDRs SEQ ID NO: 226, SEQ ID NO: 276, and SEQ ID NO: 319.
• a SIRPy antibody wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 328 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%
• a SIRPy antibody wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 347 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and/or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 394, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 9
• a SIRPy antibody wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 348 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%
• a SIRPy antibody wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 354 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and/or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 401, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 9
• a SIRPy antibody wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 363 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and/or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 410, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 9
• the SIRPy antibodies provided herein are capable of inducing the depletion of T-cells, B-cells, or NK-cells.
• the cells are in an activated state.
• T-cell subsets there is differential depletion of T-cell subsets, possibly driven by differential expression of specific isoforms on different T-cell subsets.
• T-cell subsets include cells that are in different cell states, e.g. stimulated, exhausted; subsets also include T-cells that express different subsets of markers.
• the SIRPy antibodies provided herein are capable of inducing the preferential depletion of specific T-cell subsets expressing specific SIRPy isoforms.
• a SIRPy antibody wherein the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 422, or a nucleic acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and/or the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 469, or a nucleic acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%
• a SIRPy antibody wherein the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 426, or a nucleic acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and/or the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 473, or a nucleic acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%,
• a SIRPy antibody wherein the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 431, or a nucleic acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and/or the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 478, or a nucleic acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 8
• a SIRPy antibody wherein the heavy chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 450, or a nucleic acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and/or the light chain variable domain of the antibody is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 497, or a nucleic acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%,
• the preferential binding may be at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10- fold, at least 15-fold, at least 20-fold, at least 25-fold, or even at least 50-fold, as compared to the binding that is observed in a reference cell type or a reference cell state.
• SIRPy antibodies of the disclosure exhibit preferential binding to and depletion of an activated (stimulated) T-cell, as compared to an unstimulated T- cell.
• certain SIRPy antibodies of the disclosure exhibit preferential binding to and depletion of a SIRPy-expressing CD4+ T-cell, when compared to a SIRPy- expressing CD8+ T-cell.
• contacting a SIRPy-expressing cell with a Fc-containing SIRPy antibody of the disclosure leads to depletion of the SIRPy-expressing cell by ADCC and CDC.
• the SIRPy antibody increases each of ADCC and CDC of a by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%.
• the method may be carried out in vitro or in vivo.
• the SIRPy-expressing cell may be in an activated state.
• contacting a SIRPy-expressing cell with a Fc-containing SIRPy antibody of the disclosure leads to depletion of the SIRPy-expressing cell by ADCC, ADCP, and CDC.
• the SIRPy antibody increases each of ADCC, ADCP, and CDC of a by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%.
• the method may be carried out in vitro or in vivo.
• the SIRPy-expressing cell may be in an activated state.
• the SIRPy-expressing cell may be a T-cell, a B-cell, or a NK-cell, as described above.
• the Fc-containing SIRPy antibodies provided herein are useful for the treatment of disease or condition in which the disease or condition is driven by CD4+/CD8+ T-cells, as it is noted that certain SIRy antibodies of the disclosure show preferential T-cell subtype binding.
• any one of the therapeutic SIRPy antibodies provided herein may be in combination with any other known drugs or treatments for diseases or conditions described above.
• Exemplary combinations, e.g. for the treatment of an oncology disease includes one of the SIRPy antibodies of the disclosure, administered in conjunction with a chemotherapeutic agent, cytotoxic agents, and corticosteroid drugs.
• Exemplary agents to be administered in combination include, but are not limited to cisplatin, Cladribine (2-CdA), Fludarabine, 6- thioguanine (6-TG), hydroxyurea, prednisone, dexamethasone, methotrexate (MTX), 6- mercaptopurine (6-MP), Azacitidine, and Decitabine.
• Embodiment 1-1 An antibody comprising any one of the CDR combinations of Table 1 or any one of the VH/VL combinations of Table 2.
• Embodiment 1-10 The antibody embodiment 1-9, wherein the Fc domain comprises one or more amino acid substitutions relative to SEQ ID NO: 5 or SEQ ID NO: 6 at a position selected from the group consisting of: 215, 221, 222, 228, 234, 235, 236, 239, 240, 241, 243, 244, 245, 247, 250, 252, 254, 256, 262, 263, 264, 265, 266, 267, 268, 269, 270, 292, 296, 297, 298, 299, 300, 305, 313, 324, 325, 326, 327, 328, 329, 330, 332, 333, 334, 345, 396, 428, 430, 433, 434, and 440 wherein the position numbers of the amino acid residues are of the EU numbering scheme.
• Embodiment 1-12 The antibody of any one of embodiments 1-1 to I- 10, wherein the binding of the antibody disrupts the interaction between CD47 and SIRPy.
• Embodiment 1-19 The antibody of embodiment 1-18, wherein the T-cell is a naive, activated, central memory, effector memory, exhausted, or terminal effector memory cell.
• Embodiment 1-2 The antibody of embodiment 1-17, wherein the SIRPy-expressing cell is a B-cell.
• Embodiment 1-38 The antibody of any one of embodiments 1-1 to 1-34, wherein the antibody is a full-length antibody.
• Embodiment 1-39 The antibody of any one of embodiments 1-1 to 1-38, wherein the Fc domain is selected from the group consisting of human IgGl, IgG2, IgG3, and IgG4.
• Embodiment 1-55 The method of embodiment 1-47, wherein the SIRPy-expressing cells are NK-cells.
• Embodiment 1-63 The method of embodiment 1-62, wherein the disease or condition involves SIRPy-expressing cells.
• Embodiment 1-67 The method of any one of embodiments 1-64 to 1-66, wherein the T- cell is a CD4+ T-cell, CD8+ T-cell, Thl cell, Th2 cell, Thl7 cell or a T follicular helper cell.
• Embodiment 1-74 The method of embodiments 1-62 to 1-73, wherein the disease or condition comprises an autoimmune, oncology, or inflammatory disorder.
• Embodiment 1-75 The method of embodiments 1-64 to 1-69, wherein the disease or condition comprises a T-cell-mediated autoimmune disease, T-cell-mediated inflammatory disease, or T-cell-mediated oncology disease.
• Embodiment 1-79 A kit or article of manufacture comprising an antibody of any one of embodiments 1-1 to 1-43, or the pharmaceutical composition of embodiment 1-44.
• Embodiment II-9 The antibody of embodiment II-3, wherein the T-cell is a CD3+ T- cell, CD4+ T-cell, CD8+ T-cell, CD25+ T-cell, CD69+ T-cell, and/or PD1+ T-cell.
• Embodiment 11-12 The antibody of embodiment II-3, wherein the T-cell is a
• Embodiment 11-23 The antibody of embodiment II-9, wherein binding of the antibody to a SIRPy-expressing cell induces preferential effector-mediated depletion of a SIRPy- expressing CD8+/CD69+ T-cell, when compared to a SIRPy-expressing CD8+/CD69- T-cell.
• Embodiment 11-27 The antibody of embodiment II-2, wherein the SIRPy-expressing cell is an NK-cell.
• Embodiment 11-28 The antibody of any one of embodiments II- 1 to 11-27, wherein the SIRPy-expressing cell is stimulated (activated).
• Embodiment 11-34 The antibody of any one of embodiments II- 1 to 11-33, wherein the antibody comprises the CDR amino acid sequences of any one of the combinations of Table 1, as presented in embodiment 11-46.
• Embodiment 11-38 A SIRPy antibody that has low or no affinity for binding SIRPa and SIRPpi, and wherein the antibody exhibits preferential binding to a CD4+ T-cell.
• Embodiment 11-41 A SIRPy antibody that has low or no affinity for binding SIRPa and SIRPpi, and wherein the antibody exhibits preferential binding to a CD8+ T-cell, when compared to a SIRPy-expressing CD4+ T-cell.
• Embodiment 11-46 A SIRPy antibody that has low or no affinity for binding SIRPa and SIRPpi, and wherein the antibody comprises the amino acid sequences of any one of the forty-seven CDR combinations of Table 1.
• Embodiment 11-49 The antibody of any one of embodiments II- 1 to 11-48, wherein the antibody is a human antibody.
• Embodiment 11-51 The antibody of any one of embodiments II- 1 to 11-48, wherein the antibody is a chimeric antibody.
• Embodiment 11-63 A pharmaceutical composition comprising the antibody of any one of embodiments II- 1 to 11-62, and optionally a pharmaceutically acceptable carrier.
• Embodiment 11-74 The method of embodiment 11-68, wherein the T-cells are cytotoxic T-cells, helper T-cells, memory T-cells, regulatory T-cells, natural killer T-cells, mucosal associated invariant T-cells, alpha beta T-cells, or gamma delta T-cells.
• Embodiment 11-75 The method of embodiment 11-68, wherein the T-cells are Thl cells, Th2 cells, Thl7 cells or T follicular helper cells
• Embodiment 11-81 The method of embodiment 11-76, wherein the depletion is preferential for stimulated T-cells, as compared to unstimulated T-cells.
• Embodiment 11-89 The method of embodiment 11-76, wherein the depletion is preferential for SIRPy-expressing CD8+/CD25+ T-cells, when compared to SIRPy-expressing CD8+/CD25- T- cells.
• Embodiment 11-90 The method of embodiment 11-66, wherein the SIRPy-expressing cells are B-cells.
• Embodiment 11-93 The method of any one of embodiments 11-66 to 11-92, wherein the method is in vitro.
• Embodiment 11-96 The method any one of embodiments 11-66 to 11-95, wherein the population of SIRPy-expressing cells comprises circulating cells.
• Embodiment 11-99 The method of embodiment 11-98, wherein the disease or condition involves SIRPy-expressing cells.
• Embodiment 11-101 The method of embodiment II- 100, wherein the SIRPy- expressing cell is a T-cell.
• Embodiment II- 103 The method of embodiment II- 101 , wherein the T-cell is exhausted.
• Embodiment II- 115 The method of embodiment 11-106, wherein binding of the antibody is preferential for a SIRPy-expressing CD8+/CD25+ T-cell.
• Embodiment II- 116 The method of embodiment 11-106, wherein binding of the antibody is preferential for a SIRPy-expressing CD8+ T-cell, when compared to a SIRPy- expressing CD4+ T-cell.
• Embodiment 11-123 The method of embodiment 11-122, wherein the NK-cell is activated.
• Embodiment 11-130 The method of any one of embodiments 11-98 to 11-129, wherein the subject is human.
• Fc that increases effector function Fc that decreases effector function, and the like
• the human constant region could comprise any one of the Fc regions provided in this disclosure, e.g. those of SEQ ID NOS: 5-36, canonical, modified or otherwise.
• the resulting kinetic data were analyzed and fitted using a 1 : 1 binding model. Affinities were calculated as a global KD and is presented in Table 4 below. The table shows the KD (in M) of binding of selected antibodies to monomeric human SIRPy, cynomolgus monkey SIRPy, human SIRPaVl, human SIRPaV2, and human SIRPpi as assayed by ForteBio Octet.
• T-cells were identified as the CD14-, CD20-, SSClow, and CD3+ population or further identified to be CD4+ or CD8+ populations.
• B-cells were identified as the CD14-, SSClow, and CD20+ population.
• NK cells were identified as CD14-, CD20-, CD3-, and CD56+.
• Monocytes were identified as the SSClow and CD 14+ population.
• Granulocytes were identified as the CD14-, CD20-, CD3-, SSChigh population.
• Graphs depict the median fluorescence intensity (MFI) of each population.

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