Claims for Patent: 10,259,859

Summary for Patent: 10,259,859

Title:	Constructs having a SIRP-.alpha. domain or variant thereof
Abstract:	The present disclosure features signal-regulatory protein .alpha. (SIRP-.alpha.) polypeptides and constructs that are useful, e.g., to target a cell (e.g., a cancer cell or a cell of the immune system), to increase phagocytosis of the target cell, to eliminate immune cells such as regulatory T-cells, to kill cancer cells, to treat a disease (e.g., cancer) in a subject, or any combinations thereof. The SIRP-.alpha. constructs include a high affinity SIRP-.alpha. D1 domain or variant thereof that binds CD47 with higher affinity than a wild-type SIRP-.alpha.. The SIRP-.alpha. polypeptides or constructs include a SIRP-.alpha. D1 variant fused to an Fc domain monomer, a human serum albumin (HSA), an albumin-binding peptide, or a polyethylene glycol (PEG) polymer. Compositions provided herein include (i) a polypeptide including a signal-regulatory protein .alpha. (SIRP-.alpha.) D1 variant and (ii) an antibody.
Inventor(s):	Pons; Jaume (San Carlos, CA), Deming; Laura (Palo Alto, CA), Goodman; Corey (Marshall, CA), Sim; Bang Janet (Brisbane, CA), Kauder; Steven Elliot (San Mateo, CA), Wan; Hong (Foster City, CA), Kuo; Tracy Chia-Chien (San Mateo, CA)
Assignee:	ALX ONCOLOGY INC. (Burlingame, CA)
Application Number:	15/230,186
Patent Claims:	1. A polypeptide, comprising: a signal-regulatory protein .alpha. (SIRP-.alpha.) D1 variant that comprises the amino acid sequence EEELQX.sub.1IQPDKSVLVAAGETATLRCTX.sub.2TSLX.sub.3PVGPIQWFRGAGPGRX.sub.4LI- YNQX.sub.5X.sub.6GX.sub.7FP RVTTVSDX.sub.8TKRNNMDFSIRIGX.sub.9ITPADAGTYYCX.sub.10KFRKGSPDDVEFKSGAGTEL- SVRAKPS (SEQ ID NO: 49), wherein X.sub.1 is V, L, or I; X.sub.2 is A, I, V, or L; X.sub.3 is I, F, S, or T; X.sub.4 is E, V, or L; X.sub.5 is K or R; X.sub.6 is E or Q; X.sub.7 is H, P, or R; X.sub.8 is L, T, S, or G; X.sub.9 is A; and X.sub.10 is V or I; and comprises at least two amino acid substitutions relative to a wild-type SIRP-.alpha. D1 domain having a sequence according to SEQ ID NO: 1. 2. The polypeptide of claim 1, wherein the SIRP-.alpha. D1 variant comprises an amino acid sequence according to any one of SEQ ID NOs: 78-85. 3. A polypeptide, comprising: a signal-regulatory protein .alpha. (SIRP-.alpha.) D1 variant that comprises the amino acid sequence EEELQX.sub.1IQPDKSVLVAAGETATLRCTX.sub.2TSLX.sub.3PVGPIQWFRGAGPGRX.sub.4LI- YNQX.sub.5X.sub.6GX.sub.7FP RVTTVSDX.sub.8TKRNNMDFSIRIGX.sub.9X.sub.10X.sub.11X.sub.12ADAGTYYCX.sub.1- 3KFRKGSPDDVEFKSGAGTELSVRAKPS (SEQ ID NO: 218), wherein X.sub.1 is V, L, or I; X.sub.2 is A, V, L, or I; X.sub.3 is I, S, T, or F; X.sub.4 is E, L, or V; X.sub.5 is K or R; X.sub.6 is E or Q; X.sub.7 is H, R, or P; X.sub.8 is S, G, L, or T; X.sub.9 is A; X.sub.10 is any amino acid; X.sub.11 is any amino acid; X.sub.12 is any amino acid; and X.sub.13 is V or I; and comprises at least two amino acid substitutions relative to a wild-type SIRP-.alpha. D1 domain having a sequence according to SEQ ID NO: 1. 4. The polypeptide of claim 3, wherein X.sub.10 is I. 5. The polypeptide of claim 3, wherein X.sub.11 is T. 6. The polypeptide of claim 3, wherein X.sub.12 is P. 7. A polypeptide comprising a signal-regulatory protein .alpha. (SIRP-.alpha.) D1 variant that comprises the amino acid sequence EEELQX.sub.1IQPDKSVLVAAGETATLRCTX.sub.2TSLX.sub.3PVGPIQWFRGAGPGRELIYNQX.s- ub.4EGX.sub.5FPRVTTVSDX.sub.6TKRNNMDFSIRIGX.sub.7ITPADAGTYYCVKFRKGSPDDVEFK- SGAGTELSVRAKPS (SEQ ID NO: 52), wherein X.sub.1 is V, L, or I; X.sub.2 is A, I, or L; X.sub.3 is I, T, S, or F; X.sub.4 is K or R; X.sub.5 is H, P, or R; X.sub.6 is L, T, or G; and X.sub.7 is A; and comprises at least two amino acid substitutions relative to a wild-type SIRP-.alpha. D1 domain having a sequence according to SEQ ID NO: 1. 8. The polypeptide of claim 7, wherein X.sub.1 is V or I, X.sub.2 is A or I, X.sub.3 is I or F, X.sub.4 is K or R, X.sub.5 is H or P, X.sub.6 is L or T, and X.sub.7 is A. 9. The polypeptide of claim 7, wherein the SIRP-.alpha. D1 variant comprises at least three amino acid substitutions relative to a wild-type SIRP-.alpha. D1 domain having a sequence according to SEQ ID NO: 1. 10. The polypeptide of claim 7, wherein the SIRP-.alpha. D1 variant comprises at least four amino acid substitutions relative to a wild-type SIRP-.alpha. D1 domain having a sequence according to SEQ ID NO: 1. 11. The polypeptide of claim 7, wherein the SIRP-.alpha. D1 variant comprises at least five amino acid substitutions relative to a wild-type SIRP-.alpha. D1 domain having a sequence according to SEQ ID NO: 1. 12. The polypeptide of claim 7, wherein the SIRP-.alpha. D1 variant comprises at least six amino acid substitutions relative to a wild-type SIRP-.alpha. D1 domain having a sequence according to SEQ ID NO: 1. 13. The polypeptide of claim 7, wherein the SIRP-.alpha. D1 variant comprises at least seven amino acid substitutions relative to a wild-type SIRP-.alpha. D1 domain having a sequence according to SEQ ID NO: 1. 14. The polypeptide of claim 7, wherein X.sub.1 is I. 15. The polypeptide of claim 7, wherein X.sub.2 is I. 16. The polypeptide of claim 7, wherein X.sub.3 is F. 17. The polypeptide of claim 7, wherein X.sub.4 is R. 18. The polypeptide of claim 7, wherein X.sub.5 is P. 19. The polypeptide of claim 7, wherein X.sub.6 is T. 20. The polypeptide of claim 7, wherein each of X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, and X.sub.6 is not a wild-type amino acid. 21. The polypeptide of claim 7, wherein the SIRP-.alpha. D1 variant comprises an amino acid sequence according to any one of SEQ ID NOs: 81-85. 22. The polypeptide of claim 1, 3, or 7, wherein the polypeptide binds to human CD47 with a K.sub.D less than about 5.times.10.sup.-9 M. 23. The polypeptide of claim 1, 3, or 7, further comprising an Fc domain monomer linked to the N-terminus or the C-terminus of the polypeptide, wherein the Fc domain monomer is a human IgG1, IgG2, or IgG4 Fc region. 24. The polypeptide of claim 23, wherein the Fc domain monomer comprises at least one mutation relative to a wild-type human IgG1, IgG2, or IgG4 Fc region. 25. The polypeptide of claim 24, wherein the polypeptide comprises the amino acid sequence of any one of SEQ ID NO: 135, SEQ ID NO: 136, or SEQ ID NO: 137. 26. The polypeptide of claim 24, wherein the Fc domain monomer comprises: (a) one of the following amino acid substitutions relative to wild type human IgG1: T366W, T366S, L368A, Y407V, T366Y, T394W, F405W, Y349T, Y349E, Y349V, L351T, L351H, L351N, L351K, P353S, S354D, D356K, D356R, D356S, E357K, E357R, E357Q, S364A, T366E, L368T, L368Y, L368E, K370E, K370D, K370Q, K392E, K392D, T394N, P395N, P396T, V397T, V397Q, L398T, D399K, D399R, D399N, F405T, F405H, F405R, Y407T, Y407H, Y407I, K409E, K409D, K409T, or K409I; or (b) (i) a N297A mutation relative to a human IgG1 Fc region; (ii) a L234A, L235A, and G237A mutation relative to a human IgG1 Fc region; (iii) a L234A, L235A, G237A, and N297A mutation relative to a human IgG1 Fc region; (iv) a N297A mutation relative to a human IgG2 Fc region; (v) a A330S and P331S mutation relative to a human IgG2 Fc region; (vi) a A330S, P331S, and N297A mutation relative to a human IgG2 Fc region; (vii) a S228P, E233P, F234V, L235A, and delG236 mutation relative to a human IgG4 Fc region; or (viii) a S228P, E233P, F234V, L235A, delG236, and N297A mutation relative to a human IgG4 Fc region. 27. The polypeptide of claim 24, wherein the polypeptide exhibits a reduction of phagocytosis in a phagocytosis assay compared to a polypeptide with a wild-type human IgG Fc region. 28. The polypeptide of claim 24, wherein the Fc domain monomer is linked to a second polypeptide comprising a second Fc domain monomer to form an Fc domain dimer. 29. The polypeptide of claim 28, wherein the second Fc domain monomer is linked to an additional polypeptide. 30. The polypeptide of claim 29, wherein the additional polypeptide comprises an antibody variable domain. 31. The polypeptide of claim 30, wherein the antibody variable domain targets an antigen expressed on a cell. 32. The polypeptide of claim 31, wherein the cell is a cancer cell. 33. The polypeptide of claim 32, wherein the antibody variable domain targets a cell surface protein involved in immune cell regulation. 34. The polypeptide of claim 29, wherein the additional polypeptide comprises a therapeutic protein. 35. The polypeptide of claim 34, wherein the therapeutic protein is a cytokine, an interleukin, an antigen, a steroid, an anti-inflammatory agent, or an immunomodulatory agent. 36. The polypeptide of claim 34, wherein the additional polypeptide comprises a SIRP-.alpha. D1 variant. 37. The polypeptide of claim 1, 3, or 7, further comprising a human serum albumin (HSA) (SEQ ID NO: 12). 38. The polypeptide of claim 37, wherein the HSA comprises a C34S or K573P amino acid substitution relative to SEQ ID NO: 12. 39. The polypeptide of claim 37, wherein the polypeptide has an amino acid sequence according to any one of SEQ ID NOs: 152-159. 40. The polypeptide of claim 1, 3, or 7, further comprising an albumin-binding peptide. 41. The polypeptide of claim 40, wherein the albumin-binding peptide comprises the amino acid sequence DICLPRWGCLW (SEQ ID NO: 160). 42. The polypeptide of claim 1, 3, or 7, further comprising a polyethylene glycol (PEG) polymer. 43. The polypeptide of claim 42, wherein the PEG polymer is joined to a cysteine substitution in the polypeptide. 44. A polypeptide, comprising: (a) a signal-regulatory protein .alpha. (SIRP-.alpha.) D1 variant, wherein the SIRP-.alpha. D1 variant comprises the amino acid sequence, EEX.sub.1X.sub.2QX.sub.3IQPDKX.sub.4VX.sub.5VAAGEX.sub.6X.sub.7X.sub.8LX.- sub.9CTX.sub.10TSLX.sub.11PVGPIQWFRGAGPX.sub.12RX.sub.DLIYNQX.sub.14X.sub.- 15GX.sub.16FPRVTTVSX.sub.17X.sub.18TX.sub.19RX.sub.20NMDFX.sub.21IX.sub.22- IX.sub.23X.sub.24ITX.sub.25ADAGTYYCX.sub.26KX.sub.27RKGSPDX.sub.28X.sub.29- EX.sub.30KSGAGTELSVRX.sub.31KPS (SEQ ID NO: 47), wherein X.sub.1 is E, or G; X.sub.2 is L, I, or V; X.sub.3 is V, L, or I; X.sub.4 is S, or F; X.sub.5 is L, or S; X.sub.6 is S, or T; X.sub.7 is A, or V; X.sub.8 is I, or T; X.sub.9 is H, R, or L; X.sub.10 is A, V, I, or L; X.sub.11 is I, T, S, or F; X.sub.12 is A, or G; X.sub.13 is E, V, or L; X.sub.14 is K, or R; X.sub.15 is E, or Q; X.sub.16 is H, P, or R; X.sub.17 is D, or E; X.sub.18 is S, L, T, or G; X.sub.19 is K, or R; X.sub.20 is E, or N; X.sub.21 is S, or P; X.sub.22 is S, or R; X.sub.23 is S, or G; X.sub.24 is A; X.sub.25 is any amino acid; X.sub.26 is V, or I; X.sub.27 is F, L, or V; X.sub.28 is D; X.sub.29 is T, or V; X.sub.30 is F, or V; and X.sub.31 is A, or G; and comprises at least two amino acid substitutions relative to a wild-type SIRP-.alpha. D1 domain having a sequence according to any one of SEQ ID NOs: 1 to 10; and (b) an Fc variant selected from the group consisting of: (i) a human IgG1 Fc region comprising a N297A mutation; (ii) a human IgG1 Fc region comprising L234A, L235A, and G237A mutations; (iii) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations; (iv) a human IgG2 Fc region comprising a N297A mutation; (v) a human IgG2 Fc region comprising A330S and P331S mutations; (vi) a human IgG2 Fc region comprising A330S, P331S, and N297A mutations; (vii) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, and delG236 mutations; and (viii) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, delG236, and N297A mutations, wherein numbering is according to the EU index of Kabat. 45. The polypeptide of claim 44, wherein the Fc variant comprises a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index of Kabat. 46. The polypeptide of claim 44, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 98-104, 107-113, 116-122, and 135-137. 47. The polypeptide of claim 44, wherein the polypeptide exhibits ablated or reduced binding to an Fc.gamma. receptor compared to a wild-type version of a human IgG Fc region. 48. The polypeptide of claim 44, wherein the polypeptide comprises an IgG1 or IgG2 Fc variant, and wherein the polypeptide exhibits ablated or reduced binding to CD16a, CD32a, CD32b, CD32c, and CD64 Fc.gamma. receptors compared to a polypeptide comprising a wild-type version of a human IgG1 or IgG2 Fc region. 49. The polypeptide of claim 44, wherein the polypeptide comprises an IgG4 Fc variant, and wherein the polypeptide exhibits ablated or reduced binding to CD16a and CD32b Fc.gamma. receptors compared to a polypeptide comprising a wild-type version of the human IgG4 Fc region. 50. The polypeptide of claim 44, wherein the polypeptide comprises an IgG1 or IgG2 Fc variant, and wherein the polypeptide exhibits ablated or reduced binding to C1q compared to a wild-type version of a human IgG1 or IgG2 Fc fusion. 51. The polypeptide of claim 44, wherein the polypeptide binds to an Fc.gamma. receptor with a K.sub.D greater than about 5.times.10.sup.-6M. 52. A polypeptide, comprising: (a) a signal-regulartory protein .alpha. (SIRP-.alpha.) D1 variant that comprises the amino acid sequence, EEELQX.sub.1IQPDKSVLVAAGETATLRCTX.sub.2TSLX .sub.3PVGPIQWFRGAGPGRX.sub.4LIYNQX.sub.5EGX.sub.6FPRVTTVSDX.sub.7TKRNNMDF- SIRIGX.sub.8ITPADAGTYYCX.sub.9KFRKGSPDDVEFKSGAGTELSVRAKPS (SEQ ID NO: 221), wherein X.sub.1 is V or I; X.sub.2 is A or I; X.sub.3 is I or F; X.sub.4 is E or V; X.sub.5 is K or R; X.sub.6 is H or P; X.sub.7 is L or T; X.sub.8 is any amino acid other than N; and X.sub.9 is V or I; and (b) an Fc variant comprising an Fc domain dimer having two Fc domain monomers, wherein each Fc domain monomer independently is selected from the group consisting of: (i) a human IgG1 Fc region consisting of mutations L234A, L235A, G237A, and N297A; (ii) a human IgG2 Fc region comprising mutations A330S, P331S and N297A; or (iii) a human IgG4 Fc region comprising mutations S228P, E233P, F234V, L235A, delG236, and N297A. 53. The polypeptide of claim 52, wherein the two Fc domain monomers are identical. 54. The polypeptide of claim 52, wherein at least one of the Fc domain monomers is a human IgG1 Fc region comprising mutations L234A, L235A, G237A, and N297A. 55. The polypeptide of claim 52, wherein at least one of the Fc domain monomers is a human IgG2 Fc region comprising mutations A330S, P331S, and N297A. 56. The polypeptide of claim 52, wherein the Fc variant exhibits ablated or reduced binding to CD16a, CD32a, CD32b, CD32c, and CD64 Fc.gamma. receptors compared to the wild-type version of the human IgG Fc region. 57. The polypeptide of claim 52, wherein at least one of the Fc domain monomers is a human IgG4 Fc region comprising mutations S228P, E233P, F234V, L235A, delG236, and N297A. 58. The polypeptide of 57, wherein the Fc variant exhibits ablated or reduced binding to CD16a and CD32b Fc.gamma. receptors compared to the wild-type version of its human IgG4 Fc region. 59. The polypeptide of claim 52, wherein the Fc variant binds to an Fc.gamma. receptor with a K.sub.D greater than about 5.times.10.sup.-6 M. 60. The polypeptide of claim 52, wherein the signal-regulatory protein .alpha. (SIRP-.alpha.) D1 variant does not cause acute anemia in rodents and non-human primates. 61. The polypeptide of claim 52, wherein the signal-regulatory protein .alpha. (SIRP-.alpha.) D1 varitant does not cause acute anemia in humans. 62. The polypeptide of claim 52, wherein X.sub.1 is V or I; X.sub.2 is A or I; X.sub.3 is I or F; X.sub.4 is E; X.sub.5 is K or R; X.sub.6 is H or P; X.sub.7 is L or T; X.sub.8 is not N; and X.sub.9 is V. 63. A method of treating an individual having a disease or disorder, the method comprising administering to the individual a polypeptide comprising: (a) a signal-regulatory protein .alpha. (SIRP-.alpha.) D1 variant, wherein the SIRP-.alpha. D1 variant comprises the amino acid sequence, EEX.sub.1X.sub.2QX.sub.3IQPDKX.sub.4VX.sub.5VAAGEX.sub.6X.sub.7- X.sub.8LX.sub.9CTX.sub.10TSLX.sub.11 PVGPIQWFRGAGPX.sub.12RX.sub.13LIY.sub.14X.sub.15GX.sub.16FPRVTTVSX.sub.17- X.sub.18TX.sub.19RX.sub.20NMDFX.sub.21IX.sub.22IX.sub.23X.sub.24ITX.sub.25- ADAGTYYCX.sub.26KX.sub.27RKGSPDX.sub.28X.sub.29EX.sub.30KSGAGTELSVRX.sub.3- 1KPS (SEQ ID NO: 47), wherein X.sub.1 is E, or G; X.sub.2 is L, I, or V; X.sub.3 is V, L, or I; X.sub.4 is S, or F; X.sub.5 is L, or S; X.sub.6 is S, or T; X.sub.7 is A, or V; X.sub.8 is I, or T; X.sub.9 is H, R, or L; X.sub.10 is A, V, I, or L; X.sub.11 is I, T, S, or F; X.sub.12 is A, or G; X.sub.13 is E, V, or L; X.sub.14 is K, or R; X.sub.15 is E, or Q; X.sub.16 is H, P, or R; X.sub.17 is D, or E; X.sub.18 is S, L, T, or G; X.sub.19 is K, or R; X.sub.20 is E, or N; X.sub.21 is S, or P; X.sub.22 is S, or R; X.sub.23 is S, or G; X.sub.24 is A; X.sub.25 is any amino acid; X.sub.26 is V, or I; X.sub.27 is F, L, or V; X.sub.28 is D; X.sub.29 is T, or V; X.sub.30 is F, or V; and X.sub.31 is A, or G; and comprises at least two amino acid substitutions relative to a wild-type SIRP-.alpha. D1 domain having a sequence according to any one of SEQ ID NOs: 1 to 10; and (b) an Fc variant selected from the group consisting of: (i) a human IgG1 Fc region comprising a N297A mutation; (ii) a human IgG1 Fc region comprising L234A, L235A, and G237A mutations; (iii) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations; (iv) a human IgG2 Fc region comprising a N297A mutation; (v) a human IgG2 Fc region comprising A330S and P331S mutations; (vi) a human IgG2 Fc region comprising A330S, P331S, and N297A mutations; (vii) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, and delG236 mutations; and (viii) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, delG236, and N297A mutations, wherein numbering is according to the EU index of Kabat. 64. The method of claim 63, wherein the disease or disorder is a cancer, an autoimmune disease, or an inflammatory disease. 65. The method of claim 63, wherein the disease or disorder is a cancer, and the cancer is selected from solid tumor cancer, hematological cancer, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, multiple myeloma, bladder cancer, pancreatic cancer, cervical cancer, endometrial cancer, lung cancer, bronchus cancer, liver cancer, ovarian cancer, colon and rectal cancer, stomach cancer, gastric cancer, gallbladder cancer, gastrointestinal stromal tumor cancer, thyroid cancer, head and neck cancer, oropharyngeal cancer, esophageal cancer, melanoma, non-melanoma skin cancer, Merkel cell carcinoma, virally induced cancer, neuroblastoma, breast cancer, prostate cancer, renal cancer, renal cell cancer, renal pelvis cancer, leukemia, lymphoma, sarcoma, glioma, brain tumor, and carcinoma. 66. The method of claim 63, wherein the disease or disorder is an autoimmune disease or an inflammatory disease, and the autoimmune disease or the inflammatory disease is selected from multiple sclerosis, rheumatoid arthritis, a spondyloarthropathy, systemic lupus erythematosus, an antibody-mediated inflammatory or autoimmune disease, graft versus host disease, sepsis, diabetes, psoriasis, atherosclerosis, Sjogren's syndrome, progressive systemic sclerosis, scleroderma, acute coronary syndrome, ischemic reperfusion, Crohn's Disease, endometriosis, glomerulonephritis, myasthenia gravis, idiopathic pulmonary fibrosis, asthma, acute respiratory distress syndrome (ARDS), vasculitis, and inflammatory autoimmune myositis. 67. The method of claim 63, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 98-104, 107-113, 116-122, and 135-137. 68. The method of claim 67, further comprising administration of at least one additional agent. 69. The method of claim 68, wherein the at least one additional agent is an antibody, tumor associated antigen, or a non-antibody therapeutic. 70. The method of claim 69, wherein at least two additional agents are administered. 71. The method of claim 70, wherein the at least two additional agents comprise two antibodies. 72. The method of claim 70, wherein the at least two additional agents comprise an antibody and a tumor associated antigen. 73. The method of claim 69, wherein the at least one additional agent is an antibody. 74. The method of claim 73, wherein the antibody is a human IgG1 isotype antibody. 75. The method of claim 73, wherein the antibody is a human IgG2 isotype antibody. 76. The method of claim 73, wherein the antibody is a human IgG4 isotype antibody. 77. The method of claim 73, wherein the antibody is selected from an anti-HER2 antibody, anti-CD20 antibody, anti-CD19 antibody, anti-CS1 antibody, anti-CD38 antibody, anti-EGFR antibody, anti-PD1 antibody, anti-OX40 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-RANKL antibody, anti-CD274 antibody, anti-CTLA-4 antibody, anti-CD137 antibody, anti-4-1BB antibody, anti-B7-H3 antibody, anti-FZD7 antibody, anti-CD27 antibody, anti-CCR4 antibody, anti-CD38 antibody, anti-CSF1R antibody, anti-CSF antibody, anti-CD30 antibody, anti-BAFF antibody, anti-VEGF antibody, or anti-VEGFR2 antibody. 78. The method of claim 77, wherein the antibody is selected from an anti-HER2 antibody, anti-CD20 antibody, anti-CD19 antibody, anti-CS1 antibody, anti-CD38 antibody, anti-PD-1 antibody, anti-RANKL antibody, or anti-PD-L1 antibody. 79. The method of claim 73, wherein the at least one additional agent is at least one antibody and the antibody is cetuximab, necitumumab, pembrolizumab, nivolumab, pidilizumab, ipilimumab, tremelimumab, urelumab, daratumumab, trastuzumab, trastuzumab emtansine, pertuzumab, elotuzumab, rituximab, ofatumumab, obinutuzumab, panitumumab, brentuximab vedotin, MSB0010718C, belimumab, bevacizumab, denosumab, ramucirumab, or atezolizumab. 80. The method of claim 79, wherein the antibody is trastuzumab. 81. The method of claim 80, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 98-104, 107-113, 116-122, and 135-137. 82. The method of claim 79, wherein the antibody is rituximab. 83. The method of claim 82, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 98-104, 107-113, 116-122, and 135-137. 84. The method of claim 79, wherein the antibody is cetuximab. 85. The method of claim 84, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 98-104, 107-113, 116-122, and 135-137. 86. The method of claim 79, wherein the antibody is daratumumab. 87. The method of claim 86, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 98-104, 107-113, 116-122, and 135-137. 88. The method of claim 79, wherein the antibody is belimumab. 89. The method of claim 88, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 98-104, 107-113, 116-122, and 135-137. 90. The method of claim 79, wherein the antibody is bevacizumab. 91. The method of claim 90, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 98-104, 107-113, 116-122, and 135-137. 92. The method of claim 79, wherein the antibody is denosumab. 93. The method of claim 92, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 98-104, 107-113, 116-122, and 135-137. 94. The method of claim 79, wherein the antibody is panitumumab. 95. The method of claim 94, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 98-104, 107-113, 116-122, and 135-137. 96. The method of claim 79, wherein the antibody is ramucirumab. 97. The method of claim 96, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 98-104, 107-113, 116-122, and 135-137. 98. The method of claim 79, wherein the antibody is necitumumab. 99. The method of claim 98, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 98-104, 107-113, 116-122, and 135-137. 100. The method of claim 79, wherein the antibody is nivolumab. 101. The method of claim 100, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 98-104, 107-113, 116-122, and 135-137. 102. The method of claim 79, wherein the antibody is pembrolizumab. 103. The method of claim 102, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 98-104, 107-113, 116-122, and 135-137. 104. The method of claim 79, wherein the antibody is MSB0010718C. 105. The method of claim 104, herein the polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 98-104, 107-113, 116-122, and 135-137. 106. The method of claim 79, wherein the antibody is atezolizumab. 107. The method of claim 106, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 98-104, 107-113, 116-122, and 135-137. 108. The method of claim 79, wherein the antibody is pidilizumab. 109. The method of claim 108, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 98-104, 107-113, 116-122, and 135-137. 110. The method of claim 69, wherein the at least one additional agent is a tumor associated antigen and the tumor associated antigen elicits an immune response. 111. The method of claim 69, wherein the at least one additional agent is an antibody and the antibody targets a HLA/peptide or MHC/peptide complex. 112. The method of claim 111, wherein the antibody targets a HLA/peptide or MHC/peptide complex comprising a peptide derived from NY-ESO-1/LAGE1, SSX-2, a member of the MAGE protein family, gp100/pmel17, MelanA/MART1, gp75/TRP1, tyrosinase, TRP2, CEA, PSA, TAG-72, Immature laminin receptor, MOK/RAGE-1, WT-1, Her2/neu, EphA3, SAP-1, BING-4, Ep-CAM, MUC1, PRAME, survivin, Mesothelin, BRCA1, BRCA2, CDK4, CML66, MART-2, p53, Ras, .beta.-catenin, HPV E6, or HPV E7. 113. An isolated nucleic acid encoding the polypeptide of claim 44. 114. A vector comprising the nucleic acid of claim 113. 115. A host cell comprising the nucleic acid of claim 113. 116. A method of producing a polypeptide comprising culturing the host cell of claim 115 under appropriate conditions to cause expression of the polypeptide and recovering the polypeptide. 117. A pharmaceutical composition comprising the polypeptide of claim 44 and a pharmaceutically acceptable carrier. 118. The polypeptide of claim 44, wherein the SIRP-.alpha. D1 variant comprises the amino acid sequence set forth in SEQ ID NO: 78. 119. The polypeptide of claim 44, wherein the SIRP-.alpha. D1 variant comprises the amino acid sequence set forth in SEQ ID NO: 82. 120. The polypeptide of claim 44, wherein the SIRP-.alpha. D1 variant comprises the amino acid sequence set forth in SEQ ID NO: 85. 121. The polypeptide of claim 44, wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 101. 122. The polypeptide of claim 44, wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 110. 123. The polypeptide of claim 44, wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 136. 124. The method of claim 63, wherein the SIRP-.alpha. D1 variant comprises the amino acid sequence set forth in SEQ ID NO: 78. 125. The method of claim 63, wherein the SIRP-.alpha. D1 variant comprises the amino acid sequence set forth in SEQ ID NO: 82. 126. The method of claim 63, wherein the SIRP-.alpha. D1 variant comprises the amino acid sequence set forth in SEQ ID NO: 85. 127. The method of claim 63, wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 101. 128. The method of claim 63, wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 110. 129. The method of claim 63, wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 136. 130. A composition comprising the polypeptide of claim 44, wherein the polypeptide is a dimer. 131. The polypeptide of claim 52, wherein the two Fc domain monomers are different. 132. The composition of claim 130, wherein the SIRP-.alpha. D1 variant comprises the amino acid sequence set forth in SEQ ID NO: 78. 133. The composition of claim 130, wherein the SIRP-.alpha. D1 variant comprises the amino acid sequence set forth in SEQ ID NO: 82. 134. The composition of claim 130, wherein the SIRP-.alpha. D1 variant comprises the amino acid sequence set forth in SEQ ID NO: 85. 135. The composition of claim 130, wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 101. 136. The composition of claim 130, wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 110. 137. The composition of claim 130, wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 136.

Details for Patent 10,259,859

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2035-08-07
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2035-08-07
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2035-08-07
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2035-08-07