ANTIBODIES AGAINST SIGNAL-REGULATORY PROTEIN ALPHA AND METHODS OF USE
Provided herein, inter alia, are isolated antibodies that bind an extracellular domain of a human SIRP-α v1 polypeptide (e.g., the D1 domain), an extracellular domain of a human SIRP-α v2 polypeptide, or both. In some embodiments, the antibodies also bind an extracellular domain of a monkey SIRP-α polypeptide, an extracellular domain of a mouse SIRP-α polypeptide, an extracellular domain of a human SIRP-β polypeptide, and/or an extracellular domain of a human SIRP-γ polypeptide. In some embodiments, the antibodies block or do not binding between an extracellular domain of a human SIRP-α polypeptide and an IgSF domain of a human CD47 polypeptide, while in some embodiments, the antibodies reduce the affinity of a human SIRP-α polypeptide for binding an IgSF domain of a human CD47 polypeptide. Further provided herein are methods, polynucleotides, vectors, and host cells related thereto.
1 - 148 . (canceled)
149 . A method of treating or delaying progression of cancer in an individual, the method comprising administering to the individual an effective amount of an antibody that binds an extracellular domain of a human SIRP-α polypeptide, wherein the antibody is capable of binding the extracellular domain of a human SIRP-α v1 polypeptide and is capable of binding the extracellular domain of a human SIRP-α v2 polypeptide.
150 . The method of claim 149 , further comprising administering to the individual an effective amount of a second antibody that binds an antigen expressed by the cancer.
151 . (canceled)
152 . The method of claim 149 , further comprising administering to the individual an effective amount of an immunotherapeutic agent.
153 - 199 . (canceled)
200 . The method of claim 149 , wherein the antibody binds an extracellular domain of a cynomolgus SIRP-α polypeptide comprising the amino acid sequence of SEQ ID NO:11.
201 . The method of claim 149 , wherein the antibody binds an extracellular domain of a murine SIRP-α polypeptide comprising the amino acid sequence of SEQ ID NO:7.
202 . The method of claim 149 , wherein the antibody binds an extracellular domain of a human SIRP-β polypeptide.
203 . The method of claim 149 , wherein the antibody binds an extracellular domain of a human SIRP-γ polypeptide.
204 . The method of claim 149 , wherein the antibody:
(a) modulates SIRP-α signaling in a cell expressing a human SIRP-α polypeptide;
(b) inhibits SIRP-α signaling in a macrophage expressing a human SIRP-α polypeptide;
(c) enhances phagocytosis by a macrophage expressing a human SIRP-α polypeptide;
(d) enhances activation of a dendritic cell expressing a human SIRP-α polypeptide; and/or
(e) inhibits in vivo growth of a tumor that expresses CD47.
205 . The method of claim 149 , wherein the antibody blocks binding between an extracellular domain of a human SIRP-α polypeptide and an IgSF domain of a human CD47 polypeptide.
206 . The method of claim 149 , wherein the antibody does not block binding between an extracellular domain of a human SIRP-α polypeptide and an IgSF domain of a human CD47 polypeptide.
207 . The method of claim 149 , wherein the antibody comprises:
(a) an HVR-H1 sequence comprising the amino acid sequence of GFSFSX 1 X 2 AMX 3 , wherein X 1 is N or I; X 2 is F or Y; and X 3 is T or S (SEQ ID NO:185);
(b) an HVR-H2 sequence comprising the amino acid sequence of TIGX 4 X 5 DTYYADSVKG, wherein X 4 is S or A and X 5 is G or D (SEQ ID NO:186);
(c) an HVR-H3 sequence comprising the amino acid sequence of DSTVX 6 WSGDFFDY, wherein X 6 is S or G (SEQ ID NO:187);
(d) an HVR-L1 sequence comprising the amino acid sequence of RASQNVX 7 X 8 DX 9 A, wherein X 7 is K or R; X 8 is N or S; and X 9 is L or I (SEQ ID NO:188);
(e) an HVR-L2 sequence comprising the amino acid sequence of AAX 10 X 11 RX 12 T, wherein X 10 is R or S; X 11 is I or S; and X 12 is E or D (SEQ ID NO:189); and
(f) an HVR-L3 sequence comprising the amino acid sequence of QQYYDWPPFT (SEQ ID NO:148).
208 . The method of claim 149 , wherein the antibody comprises:
(a) a heavy chain variable (VH) domain comprising:
(i) an HVR-H1 sequence comprising the amino acid sequence of X 1 X 2 DX 3 N, wherein X 1 is S or T; X 2 is Y or S; and X 3 is M, L, or V (SEQ ID NO:307);
(ii) an HVR-H2 sequence comprising the amino acid sequence of LISGSGEIX 1 YYADSVKG, wherein X 1 is I or T (SEQ ID NO:308); and
(iii) an HVR-H3 sequence comprising the amino acid sequence of EX 1 X 2 X 3 YRFFDX 4 , wherein X 1 is N or D; X 2 is N or D; X 3 is R or M; and X 4 is D or Y (SEQ ID NO:309); and
(b) a light chain variable (VL) domain comprising:
(i) an HVR-L1 sequence comprising the amino acid sequence of RAX 1 QSVYX 2 YLA, wherein X 1 is S or D; and X 2 is T or S (SEQ ID NO:310);
(ii) an HVR-L2 sequence comprising the amino acid sequence of X 1 AX 2 X 3 RAX 4 , wherein X 1 is G, A, or D; X 2 is S or R; X 3 is S, N, or T; and X 4 is T or A (SEQ ID NO:311); and
(iii) an HVR-L3 sequence comprising the amino acid sequence of QQYYDRPPLT (SEQ ID NO:160).
209 . The method of claim 208 , wherein the antibody comprises:
(a) a heavy chain variable (VH) domain comprising (i) an HVR-H1 sequence comprising the amino acid sequence of SYDMN (SEQ ID NO:270), SYDVN (SEQ ID NO:221), or SYDLN (SEQ ID NO:313), (ii) an HVR-H2 sequence comprising the amino acid sequence of LISGSGEIIYYADSVKG (SEQ ID NO:156), and (iii) an HVR-H3 sequence comprising the amino acid sequence of ENNRYRFFDD (SEQ ID NO:157); and
(b) a light chain variable (VL) domain comprising (i) an HVR-L1 sequence comprising the amino acid sequence of RASQSVYTYLA (SEQ ID NO:158), (ii) an HVR-L2 sequence comprising the amino acid sequence of GASSRAT (SEQ ID NO:159), and (iii) an HVR-L3 sequence comprising the amino acid sequence of QQYYDRPPLT (SEQ ID NO:160).
210 . The method of claim 208 , wherein the antibody comprises:
(a) the VH domain comprises the amino acid sequence of SEQ ID NO:133, and the VL domain comprises the amino acid sequence of SEQ ID NO:134;
(b) the VH domain comprises the amino acid sequence of SEQ ID NO:260, and the VL domain comprises the amino acid sequence of SEQ ID NO:134;
(c) the VH domain comprises the amino acid sequence of SEQ ID NO:329, and the VL domain comprises the amino acid sequence of SEQ ID NO:134;
(d) the VH domain comprises the amino acid sequence of SEQ ID NO:133, and the VL domain comprises the amino acid sequence of SEQ ID NO:250;
(e) the VH domain comprises the amino acid sequence of SEQ ID NO:260, and the VL domain comprises the amino acid sequence of SEQ ID NO:250;
(f) the VH domain comprises the amino acid sequence of SEQ ID NO:329, and the VL domain comprises the amino acid sequence of SEQ ID NO:250;
(g) the VH domain comprises the amino acid sequence of SEQ ID NO:133, and the VL domain comprises the amino acid sequence of SEQ ID NO:251;
(h) the VH domain comprises the amino acid sequence of SEQ ID NO:260, and the VL domain comprises the amino acid sequence of SEQ ID NO:251;
(i) the VH domain comprises the amino acid sequence of SEQ ID NO:329, and the VL domain comprises the amino acid sequence of SEQ ID NO:251;
(j) the VH domain comprises the amino acid sequence of SEQ ID NO:249, and the VL domain comprises the amino acid sequence of SEQ ID NO:134;
(k) the VH domain comprises the amino acid sequence of SEQ ID NO:249, and the VL domain comprises the amino acid sequence of SEQ ID NO:250; or
(l) the VH domain comprises the amino acid sequence of SEQ ID NO:249, and the VL domain comprises the amino acid sequence of SEQ ID NO:251.
211 . The method of claim 149 , wherein the antibody comprises:
(a) a heavy chain variable (VH) domain comprising:
(i) an HVR-H1 sequence comprising the amino acid sequence of X 1 X 2 AX 3 S, wherein X 1 is S or T; X 2 is N, Y, H, or D; and X 3 is M, L, or V (SEQ ID NO:297);
(ii) an HVR-H2 sequence comprising the amino acid sequence of GISX 1 X 2 X 3 X 4 X 5 X 6 YYX 7 X 8 SX 9 KG, wherein X 1 is A or S; X 2 is G, S, or absent; X 3 is S, D or G; X 4 is G or S; X 5 is D, S, or G; X 6 is T or A; X 7 is P, G, V, I, A, or S; X 8 is A, D, or G; and X 9 is V or M (SEQ ID NO:298); and
(iii) an HVR-H3 sequence comprising the amino acid sequence of ETWNHLFDY (SEQ ID NO:193); and
(b) a light chain variable (VL) domain comprising:
(i) an HVR-L1 sequence comprising the amino acid sequence of SGGX 1 X 2 X 3 SX 4 YYX 5 , wherein X 1 is D, G, S, I, or absent; X 2 is 5, W, G, Y, D, or absent; X 3 is S, Y, T, or D; X 4 is H, T, S, or Y; and X 5 is G or A (SEQ ID NO:299);
(ii) an HVR-L2 sequence comprising the amino acid sequence of SDX 1 X 2 RPX 3 , wherein X 1 is D or N; X 2 is E, K, or Q; and X 3 is S or P (SEQ ID NO:300); and
(iii) an HVR-L3 sequence comprising the amino acid sequence of X 1 X 2 YDX 3 X 4 X 5 YX 6 NX 7 , wherein X 1 is G or A; X 2 is G or A; X 3 is G, Y, Q, S, or A; X 4 is S, R, or T; X 5 is T or S; X 6 is A, I, V, L, or T; and X 7 is T, A, D, or P (SEQ ID NO:301).
212 . The method of claim 211 , wherein the antibody comprises:
(a) a VH domain comprising (i) an HVR-H1 sequence comprising the amino acid sequence of SNAMS (SEQ ID NO:194), SNAVS (SEQ ID NO:271), or SNALS (SEQ ID NO:318), (ii) an HVR-H2 sequence comprising the amino acid sequence of GISAGGSDTYYPASVKG (SEQ ID NO:195), and (iii) an HVR-H3 sequence comprising the amino acid sequence of ETWNHLFDY (SEQ ID NO:193), and a VL domain comprising (i) an HVR-L1 sequence comprising the amino acid sequence of SGGSYSSYYYA (SEQ ID NO:170), (ii) an HVR-L2 sequence comprising the amino acid sequence of SDDKRPS (SEQ ID NO:336), and (iii) an HVR-L3 sequence comprising the amino acid sequence of GGYDQSSYTNP (SEQ ID NO:172);
(b) a VH domain comprising (i) an HVR-H1 sequence comprising the amino acid sequence of SNAMS (SEQ ID NO:194), SNAVS (SEQ ID NO:271), or SNALS (SEQ ID NO:318), (ii) an HVR-H2 sequence comprising the amino acid sequence of GISSGSDTYYGDSVKG (SEQ ID NO:197), and (iii) an HVR-H3 sequence comprising the amino acid sequence of ETWNHLFDY (SEQ ID NO:193), and a VL domain comprising (i) an HVR-L1 sequence comprising the amino acid sequence of SGGSYSSYYYA (SEQ ID NO:170), (ii) an HVR-L2 sequence comprising the amino acid sequence of SDDKRPS (SEQ ID NO:336), and (iii) an HVR-L3 sequence comprising the amino acid sequence of GGYDQSSYTNP (SEQ ID NO:172);
(c) a VH domain comprising (i) an HVR-H1 sequence comprising the amino acid sequence of SYAMS (SEQ ID NO:200), SYAVS (SEQ ID NO:272), or SYALS (SEQ ID NO:319), (ii) an HVR-H2 sequence comprising the amino acid sequence of GISSGGDTYYVDSVKG (SEQ ID NO:201), and (iii) an HVR-H3 sequence comprising the amino acid sequence of ETWNHLFDY (SEQ ID NO:193), and a VL domain comprising (i) an HVR-L1 sequence comprising the amino acid sequence of SGGSYSSYYYA (SEQ ID NO:170), (ii) an HVR-L2 sequence comprising the amino acid sequence of SDDKRPS (SEQ ID NO:336), and (iii) an HVR-L3 sequence comprising the amino acid sequence of GGYDQSSYTNP (SEQ ID NO:172);
(d) a VH domain comprising (i) an HVR-H1 sequence comprising the amino acid sequence of SNAMS (SEQ ID NO:194), SNAVS (SEQ ID NO:271), or SNALS (SEQ ID NO:318), (ii) an HVR-H2 sequence comprising the amino acid sequence of GISAGGSDTYYPASVKG (SEQ ID NO:195), and (iii) an HVR-H3 sequence comprising the amino acid sequence of ETWNHLFDY (SEQ ID NO:193), and a VL domain comprising (i) an HVR-L1 sequence comprising the amino acid sequence of SGGAYSSYYYA (SEQ ID NO:261), (ii) an HVR-L2 sequence comprising the amino acid sequence of SDDKRPS (SEQ ID NO:336), and (iii) an HVR-L3 sequence comprising the amino acid sequence of GGYDQSSYTNP (SEQ ID NO:172);
(e) a VH domain comprising (i) an HVR-H1 sequence comprising the amino acid sequence of SNAMS (SEQ ID NO:194), SNAVS (SEQ ID NO:271), or SNALS (SEQ ID NO:318), (ii) an HVR-H2 sequence comprising the amino acid sequence of GISSGSDTYYGDSVKG (SEQ ID NO:197), and (iii) an HVR-H3 sequence comprising the amino acid sequence of ETWNHLFDY (SEQ ID NO:193), and a VL domain comprising (i) an HVR-L1 sequence comprising the amino acid sequence of SGGAYSSYYYA (SEQ ID NO:261), (ii) an HVR-L2 sequence comprising the amino acid sequence of SDDKRPS (SEQ ID NO:336), and (iii) an HVR-L3 sequence comprising the amino acid sequence of GGYDQSSYTNP (SEQ ID NO:172); or
(f) a VH domain comprising (i) an HVR-H1 sequence comprising the amino acid sequence of SYAMS (SEQ ID NO:200), SYAVS (SEQ ID NO:272), or SYALS (SEQ ID NO:319), (ii) an HVR-H2 sequence comprising the amino acid sequence of GISSGGDTYYVDSVKG (SEQ ID NO:201), and (iii) an HVR-H3 sequence comprising the amino acid sequence of ETWNHLFDY (SEQ ID NO:193), and a VL domain comprising (i) an HVR-L1 sequence comprising the amino acid sequence of SGGAYSSYYYA (SEQ ID NO:261), (ii) an HVR-L2 sequence comprising the amino acid sequence of SDDKRPS (SEQ ID NO:336), and (iii) an HVR-L3 sequence comprising the amino acid sequence of GGYDQSSYTNP (SEQ ID NO:172).
213 . The method of claim 211 , wherein the antibody comprises:
(a) a heavy chain variable (VH) domain comprising:
(i) an HVR-H1 sequence comprising the amino acid sequence of SX 1 AX 2 S, wherein X 1 is N or Y; and wherein X 2 is M, L, or V (SEQ ID NO:302);
(ii) an HVR-H2 sequence comprising the amino acid sequence of GISX 1 GX 2 X 3 DTYYX 4 X 5 SVKG, wherein X 1 is A or S; X 2 is G or absent; X 3 is S or G; X 4 is P, G, or V; and X 5 is A or D (SEQ ID NO:303); and
(iii) an HVR-H3 sequence comprising the amino acid sequence of ETWNHLFDY (SEQ ID NO:193); and
(b) a light chain variable (VL) domain comprising:
(i) an HVR-L1 sequence comprising the amino acid sequence of SGGX 1 YSSYYYA, wherein X 1 is S or A (SEQ ID NO:304);
(ii) an HVR-L2 sequence comprising the amino acid sequence of SDDKRPS (SEQ ID NO:336); and
(iii) an HVR-L3 sequence comprising the amino acid sequence of GGYDQSSYTNP (SEQ ID NO:172).
214 . The method of claim 213 , wherein the antibody comprises:
(a) a heavy chain that comprises a heavy chain variable (VH) domain comprising:
(i) an HVR-H1 sequence comprising the amino acid sequence of SNAMS (SEQ ID NO:194),
(ii) an HVR-H2 sequence comprising the amino acid sequence of GISAGGSDTYYPASVKG (SEQ ID NO:195), and
(iii) an HVR-H3 sequence comprising the amino acid sequence of ETWNHLFDY (SEQ ID NO:193); and
(b) a light chain that comprises a light chain variable (VL) domain comprising:
(i) an HVR-L1 sequence comprising the amino acid sequence of SGGSYSSYYYA (SEQ ID NO:170),
(ii) an HVR-L2 sequence comprising the amino acid sequence of SDDKRPS (SEQ ID NO:336), and
(iii) an HVR-L3 sequence comprising the amino acid sequence of GGYDQSSYTNP (SEQ ID NO:172).
215 . The method of claim 211 , wherein the antibody comprises:
(a) a VH domain comprising the amino acid sequence of SEQ ID NO:263, and a VL domain comprising the amino acid sequence of SEQ ID NO:252;
(b) a VH domain comprising the amino acid sequence of SEQ ID NO:264, and a VL domain comprising the amino acid sequence of SEQ ID NO:252;
(c) a VH domain comprising the amino acid sequence of SEQ ID NO:330, and a VL domain comprising the amino acid sequence of SEQ ID NO:252;
(d) a VH domain comprising the amino acid sequence of SEQ ID NO:135, and a VL domain comprising the amino acid sequence of SEQ ID NO:252;
(e) a VH domain comprising the amino acid sequence of SEQ ID NO:137, and a VL domain comprising the amino acid sequence of SEQ ID NO:252;
(f) a VH domain comprising the amino acid sequence of SEQ ID NO:139, and a VL domain comprising the amino acid sequence of SEQ ID NO:252;
(g) a VH domain comprising the amino acid sequence of SEQ ID NO:265, and a VL domain comprising the amino acid sequence of SEQ ID NO:252;
(h) a VH domain comprising the amino acid sequence of SEQ ID NO:266, and a VL domain comprising the amino acid sequence of SEQ ID NO:252;
(i) a VH domain comprising the amino acid sequence of SEQ ID NO:331, and a VL domain comprising the amino acid sequence of SEQ ID NO:252;
(j) a VH domain comprising the amino acid sequence of SEQ ID NO:267, and a VL domain comprising the amino acid sequence of SEQ ID NO:252;
(k) a VH domain comprising the amino acid sequence of SEQ ID NO:268, and a VL domain comprising the amino acid sequence of SEQ ID NO:252;
(l) a VH domain comprising the amino acid sequence of SEQ ID NO:332, and a VL domain comprising the amino acid sequence of SEQ ID NO:252;
(j) a VH domain comprising the amino acid sequence of SEQ ID NO:263, and a VL domain comprising the amino acid sequence of SEQ ID NO:262;
(m) a VH domain comprising the amino acid sequence of SEQ ID NO:264, and a VL domain comprising the amino acid sequence of SEQ ID NO:262;
(n) a VH domain comprising the amino acid sequence of SEQ ID NO:330, and a VL domain comprising the amino acid sequence of SEQ ID NO:262;
(o) a VH domain comprising the amino acid sequence of SEQ ID NO:265, and a VL domain comprising the amino acid sequence of SEQ ID NO:262;
(p) a VH domain comprising the amino acid sequence of SEQ ID NO:266, and a VL domain comprising the amino acid sequence of SEQ ID NO:262;
(q) a VH domain comprising the amino acid sequence of SEQ ID NO:331, and a VL domain comprising the amino acid sequence of SEQ ID NO:262;
(r) a VH domain comprising the amino acid sequence of SEQ ID NO:267, and a VL domain comprising the amino acid sequence of SEQ ID NO:262;
(s) a VH domain comprising the amino acid sequence of SEQ ID NO:268, and a VL domain comprising the amino acid sequence of SEQ ID NO:262;
(t) a VH domain comprising the amino acid sequence of SEQ ID NO:332, and a VL domain comprising the amino acid sequence of SEQ ID NO:262;
(u) a VH domain comprising the amino acid sequence of SEQ ID NO:135, and a VL domain comprising the amino acid sequence of SEQ ID NO:262;
(v) a VH domain comprising the amino acid sequence of SEQ ID NO:137, and a VL domain comprising the amino acid sequence of SEQ ID NO:262; or
(w) a VH domain comprising the amino acid sequence of SEQ ID NO:139, and a VL domain comprising the amino acid sequence of SEQ ID NO:262.
216 . The method of claim 207 , wherein the antibody comprises a heavy chain comprising the VH domain and a human IgG1 Fc region, a human IgG2 Fc region, or a human IgG4 Fc region.
217 . The method of claim 216 , wherein the Fc region is:
(a) a human IgG1 Fc region comprising one or more mutations selected from the group consisting of L234A, L235A, G237A, and N297A, according to EU numbering;
(b) a human IgG2 Fc region comprising one or more mutations selected from the group consisting of A330S, P331S and N297A, according to EU numbering; or
(c) a human IgG4 Fc region comprising one or more mutations selected from the group consisting of S228P, E233P, F234V, L235A, L235E, delG236, and N297A, according to EU numbering.
218 . The method of claim 207 , wherein the antibody comprises a heavy chain comprising the VH domain and an amino acid sequence selected from the group consisting of SEQ ID NOs:320-324.
219 . The method of claim 207 , wherein the antibody comprises a light chain comprising the VL domain and the amino acid sequence of SEQ ID NO:325, 326, or 426.
220 . The method of claim 208 , wherein the antibody comprises a heavy chain comprising the VH domain and a human IgG1 Fc region, a human IgG2 Fc region, or a human IgG4 Fc region.
221 . The method of claim 220 , wherein the Fc region is:
(a) a human IgG1 Fc region comprising one or more mutations selected from the group consisting of L234A, L235A, G237A, and N297A, according to EU numbering;
(b) a human IgG2 Fc region comprising one or more mutations selected from the group consisting of A330S, P331S and N297A, according to EU numbering; or
(c) a human IgG4 Fc region comprising one or more mutations selected from the group consisting of S228P, E233P, F234V, L235A, L235E, delG236, and N297A, according to EU numbering.
222 . The method of claim 208 , wherein the antibody comprises a heavy chain comprising the VH domain and an amino acid sequence selected from the group consisting of SEQ ID NOs:320-324.
223 . The method of claim 208 , wherein the antibody comprises a light chain comprising the VL domain and the amino acid sequence of SEQ ID NO:325, 326, or 426.
224 . The method of claim 211 , wherein the antibody comprises a heavy chain comprising the VH domain and a human IgG1 Fc region, a human IgG2 Fc region, or a human IgG4 Fc region.
225 . The method of claim 224 , wherein the Fc region is:
(a) a human IgG1 Fc region comprising one or more mutations selected from the group consisting of L234A, L235A, G237A, and N297A, according to EU numbering;
(b) a human IgG2 Fc region comprising one or more mutations selected from the group consisting of A330S, P331S and N297A, according to EU numbering; or
(c) a human IgG4 Fc region comprising one or more mutations selected from the group consisting of S228P, E233P, F234V, L235A, L235E, delG236, and N297A, according to EU numbering.
226 . The method of claim 211 , wherein the antibody comprises a heavy chain comprising the VH domain and an amino acid sequence selected from the group consisting of SEQ ID NOs:320-324.
227 . The method of claim 211 , wherein the antibody comprises a light chain comprising the VL domain and the amino acid sequence of SEQ ID NO:325, 326, or 426.
228 . The method of claim 149 , wherein the antibody binds to the human SIRP-α v1 polypeptide at one or more amino acid positions selected from the group consisting of 131, V33, Q52, K53, T67, R69, N70, and K96, according to SEQ ID NO:296.
229 . The method of claim 149 , wherein the antibody binds to the human SIRP-α v1 polypeptide at one or more amino acid positions selected from the group consisting of I7, P9, D10, K11, S12, A42, A108, and E111, according to SEQ ID NO:296.
230 . The method of claim 149 , wherein the antibody binds to the human SIRP-α v1 polypeptide at one or more amino acid positions selected from the group consisting of E47, L48, P58, R59, T82, and A84, according to SEQ ID NO:296.
231 . The method of claim 149 , wherein the antibody binds the extracellular domain of the human SIRP-α v1 polypeptide with a dissociation constant (K D ) of less than 100 nM, and wherein the antibody blocks binding between an extracellular domain of a human SIRP-α polypeptide and an IgSF domain of a human CD47 polypeptide.
232 . The method of claim 149 , wherein the antibody binds the D1 domain of a human SIRP-α polypeptide, and wherein the antibody does not block binding between an extracellular domain of a human SIRP-α polypeptide and an IgSF domain of a human CD47 polypeptide.
233 . The method of claim 149 , wherein the antibody competes for binding the extracellular domain of the human SIRP-α polypeptide with a reference anti-SIRP-α antibody comprising a heavy chain variable (VH) domain and a light chain variable (VL) domain of an antibody selected from the group consisting of:
(a) antibodies 119, 120, 121, 122, 21, 25, 27, 66, and 135;
(b) antibodies 136 and 137;
(c) antibodies 3, 213, 173, and 209;
(d) antibodies 115, 116, 117, 118, and 132;
(e) antibodies 218, 123, 149, 161, 162, and 194; or
(f) antibody 45.
234 . The method of claim 149 , wherein the antibody is conjugated to a cytotoxic agent or label.
235 . The method of claim 149 , wherein the antibody is a bispecific antibody that antibody comprises a first antigen binding domain that binds the extracellular domain of a human SIRP-α polypeptide and a second antigen binding domain that binds an antigen expressed by a cancer cell.
236 . The method of claim 150 , wherein the antigen expressed by the cancer is selected from the group consisting of CD19, CD20, CD22, CD30, CD33, CD38, CD52, CD56, CD70, CD74, CD79b, CD123, CD138, CS1/SLAMF7, Trop-2, 5T4, EphA4, BCMA, Mucin 1, Mucin 16, PTK7, STEAP1, Endothelin B Receptor, mesothelin, EGFRvIII, ENPP3, SLC44A4, GNMB, nectin 4, NaPi2b, LIV-1A, Guanylyl cyclase C, DLL3, EGFR, HER2, VEGF, VEGFR, integrin αVβ3, integrin α5β1, MET, IGF1R, TRAILR1, TRAILR2, RANKL, FAP, Tenascin, Le y , EpCAM, CEA, gpA33, PSMA, TAG72, a mucin, CAIX, EPHA3, folate receptor α, GD2, GD3, and an MHC/peptide complex comprising a peptide from NY-ESO-1/LAGE, SSX-2, a MAGE family protein, MAGE-A3, gp100/pmel17, Melan-A/MART-1, gp75/TRP1, tyrosinase, TRP2, CEA, PSA, TAG-72, immature laminin receptor, MOK/RAGE-1, WT-1, SAP-1, BING-4, EpCAM, MUC1, PRAME, survivin, BRCA1, BRCA2, CDK4, CML66, MART-2, p53, Ras, β-catenin, TGF-βRII, HPV E6, or HPV E7.
237 . The method of claim 152 , wherein the immunotherapeutic agent comprises a second antibody that binds to an antigen selected from the group consisting of PD-1, PD-L1, OX40, CTLA-4, CD137/4-1BB, TNFR2, B7-H3, FZD7, CD27, CCR4, CSF1R, CSF, TIM-3, LAG-3, VISTA, ICOS, CCR2, IDO, A2R, CD39, CD73, TIGIT, CD80, CD47, arginase, TDO, and PVRIG.
238 . The method of claim 237 , wherein the antibody that is capable of binding the extracellular domain of a human SIRP-α v1 polypeptide and is capable of binding the extracellular domain of a human SIRP-α v2 polypeptide binds the extracellular domains of both a human SIRP-α v1 polypeptide and a human SIRP-α v2 polypeptide with a dissociation constant (K D ) of less than 100 nM and blocks binding between an extracellular domain of a human SIRP-α polypeptide and an IgSF domain of a human CD47 polypeptide, and wherein the second antibody binds to PD-1 or PD-L1.
239 . The method of claim 237 , wherein the antibody that is capable of binding the extracellular domain of a human SIRP-α v1 polypeptide and is capable of binding the extracellular domain of a human SIRP-α v2 polypeptide binds the D1 domain of a human SIRP-αpolypeptide and does not block binding between an extracellular domain of a human SIRP-α polypeptide and an IgSF domain of a human CD47 polypeptide, and wherein the second antibody binds to PD-1 or PD-L1.
240 . The method of claim 149 , wherein the cancer is a carcinoma, sarcoma, lymphoma, leukemia, lymphoma, or blastoma.
241 . The method of claim 149 , wherein the cancer is lung cancer, squamous cell cancer, a brain tumor, glioblastoma, head and neck cancer, hepatocellular cancer, colorectal cancer, liver cancer, bladder cancer, gastric or stomach cancer, pancreatic cancer, cervical cancer, ovarian cancer, cancer of the urinary tract, breast cancer, peritoneal cancer, uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, anal carcinoma, penile carcinoma, melanoma, multiple myeloma, B-cell lymphoma, non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), Merkel cell carcinoma, hairy cell leukemia, chronic myeloblastic leukemia (CIVIL), or an associated metastasis thereof.