Use of anti-sirp-alpha antibodies for the treatment of cancer

Abstract

The present disclosure relates to the treatment of cancer by using anti-SIRPa (signal regulatory protein alpha) antibodies or antigen-binding fragments thereof. In particular, the present disclosure relates to a method of treating cancer comprising using an anti-SIRPa antibody or antigen-binding fragment thereof in a treatment regimen, and the use of an anti-SIRPa antibody or antigen-binding fragment thereof for treating cancer, the treatment regimen optionally comprising the administration of an additional therapeutic agent.

Description

sequence list

[0001] This application contains a sequence list, which has been electronically submitted in XML format and incorporated herein by reference in its entirety. The XML copy was created on September 27, 2024, named 105218-03-5014-WO_SequenceListing.xml, and is 291,533 bytes in size. The relevant application is made public.

[0002] This application claims priority to U.S. Provisional Application No. 63 / 542,980, filed October 6, 2023, and U.S. Provisional Application No. 63 / 654,781, filed May 31, 2024, each of which is incorporated herein by reference in its entirety. Technical Field

[0003] This disclosure relates to the use of anti-SIRPα (signal regulatory protein α) antibodies or antigen-binding fragments thereof to treat cancer. In particular, this disclosure relates to methods of treating cancer using anti-SIRPα antibodies or antigen-binding fragments thereof in a treatment regimen, and the use of anti-SIRPα antibodies or antigen-binding fragments thereof for treating cancer, the treatment regimen optionally including the administration of another therapeutic agent. Background Technology

[0004] SIRPα is an inhibitory receptor expressed on bone marrow cells, including macrophages, neutrophils, and dendritic cell subsets. SIRPα contains three Ig-like domains, a single transmembrane domain, and a cytoplasmic tail region with four tyrosine residues forming two typical immunoreceptor tyrosine-based inhibitory motifs (ITIMs). The natural ligand of SIRPα is CD47, which is expressed on many cells, including erythrocytes and platelets. Binding of SIRPα to CD47 leads to phosphorylation of tyrosine residues in the intracellular ITIM domain of SIRPα, subsequently recruiting and activating SHP-1 and SHP-2 phosphatases at the cell membrane. These phosphatases can then regulate cellular functions, including phagocytosis and antigen presentation, through dephosphorylation of downstream targets.

[0005] The development of effective SIRPα antagonists is complicated by polymorphisms within the CD47 binding domain. Up to ten allelic variants have been reported in the general population (Takenaka 2007; Nat Immunol 2007 Dec; 8(12):1313-23), and recent studies (Treffers, 2018, Eur J Immunol. 2018 Feb; 48(2):344-354; MAbs 2019 Aug / Sep; 11(6):1036-1052) highlight that two SIRPα variants, V1 and V2, constitute the most prevalent alleles: iso-conjugating V1 / V1, iso-conjugating V2 / V2, and iso-conjugating V1 / V2. These variants differ on 13 of the 118 amino acid residues in the N-terminal immunoglobulin-like domain of SIRPα responsible for CD47 binding. These polymorphic residues are located outside the CD47 binding site, and therefore CD47 has similar binding affinity to SIRPα variants (Hatherley D, 2008 Immunity, November 14, 2008; 29(5):675-8). Therefore, therapeutic targeting of SIRPα in different patient populations, independent of SIRPα genotype, necessitates pan-allele antibodies that cross-react with the two major SIRPα alleles (V1 and V2).

[0006] In addition to considering polymorphic variants when targeting SIRPα, SIRPβ1 and SIRPγ, SIRPα’s closest related species, should also be considered due to their high sequence conservation, especially in the N-terminal domain. Like SIRPα, SIRPβ1 is also primarily expressed in bone marrow lineage cells, but unlike SIRPα, it lacks its own signal transduction cytoplasmic domain. Instead, it has positively charged amino acid residues in its transmembrane region, allowing for stable association with the ITAM-containing adaptor molecule DAP12, and is therefore presumed to act as an activation receptor. SIRPβ1 does not bind to CD47, and its ligand has not yet been identified. At least two SIRPβ1 isotypes exist, generated by tandem replication of genes within the SIRP family gene cluster (Liu et al. 2007 J Mol Biol. 19 Jan 2007; 365(3):680-93; Brooke et al. 2004 J Immunol. 15 Aug 2004; 173(4):2562-70). SIRPγ is expressed only on T cells and activated NK cells and binds to CD47 with an affinity 10 times lower than that of SIRPα:CD47 interaction. Although it does not have intrinsic signaling capabilities, it has been reported to play a role in T cell transendothelial migration (TEM) and antigen presentation.

[0007] The interaction between SIRPα and CD47 is an important immune checkpoint involved in the innate response to bone marrow function regulation. This interaction provides a downregulated signal that inhibits host cell phagocytosis. Because CD47 is widely overexpressed in some cancer cells, it acts as a "don't eat me" signal within tumors containing these cells, thereby preventing phagocytosis. To enhance macrophage phagocytosis, anti-human SIRPα antibodies have been developed that disrupt the binding between SIRPα and CD47. Nevertheless, there is still a need to refine the use of these antibodies, particularly to modulate their effects in vivo, for example, by enhancing patient responses to anti-SIRPα antibodies or their antigen-binding fragments. Further improvements are needed in the use of these antibodies in combination with other therapeutic agents. Summary of the Invention

[0008] This disclosure provides a method for treating cancer in a subject in need by administering a dose of an anti-SIRPα antibody or an antigen-binding fragment thereof to the subject.

[0009] In one aspect, this disclosure provides a method of treating cancer in a subject in need, comprising administering to the subject a dose of an anti-SIRPα antibody or an antigen-binding fragment thereof in the amount of about 800 mg to about 3600 mg; wherein the anti-SIRPα antibody or the antigen-binding fragment thereof comprises: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 34 (H-CDR2); and the amino acid sequence of SEQ ID NO: 35 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 37 (L-CDR1); the amino acid sequence of SEQ ID NO: 38 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3), or b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 223 (H-CDR1); SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 323 (H-CDR1); SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 323 (H-CDR1); SEQ ID NO: 2, SEQ ID NO: 323 (H-CDR1); SEQ ID NO: 33, SEQ ID NO: 323 (H-CDR2); SEQ ID NO: 33, SEQ ID NO: 323 (H-CDR3 ...1); SEQ ID NO: 33, SEQ ID NO: 323 (H-CDR2); SEQ ID NO: 33, NO: 4, SEQ ID NO: 5 or SEQ ID NO: 224 amino acid sequence (H-CDR2); and SEQ ID NO: 6 amino acid sequence (H-CDR3); and light chain variable region comprising SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 225 amino acid sequence (L-CDR1); SEQ ID NO: 10, SEQ ID NO: 11 or SEQ ID NO: 226 amino acid sequence (L-CDR2); and SEQ ID NO: 12 or SEQ ID NO: 227 amino acid sequence (L-CDR3), or c) heavy chain variable region comprising SEQ ID NO: 52 amino acid sequence (H-CDR1); SEQ ID NO: 53 amino acid sequence (H-CDR2); and SEQ ID NO: 54 amino acid sequence (H-CDR3); and light chain variable region comprising SEQ ID NO: Amino acid sequence of SEQ ID NO: 55 (L-CDR1); amino acid sequence of SEQ ID NO: 56 (L-CDR2); and amino acid sequence of SEQ ID NO: 57 (L-CDR3), or d) heavy chain variable region comprising amino acid sequence of SEQ ID NO: 33 (H-CDR1); amino acid sequence of SEQ ID NO: 70 (H-CDR2); and amino acid sequence of SEQ ID NO: 71 (H-CDR3); and light chain variable region comprising amino acid sequence of SEQ ID NO: 36 (L-CDR1); and amino acid sequence of SEQ ID NO: 72 (L-CDR2);and the amino acid sequence of SEQ ID NO: 39 (L-CDR3), or e) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 243 (H-CDR1); the amino acid sequence of SEQ ID NO: 87 (H-CDR2); and the amino acid sequence of SEQ ID NO: 88 (H-CDR3); and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 89 (L-CDR3).

[0010] In another aspect, this disclosure provides a method of treating cancer in a subject in need, comprising administering to the subject a dose of about 800 mg to about 3600 mg of an anti-SIRPα antibody or an antigen-binding fragment thereof, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof comprises: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 34 (H-CDR2); the amino acid sequence of SEQ ID NO: 35 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 233, wherein amino acid X1 = D or G and X2 = L or A (L-CDR1); the amino acid sequence of SEQ ID NO: 38 (L-CDR2); the amino acid sequence of SEQ ID NO: 39 (L-CDR3), or b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 228 (H-CDR1), wherein amino acid X1 = N or D; SEQ ID NO: The amino acid sequence of SEQ ID NO: 229, wherein X1=Y or D, X2=N or T, X3=N or Q and X4=S or P (H-CDR2); the amino acid sequence of SEQ ID NO: 6 (H-CDR3); and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 230, wherein X1=K or R, X2=N or T, X3=G or A and X4=N, A or T (L-CDR1); the amino acid sequence of SEQ ID NO: 231, wherein X1=L, Q or G and X2=N or S (L-CDR2); and the amino acid sequence of SEQ ID NO: 232, wherein X1=M or G (L-CDR3).

[0011] In another aspect, this disclosure provides an anti-SIRPα antibody or an antigen-binding fragment thereof for treating cancer in a subject of need, wherein the subject is administered an anti-SIRPα antibody or an antigen-binding fragment thereof in a dose of about 800 mg to about 3600 mg; wherein the anti-SIRPα antibody or an antigen-binding fragment thereof comprises: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 34 (H-CDR2); and the amino acid sequence of SEQ ID NO: 35 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 37 (L-CDR1); the amino acid sequence of SEQ ID NO: 38 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3), or b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 223 (H-CDR1); SEQ ID NO: 2. The amino acid sequence of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 or SEQ ID NO: 224 (H-CDR2); and the amino acid sequence of SEQ ID NO: 6 (H-CDR3); and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 225 (L-CDR1); the amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11 or SEQ ID NO: 226 (L-CDR2); and the amino acid sequence of SEQ ID NO: 12 or SEQ ID NO: 227 (L-CDR3), or c) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 52 (H-CDR1); the amino acid sequence of SEQ ID NO: 53 (H-CDR2); and the amino acid sequence of SEQ ID NO: 54 (H-CDR3); and the light ...2); the amino acid sequence of SEQ ID NO: 54 (H-CDR3); and the amino acid sequence of SEQ ID NO: 54 (H-CDR3); and the amino acid sequence of SEQ ID NO: 52 (H-CDR2); the amino acid sequence of SEQ ID NO: 54 (H-CDR3); and the amino acid sequence of SEQ ID NO: 54 (H-CDR2); and the amino acid sequence of SEQ ID NO: 54 (H-CDR3); and the amino acid sequence of SEQ ID NO: 54 (H-CDR2); and the amino acid sequence of SEQ ID NO: The amino acid sequence of SEQ ID NO: 55 (L-CDR1); the amino acid sequence of SEQ ID NO: 56 (L-CDR2); and the amino acid sequence of SEQ ID NO: 57 (L-CDR3), or d) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 70 (H-CDR2); and the amino acid sequence of SEQ ID NO: 71 (H-CDR3); and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 (L-CDR1);The amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3), or e) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 243 (H-CDR1); the amino acid sequence of SEQ ID NO: 87 (H-CDR2); and the amino acid sequence of SEQ ID NO: 88 (H-CDR3); and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 89 (L-CDR3).

[0012] In another aspect, this disclosure provides the use of an anti-SIRPα antibody or an antigen-binding fragment thereof in the manufacture of a medicament for treating cancer, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof is formulated for administration at a dose of about 800 mg to about 3600 mg; wherein the anti-SIRPα antibody or the antigen-binding fragment thereof comprises: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 34 (H-CDR2); and the amino acid sequence of SEQ ID NO: 35 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 37 (L-CDR1); the amino acid sequence of SEQ ID NO: 38 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3), or b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 ... The amino acid sequence of SEQ ID NO: 223 (H-CDR1); the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 or SEQ ID NO: 224 (H-CDR2); and the amino acid sequence of SEQ ID NO: 6 (H-CDR3); and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 225 (L-CDR1); the amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11 or SEQ ID NO: 226 (L-CDR2); and the amino acid sequence of SEQ ID NO: 12 or SEQ ID NO: 227 (L-CDR3), or c) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 52 (H-CDR1); the amino acid sequence of SEQ ID NO: 53 (H-CDR2); and SEQ ID NO: 54. Amino acid sequence (H-CDR3); and light chain variable region comprising amino acid sequence (L-CDR1) of SEQ ID NO: 55; amino acid sequence (L-CDR2) of SEQ ID NO: 56; and amino acid sequence (L-CDR3) of SEQ ID NO: 57, or d) heavy chain variable region comprising amino acid sequence (H-CDR1) of SEQ ID NO: 33; amino acid sequence (H-CDR2) of SEQ ID NO: 70; and amino acid sequence (H-CDR3) of SEQ ID NO: 71;and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3), or e) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 243 (H-CDR1); the amino acid sequence of SEQ ID NO: 87 (H-CDR2); and the amino acid sequence of SEQ ID NO: 88 (H-CDR3); and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 89 (L-CDR3).

[0013] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg.

[0014] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of about 1400 mg to about 1800 mg.

[0015] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg.

[0016] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of approximately 1400 mg.

[0017] In one implementation, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of approximately 1500 mg.

[0018] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of approximately 1600 mg.

[0019] In one implementation, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of approximately 1700 mg.

[0020] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of approximately 1800 mg.

[0021] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dosing cycle of approximately once every 2 weeks (Q2W), approximately once every 3 weeks (Q3W), approximately once every 4 weeks (Q4W), approximately once every 5 weeks (Q5W), approximately once every 6 weeks (Q6W), approximately once every 7 weeks (Q7W), or approximately once every 8 weeks (Q8W).

[0022] In one implementation, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of approximately once every 2 weeks (Q2W).

[0023] In one implementation, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of approximately once every 3 weeks (Q3W).

[0024] In some embodiments, the method further comprises administering pembrolizumab to the subject. In one embodiment, pembrolizumab is administered at a dose of approximately 400 mg. In one embodiment, an anti-SIRPα antibody or its antigen-binding fragment and pembrolizumab are administered at a dosing cycle of approximately every 3 weeks (Q3W). In one embodiment, an anti-SIRPα antibody or its antigen-binding fragment and pembrolizumab are administered at a dosing cycle of approximately every 6 weeks (Q6W).

[0025] In some embodiments, the method further includes administering cetuximab to the subject. In one embodiment, cetuximab is administered at approximately 500 mg / m². 2 The dosage is (e.g., milligrams of antibody per patient's body surface area). In one embodiment, cetuximab is administered at approximately 500 mg / m². 2 The dosage is as follows. In one embodiment, cetuximab is administered at an initial dose of approximately 400 mg / m² and a subsequent dose of approximately 250 mg / m². 2 Subsequent dose administration. In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dosing cycle of approximately every 2 weeks (Q2W), pembrolizumab at a dosing cycle of approximately every 6 weeks (Q6W), and cetuximab at a dosing cycle of approximately every 2 weeks (Q2W).

[0026] In one embodiment, cetuximab is administered on a dosing cycle of approximately every 2 weeks (Q2W). In another embodiment, subsequent doses are administered on a dosing cycle of approximately once a week (Q1W).

[0027] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 34 (H-CDR2); and the amino acid sequence of SEQ ID NO: 35 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 37 (L-CDR1); the amino acid sequence of SEQ ID NO: 38 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3).

[0028] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 223 (H-CDR1); the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 or SEQ ID NO: 224 (H-CDR2); and the amino acid sequence of SEQ ID NO: 6 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 225 (L-CDR1); the amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11 or SEQ ID NO: 226 (L-CDR2); and the amino acid sequence of SEQ ID NO: 12 or SEQ ID NO: 227 (L-CDR3).

[0029] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 52 (H-CDR1); the amino acid sequence of SEQ ID NO: 53 (H-CDR2); and the amino acid sequence of SEQ ID NO: 54 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 55 (L-CDR1); the amino acid sequence of SEQ ID NO: 56 (L-CDR2); and the amino acid sequence of SEQ ID NO: 57 (L-CDR3).

[0030] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 70 (H-CDR2); and the amino acid sequence of SEQ ID NO: 71 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3).

[0031] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 243 (H-CDR1); the amino acid sequence of SEQ ID NO: 87 (H-CDR2); and the amino acid sequence of SEQ ID NO: 88 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 89 (L-CDR3).

[0032] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment comprises a heavy chain variable region containing the amino acid sequence of any one of SEQ ID NO: 100, 110, 111, 112, 113, 114, 115, 116 or 117; and a light chain variable region containing the amino acid sequence of any one of SEQ ID NO: 105, 125 or 126.

[0033] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment comprises a heavy chain variable region containing the amino acid sequence of any one of SEQ ID NO: 104, 118, 119, 120, 121, 122, 123, 124 or 221; and a light chain variable region containing the amino acid sequence of any one of SEQ ID NO: 109, 127, 128, 129, 130 or 222.

[0034] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment comprises a heavy chain variable region containing the amino acid sequence of any one of SEQ ID NO: 100, 101, 102, 103 or 104; and a light chain variable region containing the amino acid sequence of any one of SEQ ID NO: 105, 106, 107, 108 or 109.

[0035] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment comprises: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 105; or b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 110; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 125; or c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 111; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 125; or d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 112; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 125; or e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 113; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 125; or f) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 113; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 125; or f) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 114 ... The amino acid sequence of SEQ ID NO: 114; and the light chain variable region containing the amino acid sequence of SEQ ID NO: 125; or g) the heavy chain variable region containing the amino acid sequence of SEQ ID NO: 115; and the light chain variable region containing the amino acid sequence of SEQ ID NO: 125; or h) the heavy chain variable region containing the amino acid sequence of SEQ ID NO: 116; and the light chain variable region containing the amino acid sequence of SEQ ID NO: 125; or i) the heavy chain variable region containing the amino acid sequence of SEQ ID NO: 117; and the light chain variable region containing the amino acid sequence of SEQ ID NO: 125; or j) the heavy chain variable region containing the amino acid sequence of SEQ ID NO: 110; and the light chain variable region containing the amino acid sequence of SEQ ID NO: 126; or k) the heavy chain variable region containing the amino acid sequence of SEQ ID NO: 111; and the light chain variable region containing the amino acid sequence of SEQ ID NO: 125. The amino acid sequence of SEQ ID NO: 126; or l) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 112; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 126; or m) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 113; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 126; or n) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 114; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 126; or o) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 115; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 126;Or p) the heavy chain variable region, which contains the amino acid sequence of SEQ ID NO: 117; and the light chain variable region, which contains the amino acid sequence of SEQ ID NO: 126.

[0036] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment comprises: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 104; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 109; or b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 118; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 127; or c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 118; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 128; or d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 127; or e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 129; or f) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 12 ... or f) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 129; or f) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 129; or f) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 129; or f) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 129; or f) The amino acid sequence of SEQ ID NO: 120; and the light chain variable region containing the amino acid sequence of SEQ ID NO: 127; or g) the heavy chain variable region containing the amino acid sequence of SEQ ID NO: 120; and the light chain variable region containing the amino acid sequence of SEQ ID NO: 129; or h) the heavy chain variable region containing the amino acid sequence of SEQ ID NO: 121; and the light chain variable region containing the amino acid sequence of SEQ ID NO: 127; or i) the heavy chain variable region containing the amino acid sequence of SEQ ID NO: 122; and the light chain variable region containing the amino acid sequence of SEQ ID NO: 127; or j) the heavy chain variable region containing the amino acid sequence of SEQ ID NO: 118; and the light chain variable region containing the amino acid sequence of SEQ ID NO: 130; or k) the heavy chain variable region containing the amino acid sequence of SEQ ID NO: 121; and the light chain variable region containing the amino acid sequence of SEQ ID NO: 129. The amino acid sequence of SEQ ID NO: 129; or l) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 122; and a light chain variable region containing the amino acid sequence of SEQ ID NO: 129; or m) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 119; and a light chain variable region containing the amino acid sequence of SEQ ID NO: 130; or n) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 123; and a light chain variable region containing the amino acid sequence of SEQ ID NO: 127; or o) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 120; and a light chain variable region containing the amino acid sequence of SEQ ID NO: 130;Or p) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 123; and a light chain variable region containing the amino acid sequence of SEQ ID NO: 129; or q) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 121; and a light chain variable region containing the amino acid sequence of SEQ ID NO: 130; or r) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 122; and a light chain variable region containing the amino acid sequence of SEQ ID NO: 130; or s) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 124; and a light chain variable region containing the amino acid sequence of SEQ ID NO: 129; or t) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 124; and a light chain variable region containing the amino acid sequence of SEQ ID NO: 127; or u) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 123; and a light chain variable region containing the amino acid sequence of SEQ ID NO: 129; The amino acid sequence of SEQ ID NO: 130; or v) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 124; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 130; or w) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 221; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 222.

[0037] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment comprises: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 105; or b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 101; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106; or c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 102; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 107; or d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 103; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 108; or e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 104; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 109.

[0038] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment comprises a heavy chain containing the amino acid sequence of any one of SEQ ID NO: 131, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152 or 217; and a light chain containing the amino acid sequence of any one of SEQ ID NO: 174, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195 or 218.

[0039] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 131; and a light chain comprising the amino acid sequence of SEQ ID NO: 174; or b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 138; and a light chain comprising the amino acid sequence of SEQ ID NO: 181; or c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 139; and a light chain comprising the amino acid sequence of SEQ ID NO: 182; or d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 140; and a light chain comprising the amino acid sequence of SEQ ID NO: 183; or e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 141; and a light chain comprising the amino acid sequence of SEQ ID NO: 184; or f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 142; and a light chain comprising the amino acid sequence of SEQ ID NO: 185; or g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 183 ... f) a light chain comprising the amino acid sequence of SEQ ID NO: 185; or g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 183; or f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 184; or f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 185; or f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 183; or f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 184 The heavy chain containing the amino acid sequence of SEQ ID NO: 143; and the light chain containing the amino acid sequence of SEQ ID NO: 186; or h) the heavy chain containing the amino acid sequence of SEQ ID NO: 144; and the light chain containing the amino acid sequence of SEQ ID NO: 187; or i) the heavy chain containing the amino acid sequence of SEQ ID NO: 145; and the light chain containing the amino acid sequence of SEQ ID NO: 188; or j) the heavy chain containing the amino acid sequence of SEQ ID NO: 146; and the light chain containing the amino acid sequence of SEQ ID NO: 189; or k) the heavy chain containing the amino acid sequence of SEQ ID NO: 147; and the light chain containing the amino acid sequence of SEQ ID NO: 190; or l) the heavy chain containing the amino acid sequence of SEQ ID NO: 148; and the light chain containing the amino acid sequence of SEQ ID NO: 191; or m) the heavy chain containing the amino acid sequence of SEQ ID NO: 149; and the light chain containing the amino acid sequence of SEQ ID NO: 190; The light chain containing the amino acid sequence of SEQ ID NO: 192; or n) the heavy chain containing the amino acid sequence of SEQ ID NO: 150; and the light chain containing the amino acid sequence of SEQ ID NO: 193; or o) the heavy chain containing the amino acid sequence of SEQ ID NO: 151; and the light chain containing the amino acid sequence of SEQ ID NO: 194; or p) the heavy chain containing the amino acid sequence of SEQ ID NO: 152; and the light chain containing the amino acid sequence of SEQ ID NO: 195; or q) the heavy chain containing the amino acid sequence of SEQ ID NO: 217; and the light chain containing the amino acid sequence of SEQ ID NO: 218.

[0040] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment comprises a heavy chain containing the amino acid sequence of any one of SEQ ID NO: 135, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173 or 219; and a light chain containing the amino acid sequence of any one of SEQ ID NO: 178, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216 or 220.

[0041] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 135; and a light chain comprising the amino acid sequence of SEQ ID NO: 178; or b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 153; and a light chain comprising the amino acid sequence of SEQ ID NO: 196; or c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 154; and a light chain comprising the amino acid sequence of SEQ ID NO: 197; or d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 155; and a light chain comprising the amino acid sequence of SEQ ID NO: 198; or e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 156; and a light chain comprising the amino acid sequence of SEQ ID NO: 199; or f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 157; and a light chain comprising the amino acid sequence of SEQ ID NO: 200; or g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 157; and a light chain comprising the amino acid sequence of SEQ ID NO: 198; or g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 ... The heavy chain containing the amino acid sequence of SEQ ID NO: 158; and the light chain containing the amino acid sequence of SEQ ID NO: 201; or h) the heavy chain containing the amino acid sequence of SEQ ID NO: 159; and the light chain containing the amino acid sequence of SEQ ID NO: 202; or i) the heavy chain containing the amino acid sequence of SEQ ID NO: 160; and the light chain containing the amino acid sequence of SEQ ID NO: 203; or j) the heavy chain containing the amino acid sequence of SEQ ID NO: 161; and the light chain containing the amino acid sequence of SEQ ID NO: 204; or k) the heavy chain containing the amino acid sequence of SEQ ID NO: 162; and the light chain containing the amino acid sequence of SEQ ID NO: 205; or l) the heavy chain containing the amino acid sequence of SEQ ID NO: 163; and the light chain containing the amino acid sequence of SEQ ID NO: 206; or m) the heavy chain containing the amino acid sequence of SEQ ID NO: 164; and the light chain containing the amino acid sequence of SEQ ID NO: 205; The light chain containing the amino acid sequence of SEQ ID NO: 165; or n) the heavy chain containing the amino acid sequence of SEQ ID NO: 208; or o) the heavy chain containing the amino acid sequence of SEQ ID NO: 166; and the light chain containing the amino acid sequence of SEQ ID NO: 209; or p) the heavy chain containing the amino acid sequence of SEQ ID NO: 167; and the light chain containing the amino acid sequence of SEQ ID NO: 210; or q) the heavy chain containing the amino acid sequence of SEQ ID NO: 168; and the light chain containing the amino acid sequence of SEQ ID NO: 211.Or r) a heavy chain containing the amino acid sequence of SEQ ID NO: 169; and a light chain containing the amino acid sequence of SEQ ID NO: 212; or s) a heavy chain containing the amino acid sequence of SEQ ID NO: 170; and a light chain containing the amino acid sequence of SEQ ID NO: 213; or t) a heavy chain containing the amino acid sequence of SEQ ID NO: 171; and a light chain containing the amino acid sequence of SEQ ID NO: 214; or u) a heavy chain containing the amino acid sequence of SEQ ID NO: 172; and a light chain containing the amino acid sequence of SEQ ID NO: 215; or v) a heavy chain containing the amino acid sequence of SEQ ID NO: 173; and a light chain containing the amino acid sequence of SEQ ID NO: 216; or w) a heavy chain containing the amino acid sequence of SEQ ID NO: 219; and a light chain containing the amino acid sequence of SEQ ID NO: 220.

[0042] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment comprises a heavy chain containing the amino acid sequence of any one of SEQ ID NO: 131, 133, 134, 137 or 135; and a light chain containing the amino acid sequence of any one of SEQ ID NO: 174, 176, 177, 180 or 178.

[0043] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 131; and a light chain comprising the amino acid sequence of SEQ ID NO: 174; or b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 133; and a light chain comprising the amino acid sequence of SEQ ID NO: 176; or c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 134; and a light chain comprising the amino acid sequence of SEQ ID NO: 177; or d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 137; and a light chain comprising the amino acid sequence of SEQ ID NO: 180; or e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 135; and a light chain comprising the amino acid sequence of SEQ ID NO: 178; or f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 132; and a light chain comprising the amino acid sequence of SEQ ID NO: 175; or g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 133; and a light chain comprising the amino acid sequence of SEQ ID NO: 174; or g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 175; or g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 176; or g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 17 ... The heavy chain containing the amino acid sequence SEQ ID NO: 136; and the light chain containing the amino acid sequence SEQ ID NO: 179.

[0044] In some implementation schemes, the subjects have been diagnosed with cancer that has a solid tumor, especially an advanced solid tumor.

[0045] In some implementations, the subjects have been diagnosed with SIRPα-positive cancer, CD47-positive cancer, PD-1-positive cancer, or PD-L1-positive cancer.

[0046] In some implementations, cancer is defined as a solid tumor that expresses or overexpresses SIRPα, CD47, PD-1, and / or PD-L1.

[0047] In some implementations, the subject has not been treated with anti-PD-1 or anti-PD-L1 antibodies prior to administration of the anti-SIRPα antibody or its antigen-binding fragment.

[0048] In some implementations, the subject has been treated with anti-PD-1 or anti-PD-L1 antibodies and has shown disease progression before administration of the anti-SIRPα antibody or its antigen-binding fragment. Brief description of the attached diagram

[0049] The foregoing summary of the invention and the following embodiments of this disclosure will be better understood when read in conjunction with the accompanying drawings. For illustrative purposes, the drawings show currently preferred embodiments. However, it should be understood that this disclosure is not limited to the precise configurations, embodiments, and instruments shown.

[0050] Figure 1 The concentration of SIRPα in the serum of human subjects (ng / mL) was shown from 0 to 504 hours after administration of 600 mg (n=3), 1200 mg (n=3), 1600 mg (n=3), 2400 mg (n=3), or 3600 mg (n=3) antibody A10.

[0051] Figure 2 The concentration of SIRPα in the serum of human subjects was shown to be ng / mL from 0 to 504 hours after administration of 600 mg (n=3), 1,200 mg (n=3), 1,600 mg (n=3), 2,400 mg (n=3), or 3,600 mg (n=3) antibody A10 or 6 mg / kg (n=6), 12 mg / kg (n=12), 18 mg / kg (n=6), 24 mg / kg (n=6), or 36 mg / kg (n=6) antibody X1.

[0052] Figures 3A to 3C The results showed that administering 2000 mg, 2200 mg, 2400 mg, 2600 mg, 2800 mg, 3000 mg, 3200 mg, 3400 mg, or 3600 mg of antibody A10 or 24 mg / kg of antibody X1 ( Figure 3ASIRPα concentration (mg / L) in human subjects' plasma was measured 0 to 3 weeks thereafter. Figure 3B and Figure 3C The area under the curve (AUC) (mg*h / L) and median CL of antibody A10 or antibody X1 at 3 weeks after administration of 2000 mg, 2200 mg, 2400 mg, 2600 mg, 2800 mg, 3000 mg, 3200 mg, 3400 mg or 3600 mg in human subjects are shown. min (mg / L). Detailed Implementation Plan

[0053] This disclosure relates to an anti-SIRPα antibody or an antigen-binding fragment thereof for the treatment of conditions regulated by CD47-mediated SIRPα signaling. In one aspect, this disclosure provides a method of treating a patient with cancer, comprising administering a therapeutically effective amount of an anti-SIRPα antibody or an antigen-binding fragment thereof. This disclosure also provides the use of an anti-SIRPα antibody or an antigen-binding fragment thereof in the treatment of a patient with cancer.

[0054] This disclosure also relates to specific dosages and dosing cycles for enhancing patient health, wherein the prescribed dosages are unexpectedly higher than typical dosages in the field of antibody immunotherapy. These higher dosages, whether as monotherapy or as combination therapy with other therapeutic agents such as anti-PD1 antibodies (e.g., pembrolizumab) and / or anti-epidermal growth factor receptor (EGFR) antibodies (e.g., cetuximab), are well-tolerated without any significant adverse effects. Furthermore, these higher dosages are suitable for treating patients who, despite prior cancer treatment, have not responded to previous cancer therapy or have shown disease progression. definition

[0055] The general structures of antibodies or immunoglobulins are well known to those skilled in the art; these molecules are typically heterotetrameric proteins of about 150,000 Daltons, consisting of two identical light (L) chains and two identical heavy (H) chains. Each light chain is covalently linked to the heavy chain via a disulfide bond to form a heterodimer, and heterotrimers are formed via covalent disulfide bonds between the two identical heavy chains of the heterodimer. Although the light and heavy chains are linked together by a disulfide bond, the number of disulfide bonds between the two heavy chains varies depending on the immunoglobulin isotype. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has a variable domain (VH = variable heavy chain) at the amino terminus, followed by three or four constant domains (CH1, CH2, CH3, and CH4), and a hinge region between CH1 and CH2. Each light chain has two domains: an amino-terminal variable domain (VL = variable light chain) and a carboxyl-terminal constant domain (CL). The VL and VH domains are non-covalently associated, while the CL domain is usually covalently linked to the CH1 domain via disulfide bonds. Specific amino acid residues are thought to form interfaces between the light chain variable domain and the heavy chain variable domain (Chothia et al., 1985, J. Mol. Biol. 186:651-663, Vargas-Madrazo E, Paz-García E. J Mol Recognit. 2003;16(3):113-120). Variable domains are also referred to as variable regions in this paper, and constant domains are referred to as constant regions.

[0056] Certain domains within a variable domain can vary significantly between different antibodies, a phenomenon termed "high variability." These highly variable domains contain residues directly involved in the binding and specificity of each antibody to its specific antigenic determinant. The high variability in both light and heavy chain variable domains is concentrated in three segments called complementarity-determining regions (CDRs) or highly variable loops (HVLs). CDRs are defined by sequence alignment as described in Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th edition, Public Health Service, National Institutes of Health, Bethesda, Md., while HVLs are structurally defined based on the three-dimensional structure of the variable domain, as described in Chothia and Lesk, 1987, J. Mol. Biol. 196: 901-917. When the identification results of CDRs produced by these two methods differ slightly, the structural definition is preferred. As defined by Kabat, CDR-L1 is located at approximately residues 24-34 in the light chain variable domain, CDR-L2 at approximately residues 50-56, and CDR-L3 at approximately residues 89-97; CDR-H1 is located at approximately residues 31-35 in the heavy chain variable domain, CDR-H2 at approximately residues 50-65, and CDR-H3 at approximately residues 95-102. IMGT and NORTH provide alternative definitions of CDR (see Lefranc MP. Unique database numbering system for immunogenetic analysis. Immunol Today (1997) 18:509; and North B, Lehmann A, Dunbrack RLJ. A new clustering of antibody CDR loop conformations. J Mol Biol. (2011) 406:228-56). In addition, CDRs can be defined according to the Chemical Computing Group (CCG) designation (Almagro et al., Proteins 2011; 79:3050-3066 and Maier et al., Proteins 2014; 82:1599-1610). Therefore, CDR1, CDR2, and CDR3 of the heavy and light chains define unique and functional properties specific to a given antibody.

[0057] The three CDRs within each of the heavy and light chains are separated by frame regions (FRs) containing sequences that are often less variable. From the amino terminus to the carboxyl terminus of the variable domains in both the heavy and light chains, the FRs and CDRs are arranged in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The dominant β-sheet conformation of the FRs brings the CDRs within each chain close to each other and close to the CDRs of the other chain. This conformation facilitates antigen-binding sites (see Kabat et al., 1991, NIH Publication No. 91-3242, Vol. I, pp. 647-669), but not all CDR residues are necessarily directly involved in antigen binding. Those skilled in the art can determine, in a conventional manner, which residues contain specific CDRs based on the amino acid sequence of the antibody's variable region. Therefore, the definitions of CDR1, CDR2, and CDR3 in the heavy and light chains possess unique and functional characteristics specific to a given antibody.

[0058] FR residues and Ig constant domains generally do not directly participate in antigen binding, but they contribute to antigen binding and / or mediate antibody effector functions. Some FR residues are thought to significantly influence antigen binding in at least three ways: directly and non-covalently binding to epitopes; interacting with one or more CDR residues; and influencing the interface between heavy and light chains. Constant domains do not directly participate in antigen binding, but mediate various Ig effector functions, such as antibody-dependent cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent phagocytosis (ADCP).

[0059] The light chains of vertebrate immunoglobulins are classified into two distinct categories based on the amino acid sequence of their constant domains: kappa (κ) and lambda (λ). By comparison, based on the sequence of their constant domains, the heavy chains of mammalian immunoglobulins are classified into one of five main categories: IgA, IgD, IgE, IgG, and IgM. IgG and IgA are further subdivided into subtypes (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The constant domains of the heavy chains corresponding to different categories of immunoglobulins are respectively called α... δ, ε, γ, and μ. The subunit structures and three-dimensional configurations of these classes of innate immunoglobulins are well known.

[0060] The terms “antibody” and “anti-SIRPα antibody” are used interchangeably herein and encompass monoclonal antibodies (including full-length monoclonal antibodies), multispecific antibodies (e.g., bispecific antibodies), antibodies with minor modifications (such as N-terminal or C-terminal truncation), and antibody fragments, such as variable domains and other portions of antibodies that exhibit the desired biological activity (e.g., SIRPα binding).

[0061] The term "monoclonal antibody" refers to an antibody derived from a substantially homogeneous population of antibody molecules, meaning that the individual antibodies constituting the population are identical, except for possible well-known alterations (such as removal of a C-terminal lysine from the antibody heavy chain) or post-translational modifications (such as possible amino acid isomerization or deamidation, methionine oxidation, or asparagine or glutamine deamidation). Monoclonal antibodies typically bind to one antigenic epitope. Bispecific monoclonal antibodies bind to two different antigenic epitopes. Monoclonal antibodies can be monospecific or multispecific, such as bispecific, monovalent, bivalent, or multivalent. It should be understood that monoclonal antibodies can be prepared by any technique or method known in this art; including, for example, hybridoma methods (Kohler et al., 1975, Nature 256:495) or recombinant DNA methods known in this art (see, for example, U.S. Patent No. 4,816,567), or methods using phage antibody libraries to isolate monoclonal antibodies generated in a recombinant manner, as described in Clackson et al., 1991, Nature 352:624-628, and Marks et al., 1991, J. Mol. Biol. 222:581-597.

[0062] Chimeric antibodies consist of variable regions of the heavy and light chains of an antibody from one species (e.g., a non-human mammal, such as a mouse) and constant regions of the heavy and light chains of an antibody from another species (e.g., a human), and can be obtained by linking a DNA sequence encoding the variable region of an antibody from the first species (e.g., a mouse) to a DNA sequence encoding the constant region of an antibody from the second species (e.g., a human), and transforming a host with an expression vector containing the linker sequence to produce the chimeric antibody. Alternatively, chimeric antibodies may also be antibodies in which one or more regions or domains of the heavy chain and / or light chain are identical, homologous, or variants of corresponding sequences from another immunoglobulin class or isotype or from common or germline sequences in a monoclonal antibody. Chimeric antibodies may include fragments of such antibodies, subject to the limitation that the antibody fragment exhibits the desired biological activity of its parent antibody, such as binding to the same epitope (see, for example, U.S. Patent No. 4,816,567; and Morrison et al., 1984, Proc. Natl. Acad. Sci. USA 81: 6851-6855).

[0063] The terms "antibody fragment," "antigen-binding fragment," "anti-SIRPα antibody fragment," and "engineered anti-SIRPα antibody fragment" refer to a portion of a full-length anti-SIRPα antibody that retains a variable region or functional capability, such as SIRPα binding. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, Fd, Fv, scFv and scFv-Fc fragments, biantibodies, linear antibodies, single-chain antibodies, microantibodies, biantibodies formed from antibody fragments, and multispecific antibodies formed from antibody fragments.

[0064] Antibody fragments can be obtained, for example, by treating full-length antibodies with an enzyme such as papain or pepsin to produce usable antibody fragments. Papain digestion produces two identical antigen-binding antibody fragments, each with a single antigen-binding site, called "Fab" fragments, and a residual "Fc" fragment. The Fab fragment also contains a constant domain of the light chain and a CH1 domain of the heavy chain. Pepsin treatment produces the F(ab')2 fragment, which has two antigen-binding sites and is still capable of cross-linking the antigen.

[0065] Another example of an antibody fragment according to this disclosure is a Fab' fragment. The Fab' fragment differs from the Fab fragment in that it has an additional residue at the C-terminus of the CH1 domain, said residue including one or more cysteine ​​residues from the antibody hinge region. The F(ab')2 antibody fragment is a pair of Fab' fragments linked by cysteine ​​residues in the hinge region. Other chemical conjugations of antibody fragments are also known.

[0066] The “Fv” fragment contains a complete antigen recognition and binding site, consisting of a tightly bound, non-covalently associated dimer of a heavy chain variable domain and a light chain variable domain. In this configuration, the three CDRs of each variable domain interact to define the antigen-binding site on the surface of the VH-VL dimer. The six CDRs collectively confer antigen-binding specificity to the antibody.

[0067] Antibody fragments may also include “single-chain Fv” or “scFv” fragments. A “single-chain Fv” or “scFv” antibody fragment is a single-chain Fv variant containing both the VH and VL domains of the antibody, wherein these domains are present in a single polypeptide chain. Single-chain Fvs are capable of recognizing and binding antigens. scFv polypeptides may also optionally contain a polypeptide linker located between the VH and VL domains to facilitate the formation of the desired three-dimensional structure for scFv antigen binding (see, for example, Pluckthun, 1994, The Pharmacology of Monoclonal Antibodies, Vol. 113, edited by Rosenburg and Moore, Springer-Verlag, New York, pp. 269-315).

[0068] Antibody fragments can also form tandem Fd segments, which contain a pair of tandem Fd segments (VH-CH1-VH-CH1) to form a pair of antigen-binding regions. These “linear antibodies” can be bispecific or monospecific, as described, for example, in Zapata et al. 1995, Protein Eng. 8(10):1057-1062.

[0069] As used herein, the term "human antibody" includes antibodies or fragments thereof derived from human germline immunoglobulin sequences. The term "human antibody" is not intended to include antibodies in which a CDR sequence derived from another (mammal) species (such as a mouse, rat, or rabbit) has been grafted onto a human frame sequence. Therefore, as used herein, the term "human antibody" refers to antibodies or fragments thereof in which each part of the protein (e.g., CDR, frame, CL, CH domains (e.g., CH1, CH2, CH3), hinge, VL, VH) is substantially non-immunogenic in humans, having only a few sequence variations or modifications as further described below.

[0070] Techniques for generating such “human antibodies” have been described, including but not limited to phage display or the use of transgenic animals (www.Ablexis.com / technology-alivamab.php; WO 90 / 05144; D. Marks, HR Hoogenboom, TP Bonnert, J. McCafferty, AD Griffiths and G. Winter (1991) “By-passing immunisation. Human antibodies from V-gene libraries displayed onphage.” J. Mol. Biol., 222, 581-597; Knappik et al., J. Mol. Biol. 296: 57-86, 2000; S. Carmen and L. Jermutus, “Concepts in antibody phage display.” Briefings in Functional Genomics and Proteomics 2002 1(2):189-203; Lonberg N, Huszar D. “Human antibodies from transgenic mice.” Int Rev Immunol. 1995;13(1):65-93.; Brüggemann M, Taussig MJ. “Production of human antibody repertoires in transgenic mice.” Curr Opin Biotechnol. 1997 Aug;8(4):455-8.).

[0071] Therefore, human antibodies differ from, for example, chimeric or humanized antibodies. It has been noted that human antibodies can be produced by non-human animals or prokaryotic or eukaryotic cells capable of functionally expressing genes for rearranged human immunoglobulins (e.g., heavy and / or light chains).

[0072] In one aspect, the anti-SIRPα antibody of this disclosure is a humanized antibody or an antibody fragment thereof. The humanized antibody or humanized antibody fragment is a specific type of chimeric antibody comprising an immunoglobulin amino acid sequence variant or fragment thereof, capable of binding to a predetermined antigen and comprising one or more FRs substantially having the amino acid sequence of a human immunoglobulin and one or more CDRs substantially having the amino acid sequence of a non-human immunoglobulin. This non-human amino acid sequence, commonly referred to as the “introducing” sequence, is typically derived from the “introducing” antibody domain, particularly the variable domain. Generally, humanized antibodies comprise at least a CDR or HVL of a non-human antibody inserted between FRs of a human heavy or light chain variable domain. Methods for humanizing antibodies are described, for example, by Almagro et al., (2008) Frontiers in Bioscience 13, 1619-1633 or WO12092374 A2.

[0073] The chimeric, humanized, or human antibodies or their antigen-binding fragments disclosed herein can be further engineered. Such engineering includes, but is not limited to, the removal or exchange of unwanted amino acids, for example, to reduce immunogenicity in humans, or to avoid deamidation, unwanted charges, or lipophilic or nonspecific binding. The removal or exchange of such unwanted amino acids can be induced, for example, by random or site-specific mutations in vitro or introduced by somatic mutations in vivo. Furthermore, with the conjugation of chimeric or humanized antibodies, it should be understood that certain mouse FR residues may be retained in the antibody or its fragments.

[0074] In one aspect, an anti-SIRPα antibody comprises substantially all at least one and usually two variable domains (such as those contained in, for example, Fab, Fab', F(ab')2, Fac, and Fv fragments). In another aspect, an anti-SIRPα antibody further comprises at least a portion of the Fc region of an immunoglobulin, typically at least a portion of a human immunoglobulin. Typically, the antibody will contain both a light chain and at least a variable domain of the heavy chain. The antibody may also, as desired, include one or more of the CH1, hinge, CH2, CH3, and / or CH4 regions of the heavy chain.

[0075] In one aspect, the anti-SIRPα antibody may be selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA, and IgE, and any isotypes, including IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. Alternative anti-SIRPα antibodies may comprise sequences from more than one immunoglobulin class or isotype, and specific modified or unmodified constant domains may be selected to optimize the desired effector function within the capabilities of those skilled in the art.

[0076] For example, the Fc region of an antibody mediates its serum half-life and effector functions, such as complement-dependent cytotoxicity (CDC), antibody-dependent cytotoxicity (ADCC), and antibody-dependent phagocytosis (ADCP). Fc engineering can be used to optimize antibody properties to suit its desired pharmacological activities. When such cytotoxic activity is undesirable, such as when targeting immune cells in cancer treatment, the constant domain can be an isoform with reduced effector function, such as IgG4, and / or modified with known modifications that reduce effector function. When such cytotoxic activity is desirable, such as for destroying targeted tumor cells, the constant domain can be an isoform with increased effector function, and / or modified with known modifications that increase effector function. Several mutations are known to reduce or increase effector function. See, for example, “The future of antibodies as cancer drugs” Janice M Reichert, Eugen Dhimolea, Drug Discov Today (2012) Sep;17(17-18):954-63; “Antibody Drug Discovery” (Molecular Drugs and Medicinal Chemistry, Vol. 4) Clive R. Wood, World Scientific, 2012 ISBN 1848166281, 9781848166288; “FcγR requirements leading to successful immunotherapy” Immunol Rev. (2015) Nov;268(1):104-22.

[0077] In one aspect, the constant domain of the antibody disclosed herein is IgG4Pro, which has a substitution mutation (Ser228Pro) that prevents Fab-arm exchange. In another aspect, the constant domain of the antibody disclosed herein is IgG1, which has two mutations, Leu234Ala and Leu235Ala, in the constant region to reduce effector function.

[0078] The FR and CDR or HVL of engineered anti-SIRPα antibodies or their antigen-binding fragments do not need to correspond precisely to the parental sequence. For example, the parental sequence can be altered (e.g., induced by mutation) through substitution, insertion, or deletion, such that the resulting amino acid residues are no longer identical to the original residues at corresponding positions in the parental sequence, but the antibody retains its SIRPα-binding function. Such alterations are typically not extensive and will be conserved. Typically, at least 75% of the engineered antibody residues will correspond to those residues in the parental sequence, more typically at least 90%, and most typically greater than 95%, or greater than 98%, or greater than 99%.

[0079] Immunoglobulin residues affecting the interface between the heavy chain variable region and the light chain variable region (“VL-VH interface”) are residues that influence the proximity or orientation of the two chains relative to each other. Certain residues that may participate in interchain interactions include VL residues 34, 36, 38, 44, 46, 87, 89, 91, 96, and 98, and VH residues 35, 37, 39, 45, 47, 91, 93, 95, 100, and 103 (using the numbering system described in Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md., 1987)). US Patent No. 6,407,213 also discusses the potential participation of residues such as VL residues 43 and 85, and VH residues 43 and 60 in this interaction. Although these residues are indicated only for human IgG, they are applicable to all species. Important antibody residues reasonably expected to participate in interchain interactions are selected and replaced with common sequences.

[0080] The terms "shared sequence" and "shared antibody" refer to amino acid sequences containing the most commonly occurring amino acid residues at various positions in all immunoglobulins of any particular class, isotype, or subunit structure, such as the variable domain of human immunoglobulins. Shared sequences can be based on immunoglobulins of a specific species or many species. It should be understood that a "shared" sequence, structure, or antibody encompasses shared human sequences as described in some embodiments and refers to amino acid sequences containing the most commonly occurring amino acid residues at various positions in all human immunoglobulins of any particular class, isotype, or subunit structure. Thus, a shared sequence contains amino acid sequences at various positions containing amino acids present in one or more known immunoglobulins, but it may not precisely replicate the entire amino acid sequence of any single immunoglobulin. Variable region shared sequences are not derived from any naturally occurring antibody or immunoglobulin. (Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th edition, Public Health Service, National Institutes of Health, Bethesda, Md. and its variants.) FRs and their variants, which share a common heavy and light chain sequence, provide suitable sequences for the preparation of human or humanized anti-SIRPα antibodies. See, for example, U.S. Patent Nos. 6,037,454 and 6,054,297.

[0081] "Isolated" antibodies are antibodies that have been identified, isolated, and / or recovered from components of their native environment or from cell cultures in which they are expressed. The isolated antibody or antibody fragment may have one or more co-translational or post-translational modifications that occur during the production, purification, and / or storage of the antibody or antibody fragment. Contaminants from the antibody's native environment are substances that can interfere with the diagnostic or therapeutic use of the antibody and may be enzymes, hormones, or other proteinaceous or non-proteinaceous solutes. In one aspect, the antibody will be purified to at least greater than 95% of the isolated antibody weight, for example, to at least greater than 95%, 96%, 97%, 98%, or 99%.

[0082] The isolated antibodies include in situ antibodies from recombinant cells, because at least one component of the antibody's native environment will be absent. However, the isolated antibodies are typically prepared through at least one purification step in which recombinant cellular material is removed.

[0083] "Multispecificity" refers to proteins that specifically bind to two or more different antigens or two or more different epitopes within the same antigen, such as antibodies.

[0084] "Bispecificity" refers to proteins that specifically bind to two different antigens or two different epitopes within the same antigen, such as antibodies.

[0085] In some embodiments, the antibodies or antigen-binding fragments thereof that specifically bind to SIRPα disclosed herein are bispecific antibodies. In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein are multispecific antibodies. The monospecific antibodies that specifically bind to SIRPα provided herein can be engineered into bispecific antibodies, which are also covered within the scope of this disclosure.

[0086] Full-length bispecific antibodies can be generated, for example, between two monospecific bivalent antibodies using Fab arm exchange (e.g., half-molecule exchange, exchange of a heavy-light chain pair) by introducing substitution at the heavy chain CH3 interface in each half-molecule, to facilitate the formation of heterodimers of two antibody half-molecules with unique specificity in vitro, in a cell-free environment, or using co-expression. The Fab arm exchange reaction is a result of disulfide bonding.

[0087] Bispecific antibodies can also be designed and generated using designs such as Triomab / Quadroma (TrionPharma / Fresenius Biotech), mortar and pestle (Genentech), CrossMAbs (Roche), and electrostatically induced CH3 interactions (Chugai, Amgen, NovoNordisk, Oncomed), LUZ-Y (Genentech), strand exchange engineered domains (SEEDbody) (EMD Serono), Biclonic (Merus), and DuoBody® Products (Genmab A / S).

[0088] As used herein, the term "consistency" or "percentage of consistency" in the context of two or more nucleic acid or polypeptide sequences refers to two or more sequences or subsequences that are identical for maximum correspondence comparison and alignment, or that have a specified percentage of identical nucleotide or amino acid residues. To determine the percentage of consistency, sequences are aligned for optimal comparison purposes (e.g., vacancies may be introduced in a first amino acid sequence or nucleic acid sequence to best align with a second amino acid or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, the molecule is consistent at that position. The percentage of consistency between two sequences varies with the number of consistent positions shared by these sequences (i.e., consistency % = number of identical positions / total number of positions (e.g., overlapping positions) × 100). In some embodiments, where appropriate, the two sequences being compared are of the same length after vacancies are introduced into the sequences (e.g., excluding additional sequences extending beyond the compared sequences). For example, when comparing variable region sequences, leader and / or constant domain sequences are not considered. For sequence comparisons between two sequences, the "corresponding" CDR refers to the CDR at the same position in both sequences (e.g., CDR-H1 of each sequence).

[0089] The determination of the percentage of identity or similarity between two sequences can be achieved using mathematical algorithms. A preferred, non-limiting example of a mathematical algorithm for comparing two sequences is the algorithm in Karlin and Altschul, 1990, Proc.Natl. Acad. Sci. USA 87:2264-2268, which is adapted in Karlin and Altschul, 1993, Proc.Natl. Acad. Sci. USA 90:5873-5877. Such algorithms are incorporated into the NBLAST and XBLAST programs of Altschul et al., 1990, J. Mol. Biol. 215:403-410. BLAST nucleotide searches can be performed using the NBLAST program with a score of 100 and a word length of 12 to obtain nucleotide sequences homologous to the nucleic acid encoding the protein of interest. BLAST protein searches can be performed using the XBLAST program with a score of 50 and a word length of 3 to obtain amino acid sequences homologous to the protein of interest. To obtain vacancy alignments for comparison purposes, vacancy BLAST can be used as described in Altschul et al., 1997, NucleicAcids Res. 25:3389-3402. Alternatively, PSI-Blast can be used for iterative searching, which detects distant relationships between molecules (ibid.). When using BLAST, vacancy BLAST, and PSI-Blast programs, the preset parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. Another preferred, non-limiting example of a mathematical algorithm for comparing sequences is the algorithm of Myers and Miller, CABIOS (1989). Such algorithms are incorporated into the ALIGN program (version 2.0), which is part of the GCG sequence alignment software package. When comparing amino acid sequences using the ALIGN program, the PAM120 weighted residue table, vacancy length penalty 12, and vacancy penalty 4 can be used. Additional algorithms used for sequence analysis are those known in this technique and include ADVANCE and ADAM as described in Torellis and Roboti, 1994, Comput. Appl. Biosci. 10:3-5; and FASTA as described in Pearson and Lipman, 1988, Proc. Natl. Acad. Sci. USA 85:2444-8. In FASTA, ktup is a control option that sets the sensitivity and speed of the search. If ktup=2, similar regions in the two sequences being compared are found by looking at paired aligned residues; if ktup=1, single aligned amino acids are examined. ktup can be set to 2 or 1 for protein sequences, or 1 to 6 for DNA sequences.If ktup is not specified, the default value is 2 for proteins and 6 for DNA. Alternatively, protein sequence alignment can be performed using the CLUSTALW algorithm, as described in Higgins et al., 1996, Methods Enzymol. 266:383-402.

[0090] "Chemotherapy agents" are chemical compounds used to treat cancer. Examples of such chemotherapy agents include alkylating agents, such as thiotepa and cyclophosphamide; alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimine and methylmelamine, including hexamethylmelamine, triethylenemelamine, triethylenephosphamide, triethyleneethylthiophosphamide, and trimethylolamine; polyacetyl (especially bulbatacin and bulbatacinone); camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (Including its synthetic analogues adozelesin, carzelesin, and bizelesin); cryptophycine (specifically cryptophycin 1 and cryptophycin 8); dolastatin; auristatin (including analogues monomethyl-auristatin E and monomethyl-auristatin F); duocarmycin (Including synthetic analogs KW-2189 and CBI-TMI); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustard, such as chlorambucil, naphthylambucil, chlorophosphamide, estramustine, ifosfamide, dichloromethyldiethylamine, dichloromethyldiethylamine oxide hydrochloride, melphalan, neonimustine, phenesterine, prednimustine; trofosfamide; uracil mustard; nitrosourea, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;Antibiotics, such as enediyne antibiotics (e.g., calicheamicin), especially calicheamicin γ1I and calicheamicin φI1, see, for example, Angew. Chem. Intl. Ed. Engl., 33:183-186; dynemicin, including dynemicin A; bisphosphonates, such as clodronate; esperamicin; and neomycin chromophores and related chromogenic chromophores of enedyne antibiotics; aclacinomysin; actinomycin; autramycin; azaserine; bleomycin; actinomycin C; carabicin; caminomycin; carzinophilin; chromomycin; dactinomycin; daunorubicin; detorubicin; 6-diazo-5-sideoxy-L-norleucine; doxorubicin (Adriamycin™) (including N-morpholino-doxorubicin, cyano-N-morpholino-doxorubicin, 2-pyrrololino-doxorubicin, and deoxydoxorubicin); epirubucin; esorubicin; idarubicin; marcellomycin; mitomycin, such as mitomycin C; mycophenolic acid. (acid); nogalamycin; olivomycin; peplomycin; potfiromycin; puromycin; quelamycin; rodorubicin; streptonigrin; streptozocin; tubercidin; ubenimex; zinostatin; zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as denopterin, methotrexate, pteropterin, and trimetrexate;Purine analogues, such as fludarabine, 6-mercaptopurine, thioimidapurine, and thioguanine; pyrimidine analogues, such as ancitabine, azoxyuridine, 6-azoxyuridine, carmofur, cytarabine, dideoxyuridine, deoxyfluorouridine, enocitabine, and fluorouridine; androgens, such as calusterone, drotalbutone propionate, epitiostanol, mepitiostane, and testolactone; and antiadrenal drugs, such as amioglutamine (…). Aminoglutethimide, mitotane, trilostane; folic acid supplements, such as folinic acid; acetylglucuronide; aldehyde phosphoramide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; democolcine; diaziquone; elfomithi ne); eniluracil; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids, such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitracrine Pentostatin; phenamet; pirarubicin; losoxantrone; podophylloic acid; 2-ethylhydrazine; procarbazine; PSK®; razoxane; rhizoxin; sizofuran; spirogermanium; Alternaria ketoacid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecene (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethane;Vindesine; dacarbazine; mannitol mustard; mitabronitol; mitolactalol; pipebroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; paclitaxel-like drugs, such as paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, NJ) and docetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine. (Gemzar™); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs, such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine (Navelbine™); novantrone; teniposide; edatrexate; danomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. This definition also includes anti-hormonal agents used to regulate or inhibit the effects of hormones on tumors, such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including Nolvadex™), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston™).Aromatase inhibitors that inhibit aromatase, which regulate estrogen production in the adrenal glands, such as (e.g.) 4(5)-imidazole, amiglumet, megestrol acetate (Megace™), exemestane, formestane, fadrozole, vorozole (Rivisor™), letrozole (Femara™), and anastrozole (Arimidex™); and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Any or more of these agents may bind to a human antibody or antigen-binding fragment thereof disclosed herein to provide a suitable therapeutic agent for the treatment of a variety of diseases and / or conditions.

[0091] For diagnostic and therapeutic surveillance purposes, the antibodies or antigen-binding fragments of this disclosure may also be attached to a tag, either alone or with an additional second agent (prodrug, chemotherapeutic agent, or the like). Unlike other second agents, a tag is an agent that acts as a detectable compound or composition and can bind directly or indirectly to the anti-SIRPα antibody or antigen-binding fragment of this disclosure. The tag itself may be detectable (e.g., a radioisotope tag or a fluorescent tag), or, in the case of an enzyme tag, catalyze a chemical change in the detectable substrate compound or composition. Tagged anti-SIRPα antibodies or antigen-binding fragments of this disclosure can be prepared and used in a variety of applications, including in vitro and in vivo diagnostics.

[0092] In various aspects of this disclosure, one or more domains of an anti-SIRPα antibody or its antigen-binding fragment are expressed in a recombinant manner. Such recombinant expression may employ one or more control sequences, which are polynucleotide sequences necessary for the expression of operatively linked coding sequences in a specific host organism. Control sequences suitable for prokaryotic cells include, for example, promoters, operators, and ribosome-binding site sequences. Eukaryotic control sequences include, but are not limited to, promoters, polyadenylation signals, and enhancers. These control sequences can be used to express and generate anti-SIRPα antibodies or their antigen-binding fragments in prokaryotic and eukaryotic host cells.

[0093] When a nucleic acid sequence is placed in a functional relationship with another nucleic acid sequence, it is "operably linked." For example, if a pre-sequence or secretory precursor is expressed as a pre-protein involved in polypeptide secretion, it is operably linked to the nucleic acid encoding that polypeptide; if a promoter or enhancer affects the transcription of a coding sequence, it is operably linked to that sequence; or if a ribosome binding site is positioned to facilitate translation, it is operably linked to the coding sequence. Generally, "operably linked" means that the linked DNA sequences are contiguous, and in the case of a secretory precursor, they are contiguous and within the reading frame. However, enhancers are optionally contiguous. Linkage can be achieved by conjugation at a suitable restriction site. If such a site is not available, synthetic oligonucleotide adaptors or linkers can be used.

[0094] As used herein, the terms “cell,” “cell line,” and “cell culture” are used interchangeably, and all such names include their descendants. Thus, “transformation” and “transformed cell” include primary subject cells and cultures derived therefrom, regardless of the number of transfections, which may be transfected, for example, by one or more expression vectors encoding one or more amino acid sequences of the antibody or its antigen-binding fragment disclosed herein.

[0095] For therapeutic purposes according to this disclosure, the term "mammal" means any animal classified as a mammal, including humans, domestic and agricultural animals, and zoo, sporting, or pet animals such as dogs, horses, cats, cattle, and similar animals. Preferably, the mammal is human.

[0096] As used herein, “symptom” means any condition that would benefit from treatment with the anti-SIRPα antibody or its antigen-binding fragment described herein. This includes chronic and acute symptoms or diseases, including pathological conditions that predispose mammals to the discussed symptoms. Non-limiting examples or symptoms to be treated herein include inflammatory, angiogenic, autoimmune and immunological conditions, respiratory conditions, cancer, hematologic malignancies, benign and malignant tumors, leukemia, and lymphomas.

[0097] The terms "cancer" and "cancerous" refer to or describe a physiological condition in mammals characterized by uncontrolled cell growth. Examples of cancer include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, and leukemias.

[0098] As used herein, the term "SIRPα pathway disorder" or "SIRPα pathway disease" refers to a condition that can be mitigated by modulating the interaction between SIRPα and CD47, particularly by inhibiting SIRPα / CD47 signaling. "SIRPα pathway disorder" or "SIRPα pathway disease" includes bone marrow-related diseases that express SIRPα. "SIRPα pathway disorder" or "SIRPα pathway disease" also includes conditions characterized by reduced phagocytosis by SIRPα-expressing macrophages and / or dendritic cells, requiring an increased immune response.

[0099] Examples of SIRPα pathway disorders include cancer, inflammatory diseases, autoimmune diseases, respiratory diseases, infectious diseases, or fibrosis. Examples of cancer include blood cancers (e.g., leukemia, lymphoma, myeloma, such as multiple myeloma) and metastatic lesions. Other examples include solid tumors. Examples of solid tumors include malignancies such as sarcomas and carcinomas, such as adenocarcinomas of various organ systems, such as adenocarcinomas affecting the lungs, breast, ovaries, lymph nodes, gastrointestinal tract (e.g., colon), anus, genitals and genitourinary tract (e.g., kidneys, urethral epithelium, bladder cells, prostate), pharynx, CNS (e.g., brain, nerves, or glial cells), head and neck, skin (e.g., melanoma), and pancreas, as well as adenocarcinomas of malignancies such as colon cancer, rectal cancer, renal cell carcinoma, liver cancer, stomach cancer, non-small cell lung cancer, small bowel cancer, and esophageal cancer. Cancer can be in the early, middle, late, or metastatic stages.

[0100] In some implementations, the cancer is selected from lung cancer (e.g., NSCLC (e.g., NSCLC with squamous and / or non-squamous histology, or NSCLC adenocarcinoma)), melanoma (e.g., advanced melanoma), kidney cancer (e.g., renal cell carcinoma), liver cancer, hepatocellular carcinoma, myeloma (e.g., multiple myeloma), prostate cancer, breast cancer (e.g., breast cancer that does not express one, two, or all of estrogen receptor, progesterone receptor, or HER2 / neu, such as triple-negative breast cancer), colorectal cancer, pancreatic cancer, head and neck cancer (e.g., head and neck squamous cell carcinoma (HNSCC)), anal cancer, gastroesophageal cancer, thyroid cancer, cervical cancer, lymphoproliferative disorders (e.g., post-transplant lymphoproliferative disorders) or hematologic malignancies, T-cell lymphoma, B-cell lymphoma, non-Hodgkin lymphoma, or leukemia (e.g., myeloid leukemia or lymphocytic leukemia).

[0101] In some implementations, the cancer is selected from cancerous tumors (such as advanced or metastatic cancers), melanoma, or lung cancer, such as NSCLC.

[0102] In some implementations, the cancer is selected from pancreatic cancer, prostate cancer, breast cancer, colorectal cancer, lung cancer, glioblastoma, and kidney cancer, preferably pancreatic cancer, prostate cancer, breast cancer, colorectal cancer, or lung cancer.

[0103] In some implementation schemes, the cancer is pancreatic cancer, lung cancer, breast cancer, melanoma, colorectal cancer, ovarian cancer, stomach cancer, thyroid cancer, liver cancer, or prostate cancer.

[0104] In the case of conjugates, such as antibodies or antigen-binding fragments thereof, the term "specific binding" or "specific binding" refers to a conjugate that associates more frequently, more rapidly, for a longer duration, with greater affinity, or a combination thereof with an antigen or an epitope within an antigen other than an unrelated antigen. In some embodiments, antibodies or antigen-binding fragments thereof specifically bind to an antigen or an epitope within an antigen at a KD of about 0.1 mM or less, preferably less than about 1 μM. Due to sequence consistency between homologous proteins in different species or between protein variants within a single species, specific binding may include antibodies or antigen-binding fragments thereof that recognize proteins in more than one species (e.g., human SIRPα and cynomolgus monkey SIRPα). It should be understood that in some embodiments, an antibody or antigen-binding fragment thereof that specifically binds to a first protein may specifically bind to a second protein or may not specifically bind to a second protein. Therefore, "specific binding" does not necessarily require (although it may include) exclusive binding, i.e., binding to a single protein. Thus, in some embodiments, antibodies or antigen-binding fragments thereof may specifically bind to more than one protein.

[0105] Methods for determining whether two molecules specifically bind to a protein are known in the art and include, for example, equilibrium dialysis, surface plasma resonance, and the like. In one embodiment, specific binding is characterized by a KD of about 1 × 10⁻⁷ M (100 nM) or less, about 5 × 10⁻⁸ M (50 nM) or less, about 1 × 10⁻⁸ M (10 nM) or less, or about 5 × 10⁻⁹ M (5 nM) or less.

[0106] The term "subcutaneous administration" refers to the relatively slow and continuous delivery of a drug, such as the anti-SIRPα antibody or its antigen-binding fragment disclosed herein, from a drug container into the subcutaneous tissue of a subject (such as an animal or human patient), preferably within a depression between the skin and subcutaneous tissue. A depression is created by pinching or pulling the skin away from the subcutaneous tissue.

[0107] The term "subcutaneous infusion" refers to the introduction of a drug, such as the anti-SIRPα antibody or its antigen-binding fragment disclosed herein, from a drug container into the subcutaneous tissue of a subject by relatively slow, continuous delivery, preferably within a depression between the skin and subcutaneous tissue for a period of time, including but not limited to 30 minutes or less, or 90 minutes or less. Optionally, the infusion may be performed by a drug delivery pump implanted subcutaneously under the skin of the subject, wherein the pump delivers a predetermined amount of drug for a predetermined period of time, such as 30 minutes, 90 minutes, or a period spanning the length of a treatment regimen.

[0108] The term "subcutaneous injection" refers to the administration of a drug under the skin of a subject, wherein the drug delivery is less than about 15 minutes; in another aspect, less than 5 minutes; and in yet another aspect, less than 60 seconds. In even another aspect, the administration is performed within a depression between the skin and subcutaneous tissue, wherein the depression can be created by pinching or pulling the skin away from the subcutaneous tissue. For example, "subcutaneous injection" means administering the disclosed anti-SIRPα antibody or its antigen-binding fragment to a subject within less than about 15 minutes, in another aspect, less than 5 minutes, and in yet another aspect, less than 60 seconds.

[0109] The term "therapeuticly effective dose" refers to the amount of anti-SIRPα antibody or its antigen-binding fragment that reduces or improves one or more symptoms of the condition being treated. In this case, it is the amount that has a beneficial outcome for the patient. Efficacy can be measured in a conventional manner, depending on the condition being treated.

[0110] As used herein, the terms “treatment” and “therapeutic approach” and the like mean treatment of a disease or condition, as well as preventative or inhibitory measures, that produce any clinically desired or beneficial effect, including but not limited to the reduction or relief of one or more symptoms, or the elimination, slowing, or cessation of the progression of the disease or condition. Thus, for example, the term treatment includes administering an anti-SIRPα antibody or its antigen-binding fragment before or after the onset of symptoms of a disease or condition, thereby preventing or removing one or more signs of the disease or condition. As another example, the term includes administering an anti-SIRPα antibody or its antigen-binding fragment after the clinical expression of the disease to combat the symptoms of the disease. Furthermore, administering an anti-SIRPα antibody or its antigen-binding fragment after the onset of symptoms and after the appearance of clinical symptoms includes “treatment” or “therapeutic approach” as used herein, wherein the administration affects clinical parameters of the disease or condition, such as the degree of tissue damage or the amount or extent of metastasis, regardless of whether the treatment improves the disease. Furthermore, any treatment of the underlying condition shall be deemed effective if the composition of this disclosure, alone or in combination with another therapeutic agent, alleviates or improves at least one symptom of the treated condition compared to the symptoms without the use of an anti-SIRPα antibody or its antigen-binding fragment composition or its antigen-binding fragment, regardless of whether all symptoms of the condition are alleviated.

[0111] The term "package insert" refers to the instruction leaflet typically included in the commercial packaging of a therapeutic product, which contains information about indications, usage, application, contraindications, and / or warnings regarding the use of such therapeutic products. anti-SIRPα antibody

[0112] This document describes and discloses anti-SIRPα antibodies and their antigen-binding fragments for the treatment of various diseases or conditions, particularly those that modulate CD47-mediated SIRPα signaling. In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment blocks the interaction between SIRPα and CD47, particularly the interaction between human SIRPα and human CD47. In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment does not block the interaction between SIRPα and CD47. Blocking the interaction between SIRPα and CD47 may be considered when the antibody or its antigen-binding fragment has an antagonistic effect on the CD47 / SIRPα interaction. A reduction or inhibition of the binding of CD47 to SIRPα, particularly human CD47 to human SIRPα, means that the antibody or its antigen-binding fragment reduces the interaction between SIRPα and CD47, i.e., the antibody or its antigen-binding fragment partially or completely inhibits the binding of SIRPα to CD47, or in other words, antagonizes the interaction between SIRPα and CD47. Specifically, compared to the negative control molecule in the binding assay, the anti-SIRPα antibody or its antigen-binding fragment can reduce or inhibit the binding of CD47 to SIRPα, especially the binding of human CD47 to human SIRPα by at least 50%, such as at least 60%, at least 70%, at least 80%, at least 90%, or 100%. Specifically, compared to the negative control molecule in the binding assay, the anti-SIRPα antibody or its antigen-binding fragment can reduce or inhibit the binding of CD47 to SIRPα, especially the binding of human CD47 to human SIRPα by 50% to 100%, such as 50% to 90%, 60% to 90%, or 70% to 80%.

[0113] In one embodiment, the anti-SIRPα antibody and its antigen-binding fragment disclosed herein recognize specific linear and / or conformational SIRPα antigenic epitopes and SIRPα epitopes. Suitable SIRPα antigenic epitopes and SIRPα epitopes include, but are not limited to, those epitopes disclosed in WO 2022 / 254379, which is incorporated herein by reference in its entirety.

[0114] Representative anti-SIRPα antibodies of this disclosure are provided in Tables 1 to 25 below. Heavy chain CDR-1, CDR-2, CDR3 (HCDR1-3) and light chain CDR-1, CDR-2, CDR3 (L-CDR1-3) are provided according to the numbering systems of Kabat, CCG, Chothia, IMGT and North. Table 1: KABAT Nomenclature Table 2: IMGT Nomenclature Table 3: CCG Nomenclature Table 4: CHOTHIA Nomenclature Table 5: NORTH Nomenclature Table 6: KABAT Nomenclature Table 7: IMGT Nomenclature Table 8: CCG Nomenclature Table 9: CHOTHIA Nomenclature Table 10: NORTH Nomenclature Table 11: KABAT Nomenclature Table 12: IMGT Nomenclature Table 13: CCG Nomenclature Table 14: CHOTHIA Nomenclature Table 15: NORTH Nomenclature Table 16: KABAT Nomenclature Table 17: IMGT Nomenclature Table 18: CCG Nomenclature Table 19: CHOTHIA Nomenclature Table 20: NORTH Nomenclature Table 21: KABAT Nomenclature Table 22: IMGT Nomenclature Table 23: CCG Nomenclature Table 24: CHOTHIA Nomenclature Table 25: NORTH Nomenclature anti-SIRPα antibody sequence

[0115] The heavy and light chain variable regions of representative anti-SIRPα antibodies disclosed herein are provided in Tables 26 and 27 below. Table 26: Amino acid sequence of the heavy chain variable region (VH) Table 27: Amino acid sequence of the light chain variable region

[0116] The representative anti-SIRPα antibodies disclosed herein have light chain and / or heavy chain variable region sequences as described in Table 28 or Table 29. Table 28: Amino acid sequence of the heavy chain variable region (VH) Table 29: Amino acid sequence of the light chain variable region (VL)

[0117] Representative anti-SIRPα antibodies disclosed herein may comprise the heavy and / or light chains as described in Table 30 or Table 31 below. Table 30: Full-length HC sequence of anti-SIRPα antibody. Table 31: Full-length LC sequence of anti-SIRP-α antibody.

[0118] Representative anti-SIRPα antibodies of this disclosure may include the heavy chain and / or light chain constant regions as described in Table 32 or Table 33 below. Table 32: Exemplary HC and LC sequences of the constant region of anti-SIRPα antibodies. amino acid sequence variants

[0119] Variant anti-SIRPα antibodies and their antibody fragments can be engineered based on a set of CDRs depicted in Tables 1 through 25. It should be understood that in variant anti-SIRPα antibodies and antibody fragments, the amino acid sequence of the CDR remains unchanged or has very minor changes (e.g., 1-5 changes), but surrounding regions (e.g., FR regions) can be engineered. Amino acid sequence variants of anti-SIRPα antibodies can be prepared by introducing appropriate nucleotide changes into the anti-SIRPα antibody DNA or through peptide synthesis. Such variants include, for example, the deletion and / or insertion of residues and / or substitution of residues within the amino acid sequence of the anti-SIRPα antibodies described in the embodiments herein. Any combination of deletions, insertions, and substitutions can be performed to obtain a final construct, limited by the requirement that the final construct possesses the desired characteristics. Amino acid changes can also alter the post-translational processes of human or variant anti-SIRPα antibodies, such as changing the number or location of glycosylation sites.

[0120] In some embodiments, this disclosure includes an anti-SIRPα antibody or an antibody fragment thereof having a variable heavy chain and a variable light chain, wherein the amino acid sequences of the variable heavy chain and the variable light chain are at least 90%, at least 92.5%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequences disclosed in Tables 26 to 29, subject to the limitation that the antibody or fragment thereof remains bound to SIRPα-V1 and / or SIRPα-V2.

[0121] In some embodiments, this disclosure includes an anti-SIRPα antibody or an antibody fragment thereof having a variable heavy chain and a variable light chain, wherein the amino acid sequences of the variable heavy chain and the variable light chain are respectively identical to at least 80%, at least 85%, at least 90%, at least 92.5%, at least 95%, at least 98%, or at least 99% of the amino acid sequences of SEQ ID No: 100, 101, 102, 103, 110, 111, 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121, 122, 123, 124 or 221 and SEQ ID No: 105, 106, 107, 108, 109, 126, 127, 128, 129, 130 or 222.

[0122] In some embodiments, this disclosure includes an anti-SIRPα antibody having a heavy chain and a light chain, wherein the heavy chain amino acid sequence and the light chain amino acid sequence are at least 95%, at least 98%, or at least 99% identical to the amino acid sequences disclosed in Tables 30 and 31, subject to the limitation that the antibody or a fragment thereof remains bound to SIRPα-V1 and / or SIRPα-V2.

[0123] In some embodiments, the anti-SIRPα antibody or an antibody fragment thereof comprises a variable heavy chain sequence having an amino acid sequence that is at least about 95%, about 96%, about 97%, about 98%, or about 99% sequence identical to the amino acid sequence shown in SEQ ID NO: 100, 101, 102, 103, 110, 111, 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121, 122, 123, 124, or 221. In other embodiments, the anti-SIRPα antibody or its antibody fragment retains the binding and / or functional activity of the anti-SIRPα antibody or its antibody fragment comprising a variable heavy chain sequence comprising SEQ ID NO: 100, 101, 102, 103, 110, 111, 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121, 122, 123, 124 or 221. In yet another embodiment, the anti-SIRPα antibody or its antibody fragment comprises a variable heavy chain sequence of SEQ ID NO: 100, 101, 102, 103, 110, 111, 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121, 122, 123, 124 or 221, and has one or more conserved amino acid substitutions in the variable heavy chain sequence, such as 1, 2, 3, 4, 5, 1-2, 1-3, 1-4 or 1-5 conserved amino acid substitutions. In other embodiments, one or more conserved amino acid substitutions fall within one or more framework regions of SEQ ID NO: 100, 101, 102, 103, 110, 111, 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121, 122, 123, 124 or 221 (based on the Kabat numbering system).

[0124] In some embodiments, the anti-SIRPα antibody or its antibody fragment comprises a variable heavy chain sequence having at least about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity with the anti-SIRPα heavy chain variable region sequence shown in 100, 101, 102, 103, 110, 111, 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121, 122, 123, 124, or 221, and includes one or more conserved amino acid substitutions (based on the Kabat numbering system) in the frame region, and maintains the inclusion of SEQ ID NO: The binding and / or functional activity of anti-SIRPα antibodies or antibody fragments thereof with variable heavy chain sequences as shown in SEQ ID NO: 100, 101, 102, 103, 110, 111, 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121, 122, 123, 124 or 221 and variable light chain sequences as shown in SEQ ID NO: 105, 106, 107, 108, 109, 126, 127, 128, 129, 130 or 222.

[0125] In some embodiments, the anti-SIRPα antibody or antibody fragment thereof comprises a variable light chain sequence having an amino acid sequence having at least about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 105, 106, 107, 108, 109, 126, 127, 128, 129, 130, or 222. In other embodiments, the anti-SIRPα antibody or antibody fragment thereof retains the binding and / or functional activity of the anti-SIRPα antibody or antibody fragment thereof comprising the variable light chain sequence of SEQ ID NO: 105, 106, 107, 108, 109, 126, 127, 128, 129, 130, or 222. In yet another embodiment, the anti-SIRPα antibody or antibody fragment thereof comprises a variable light chain sequence of SEQ ID NO: 105, 106, 107, 108, 109, 126, 127, 128, 129, 130, or 222, and has one or more conserved amino acid substitutions in the light chain variable sequence, such as 1, 2, 3, 4, 5, 1-2, 1-3, 1-4, or 1-5 conserved amino acid substitutions. In still another embodiment, the one or more conserved amino acid substitutions fall within one or more frame regions of SEQ ID NO: 105, 106, 107, 108, 109, 127, 128, 129, 130, or 222 (based on the Kabat numbering system).

[0126] In some embodiments, the anti-SIRPα antibody or its antibody fragment comprises a variable light chain sequence having at least about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity with the anti-SIRPα light chain variable region sequence shown in SEQ ID NO: 105, 106, 107, 108, 109, 126, 127, 128, 129, 130, or 222, containing one or more conserved amino acid substitutions (based on the Kabat numbering system) in the frame region, and retaining a variable heavy chain sequence as shown in SEQ ID NO: 100, 101, 102, 103, 110, 111, 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121, 122, 123, 124, or 221, and as shown in SEQ ID NO: The binding and / or functional activity of anti-SIRPα antibodies or antibody fragments thereof with the variable light chain sequences shown in 105, 106, 107, 108, 109, 126, 127, 128, 129, 130 or 222.

[0127] In some embodiments, this disclosure includes anti-SIRPα antibodies or antigen-binding fragments thereof having amino acid substitutions. These variants involve the removal of at least one amino acid residue from the anti-SIRPα antibody or antigen-binding fragment thereof, and the insertion of a different residue at its position. Substitution mutation induction sites of greatest concern include hypervariable regions, but also cover FR variations. Conserved substitutions are shown under the heading “Preferred Substitutions” in Table 33. If such substitutions result in a change in biological activity, further substantial changes, designated as “Exemplary Substitutions” or as further described below with respect to amino acid categories, may be introduced, and products screened. Table 33: Exemplary Amino Acid Substitutions

[0128] In protein chemistry, it is generally accepted that the biological properties of antibodies can be achieved by selecting substitutions that significantly differ in their effect on maintaining: (a) the structure of the polypeptide backbone in the substituted region, such as sheet or helical conformation; (b) the charge or hydrophobicity of the molecule at the target site; or (c) the volume of the side chains. Naturally occurring residues are grouped based on common side chain characteristics as follows: (1) Hydrophobic: ortholeucine, met, ala, val, leu, ile; (2) Neutral hydrophilicity: cys, ser, thr; (3) Acidic: asp, glu; (4) Alkaline: asn, gin, his, lys, arg; (5) Residues that affect chain orientation: gly, pro; and (6) Aromatics: trp, tyr, phe. Non-conservative substitution will necessarily involve replacing members of one of these categories with members of another category.

[0129] Any cysteine ​​residues that do not participate in maintaining the proper conformation of the anti-SIRPα antibody or its antigen-binding fragment may generally be substituted with serine to improve the oxidative stability of the molecule, prevent undesirable cross-linking, or provide a well-established binding site for cytotoxic or cell growth-inhibiting compounds. Conversely, one or more cysteine ​​bonds may be added to the antibody or its antigen-binding fragment to improve its stability (especially when the antibody is an antibody fragment such as the Fv fragment).

[0130] Another type of amino acid variant of antibodies involves altering the antibody's original glycosylation pattern. The term "alteration" in this context means the deletion of one or more carbohydrate moieties found in the antibody, and / or the addition of one or more glycosylation sites not previously present in the antibody. For example, an antibody may contain an amino acid substitution at position 297 of the human IgG1 heavy chain to eliminate oligosaccharide transferase complex-mediated glycosylation by replacing asparagine 297 (e.g., N297A, N297G).

[0131] Nucleic acid molecules encoding amino acid sequence variants of anti-SIRPα antibodies or their antigen-binding fragments are prepared by a variety of methods known in the art. These methods include, but are not limited to, isolation from natural sources (in the case of naturally occurring amino acid sequence variants), or preparation by oligonucleotide-mediated (or site-directed) mutagenesis, PCR mutagenesis, and cassette mutagenesis of previously prepared variant or non-variant forms of anti-SIRPα antibodies or their antigen-binding fragments.

[0132] In some embodiments, the anti-SIRPα antibody is an antibody fragment. Techniques for generating antibody fragments have been developed. Fragments can be derived via proteolytic digestion of the intact antibody (see, for example, Morimoto et al., 1992, Journal of Biochemical and Biophysical Methods 24: 107-117; and Brennan et al., 1985, Science 229: 81). Alternatively, fragments can be generated directly in recombinant host cells. For example, the Fab'-SH fragment can be directly recovered from E. coli and chemically conjugated to form the F(ab')2 fragment (see, for example, Carter et al., 1992, Bio / Technology 10: 163-167). Alternatively, the F(ab')2 fragment can be isolated directly from recombinant host cell cultures. Other techniques for generating antibody fragments will be apparent to those skilled in the art.

[0133] In one embodiment, the anti-SIRPα antibody and its antigen-binding fragment may include modifications such as glycosylation, oxidation, or deamidation.

[0134] In some embodiments, it may be necessary to use an anti-SIRPα antibody fragment instead of the complete antibody. The antibody fragment may need to be modified to extend its serum half-life. This can be achieved, for example, by incorporating a rescue receptor-binding epitope into the antibody fragment. In one approach, a suitable region of the antibody fragment may be altered (e.g., mutated), or the epitope may be incorporated into a peptide tag, which is then fused to the antibody fragment at either end or in the middle, for example, via DNA or peptide synthesis (see, for example, WO 96 / 32478). For example, if the use of a full-length IgG backbone is not desirable, the antibody fragment of this disclosure may also be fused to human serum albumin to extend the serum half-life. Such fusion proteins of antibody fragments and human serum albumin may be advantageous in cases where the fusion of two different antibody fragments is required to increase affinity or to produce a bispecific binding protein with extended serum half-life (see, for example, WO 05 / 077042 A2).

[0135] The removal of any carbohydrate moieties present on the antibody can be achieved chemically or enzymatically. Chemical deglycosylation is described by Hakimuddin et al., 1987, Arch. Biochem. Biophys. 259:52 and Edge et al., 1981, Anal. Biochem., 118:131. Enzymatic cleavage of carbohydrate moieties on the antibody can be achieved using various endoglucosidases and exoglucosidases as described by Thotakura et al., 1987, Meth. Enzymol 138:350.

[0136] Another type of applicable modification includes linking the antibody to one of a variety of non-protein polymers, such as polyethylene glycol, polypropylene glycol, or polyoxyethylene, in the manner described in one or more of U.S. Patent Nos. 4,640,835, 4,496,689, 4,301,144, 4,670,417, 4,791,192, and 4,179,337. dose

[0137] Anti-SIRPα antibodies or their antigen-binding fragments can be present in doses ranging from approximately 800 mg to approximately 3600 mg (e.g., approximately 800 mg, approximately 900 mg, approximately 1000 mg, approximately 1100 mg, approximately 1200 mg, approximately 1300 mg, approximately 1400 mg, approximately 1500 mg, approximately 1600 mg, approximately 1700 mg, approximately 1800 mg, approximately 1900 mg, approximately 2000 mg, approximately 2100 mg, approximately 2200 mg, approximately 2300 mg, approximately 2400 mg, approximately 2500 mg, approximately 2600 mg, approximately 2700 mg, approximately 2800 mg, approximately 2900 mg, approximately 3000 mg, approximately 3100 mg, approximately 3200 mg, approximately 3300 mg, approximately 3400 mg, approximately 3500 mg, or approximately 3600 mg), approximately 1600 mg to approximately 3600 mg. The drug is administered to the subject in doses of approximately 1 mg, approximately 2400 mg to approximately 3600 mg, or approximately 1600 mg to approximately 2400 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject.

[0138] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1400 mg to about 1500 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1500 mg to about 1600 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1600 mg to about 1700 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1700 mg to about 1800 mg. In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg.

[0139] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of at least 800 mg to at least 3600 mg (e.g., at least 800 mg, at least 900 mg, at least 1000 mg, at least 1100 mg, at least 1200 mg, at least 1300 mg, at least 1400 mg, at least 1500 mg, at least 1600 mg, at least 1700 mg, at least 1800 mg, at least 1900 mg, at least 2000 mg, at least 2100 mg, at least 2200 mg, at least 2300 mg, at least 2400 mg, at least 2500 mg, at least 2600 mg, at least 2700 mg, at least 2800 mg, at least 2900 mg, at least 3000 mg, at least 3100 mg, at least 3200 mg, at least 3300 mg, at least 3400 mg, at least 3500 mg, or at least 3600 mg).

[0140] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of at least 1400 mg to at least 1800 mg (e.g., at least 1400 mg, at least 1500 mg, at least 1600 mg, at least 1700 mg, or at least 1800 mg). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of at least 1400 mg to at least 1500 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of at least 1500 mg to at least 1600 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of at least 1600 mg to at least 1700 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of at least 1700 mg to at least 1800 mg. In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of at least 1400 mg, at least 1500 mg, at least 1600 mg, at least 1700 mg, or at least 1800 mg.

[0141] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is formulated for use at doses of about 800 mg to about 3600 mg (e.g., about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg), about 1600 mg to about 3600 mg. Administered at doses of approximately 1 mg, approximately 2400 mg to approximately 3600 mg, or approximately 1600 mg to approximately 2400 mg.

[0142] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is formulated for administration at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is formulated for administration at a dose of about 1400 mg to about 1500 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is formulated for administration at a dose of about 1500 mg to about 1600 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is formulated for administration at a dose of about 1600 mg to about 1700 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is formulated for administration at a dose of about 1700 mg to about 1800 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is formulated for administration at doses of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg.

[0143] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is formulated for administration at a dose of at least 800 mg to at least 3600 mg (e.g., at least 800 mg, at least 900 mg, at least 1000 mg, at least 1100 mg, at least 1200 mg, at least 1300 mg, at least 1400 mg, at least 1500 mg, at least 1600 mg, at least 1700 mg, at least 1800 mg, at least 1900 mg, at least 2000 mg, at least 2100 mg, at least 2200 mg, at least 2300 mg, at least 2400 mg, at least 2500 mg, at least 2600 mg, at least 2700 mg, at least 2800 mg, at least 2900 mg, at least 3000 mg, at least 3100 mg, at least 3200 mg, at least 3300 mg, at least 3400 mg, at least 3500 mg, or at least 3600 mg).

[0144] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is formulated for administration at a dose of at least 1400 mg to at least 1800 mg (e.g., at least 1400 mg, at least 1500 mg, at least 1600 mg, at least 1700 mg, or at least 1800 mg). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is formulated for administration at a dose of at least 1400 mg to at least 1500 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is formulated for administration at a dose of at least 1500 mg to at least 1600 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is formulated for administration at a dose of at least 1600 mg to at least 1700 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is formulated for administration at a dose of at least 1700 mg to at least 1800 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is formulated for administration at a dose of at least 1400 mg, at least 1500 mg, at least 1600 mg, at least 1700 mg, or at least 1800 mg.

[0145] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject more than once. In other words, the anti-SIRPα antibody or its antigen-binding fragment is administered at regular dosing intervals, where a dosing interval is the time between one administration of the anti-SIRPα antibody or its antigen-binding fragment and the next administration, such as the period between the first administration of the anti-SIRPα antibody or its antigen-binding fragment and the second administration. In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment is administered several times according to a regular dosing interval, for example, with the same time interval between each administration, such as every two weeks (Q2W). In some embodiments, the dosing interval is interrupted by a treatment-free period. In other embodiments, the dosing interval is not interrupted by a treatment-free period.

[0146] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dosing cycle (dosing interval) of approximately once every 2 weeks (Q2W) to approximately once every 8 weeks (Q8W) (e.g., approximately once every 2 weeks (Q2W), approximately once every 3 weeks (Q3W), approximately once every 4 weeks (Q4W), approximately once every 5 weeks (Q5W), approximately once every 6 weeks (Q6W), approximately once every 7 weeks (Q7W), or approximately once every 8 weeks (Q8W)). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dosing cycle (dosing interval) of approximately once every 2 weeks (Q2W). In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dosing cycle (dosing interval) of approximately once every 3 weeks (Q3W).

[0147] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is in the form of about 800 mg to about 3600 mg (e.g., about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg), about 1600 mg to about 3600 mg, about 2400 mg, or about 3600 mg. The drug is administered to the subject at doses of approximately 3600 mg to approximately 1600 mg to approximately 2400 mg at a dosing cycle (dosing interval) of approximately once every 2 weeks (Q2W) to approximately once every 8 weeks (Q8W) (e.g., approximately once every 2 weeks (Q2W), approximately once every 3 weeks (Q3W), approximately once every 4 weeks (Q4W), approximately once every 5 weeks (Q5W), approximately once every 6 weeks (Q6W), approximately once every 7 weeks (Q7W), or approximately once every 8 weeks (Q8W)). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is in the form of about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg. The dose of mg was administered to the subject at dosing intervals of approximately once every 2 weeks (Q2W), approximately once every 3 weeks (Q3W), approximately once every 4 weeks (Q4W), approximately once every 5 weeks (Q5W), approximately once every 6 weeks (Q6W), approximately once every 7 weeks (Q7W), or approximately once every 8 weeks (Q8W).

[0148] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is in the form of about 800 mg to about 3600 mg (e.g., about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg), about 1600 mg to about 3600 mg, about 2400 mg, or about 3600 mg. The doses are administered to the subjects at a rate of approximately 3600 mg to approximately 3600 mg or approximately 1600 mg to approximately 2400 mg at a dosing cycle (Q2W) of approximately once every 2 weeks. In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg at a dosing cycle (dosing interval) of about once every 2 weeks (Q2W).

[0149] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg) on ​​a dosing cycle (Q2W). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1400 mg to about 1500 mg on a dosing cycle (Q2W). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1500 mg to about 1600 mg on a dosing cycle (Q2W). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1600 mg to about 1700 mg on a dosing cycle (Q2W). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1700 mg to about 1800 mg on a dosing cycle (Q2W) of about once every 2 weeks. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg on a dosing cycle (Q2W) of about once every 2 weeks.

[0150] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of about 1400 mg at a dosing cycle (Q2W) of about once every 2 weeks.

[0151] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of about 1500 mg at a dosing cycle (Q2W) of about once every 2 weeks.

[0152] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of about 1600 mg at a dosing cycle (Q2W) of about once every 2 weeks.

[0153] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of about 1700 mg at a dosing cycle (Q2W) of about once every 2 weeks.

[0154] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of about 1800 mg at a dosing cycle (Q2W) of about once every 2 weeks.

[0155] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1400 mg to about 3600 mg (e.g., 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg) at a dosing cycle (Q3W). In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg at a dosing cycle (dosing interval) of about once every 3 weeks (Q3W).

[0156] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg) at a dosing cycle (dosing interval) of about once every 3 weeks (Q3W). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1400 mg to about 1500 mg at a dosing cycle (Q3W). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1500 mg to about 1600 mg at a dosing cycle (Q3W). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1600 mg to about 1700 mg at a dosing cycle (Q3W). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1700 mg to about 1800 mg at a dosing cycle (Q3W) of about once every 3 weeks. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg at a dosing cycle (Q3W) of about once every 3 weeks.

[0157] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of about 1400 mg at a dosing cycle (dosing interval) of at least once every 3 weeks (Q3W).

[0158] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of about 1500 mg at a dosing cycle (dosing interval) of at least once every 3 weeks (Q3W).

[0159] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of about 1600 mg at a dosing cycle (dosing interval) of at least once every 3 weeks (Q3W).

[0160] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of about 1700 mg at a dosing cycle (dosing interval) of at least once every 3 weeks (Q3W).

[0161] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of about 1800 mg at a dosing cycle (dosing interval) of at least once every 3 weeks (Q3W). Therapeutic uses

[0162] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment disclosed herein is suitable for treating and / or preventing SIRPα pathway disorders. In another embodiment, the anti-SIRPα antibody or its antigen-binding fragment disclosed herein is suitable as a medicine.

[0163] Therefore, in one embodiment, this disclosure provides a method for modulating the interaction between SIRPα and CD47 in a patient, comprising administering to the patient an amount of an anti-SIRPα antibody or an antigen-binding fragment thereof sufficient to block CD47-mediated SIRPα signaling in the patient. In one embodiment, this disclosure provides an anti-SIRPα antibody or an antigen-binding fragment thereof for modulating the interaction between SIRPα and CD47 in a subject. In one embodiment, this disclosure provides the use of an anti-SIRPα antibody or an antigen-binding fragment thereof in the preparation of a medicament for modulating the interaction between SIRPα and CD47 in a subject.

[0164] In one embodiment, this disclosure provides a method for enhancing the phagocytic activity of a patient's bone marrow cells, comprising administering to the patient an amount of an anti-SIRPα antibody or an antigen-binding fragment thereof sufficient to enhance the patient's immune response. In one embodiment, this disclosure provides an anti-SIRPα antibody or an antigen-binding fragment thereof for enhancing the activity of a patient's bone marrow cells. In one embodiment, this disclosure provides the use of an anti-SIRPα antibody or an antigen-binding fragment thereof in the preparation of a medicament for enhancing the phagocytic activity of a patient's bone marrow cells.

[0165] In one embodiment, this disclosure provides a method of treating a patient with a SIRPα pathway disease or condition, comprising administering to the patient an anti-SIRPα antibody or an antigen-binding fragment thereof according to this disclosure. In one embodiment, this disclosure provides an anti-SIRPα antibody or an antigen-binding fragment thereof for treating or preventing a patient with cancer, an inflammatory disease, an autoimmune disease, a respiratory disease, an infectious disease, or fibrosis. In one embodiment, this disclosure provides the use of an anti-SIRPα antibody or an antigen-binding fragment thereof in the manufacture of a medicament for treating or preventing a subject with cancer, an inflammatory disease, an autoimmune disease, a respiratory disease, an infectious disease, or fibrosis.

[0166] Therefore, in one embodiment, this disclosure provides a method for treating or preventing one of the aforementioned diseases or conditions in a patient, comprising administering to the patient an anti-SIRPα antibody or an antigen-binding fragment thereof according to this disclosure. In one embodiment, this disclosure provides an anti-SIRPα antibody or an antigen-binding fragment thereof for treating or preventing one of the aforementioned diseases or conditions in a patient. In one embodiment, this disclosure provides the use of an anti-SIRPα antibody or an antigen-binding fragment thereof in the manufacture of a medicament for treating and / or preventing one of the aforementioned diseases or conditions in a patient.

[0167] In one embodiment, the methods and uses described herein include treating cancers comprising cancer cells expressing antigens with low tumor specificity, such as CD47 and PD-L1 antigens. In one embodiment, the methods and uses described herein include treating SIRPα-positive, CD47-positive, PD-L1-positive, or PD-1-positive cancers. In one embodiment, the patient to be treated has been diagnosed with SIRPα-positive cancer, CD47-positive cancer, PD-1-positive cancer, or PD-L1-positive cancer, particularly cancers with solid tumors expressing or overexpressing SIRPα, CD47, PD-1, and / or PD-L1. SIRPα-positive, CD47-positive, PD-L1-positive, or PD-1-positive cancers are cancers in which tumor cells express SIRPα, CD47, PD-L1, and / or PD-1. "SIRPα-positive, CD47-positive, PD-L1-positive, or PD-1-positive tumor cells" refers to tumor cells that express SIRPα, CD47, PD-L1, or PD-1 on their cell surface. Cancers can be classified into subgroups of SIRPα-positive, CD47-positive, PD-L1-positive, or PD-1-positive cancers by flow cytometry assessment using primary mouse monoclonal antibodies against SIRPα, CD47, PD-1, or PD-L1, secondary antibodies, and kits for quantifying cell surface antigens. SIRPα-positive, CD47-positive, PD-L1-positive, or PD-1-positive cancers are defined by a strict specific antibody binding capacity (SABC) greater than zero.

[0168] In one embodiment, the methods and uses described herein include the treatment of cancers, including both primary and metastatic cancers, such as bladder cancer, hematologic malignancies, bone cancer, bone marrow cancer, brain cancer, breast cancer, colon cancer, esophageal cancer, gastrointestinal cancer, gingival cancer, head cancer, kidney cancer, liver cancer, lung cancer, nasopharyngeal cancer, neck cancer, ovarian cancer, prostate cancer, skin cancer, stomach cancer, testicular cancer, tongue cancer, or uterine cancer. In one embodiment, the methods and uses described herein include the treatment of ovarian cancer, pancreatic cancer, Vater's ampulla cancer, microsatellite stable (MSS) cancer, microsatellite unstable (MSI) cancer, colorectal cancer (especially MSI and MSS colorectal cancer), fibrous carcinoma, breast cancer, melanoma, kidney cancer, lung cancer (especially non-small cell lung cancer (NSCLC)), head and neck cancer (especially head and neck squamous cell carcinoma (HNSCC)), stomach cancer, and hepatocellular carcinoma.

[0169] In one embodiment, the methods and uses described herein include treating cancers with solid tumors, particularly advanced solid tumors. In one embodiment, the cancer with a solid tumor does not contain any fluid or cysts. In one embodiment, the solid tumor is a sarcoma. In one embodiment, the solid tumor is a carcinoma.

[0170] In one embodiment, the methods and uses described herein include treating cancers in patients with ovarian cancer, pancreatic cancer, ampullary carcinoma of Varder, microsatellite stable (MSS) cancer, microsatellite unstable (MSI) cancer, colorectal cancer (especially MSI and MSS colorectal cancer), fibrous carcinoma, breast cancer, melanoma, renal cancer, lung cancer (especially non-small cell lung cancer (NSCLC)), head and neck cancer (especially head and neck squamous cell carcinoma (HNSCC)), gastric cancer, or hepatocellular carcinoma, which are positive for SIRPα, PD-L1, or PD1 as described herein.

[0171] In one embodiment, the methods and uses described herein include treating patients who have previously received treatment for their cancer and have shown treatment resistance and / or whose disease has progressed despite treatment. Prior treatment may cover any standard or routine treatment for cancer. The term "standard or routine treatment" refers to any cancer treatment (medication, surgery, radiation therapy, etc.) typically administered to patients with cancer. In one embodiment, the patient has been treated with at least one, at least two, at least three, or at least four cancer treatments prior to administration of the anti-SIRPα antibody or its antigen-binding fragment. In one embodiment, the patient has been treated with one, two, three, or four cancer treatments prior to administration of the anti-SIRPα antibody or its antigen-binding fragment.

[0172] In one embodiment, the methods and uses described herein include treating patients who have been treated with immune checkpoint inhibitors, are being treated with immune checkpoint inhibitors, or will be treated with immune checkpoint inhibitors.

[0173] In one embodiment, the methods and uses described herein include treating patients who have been treated with immune checkpoint inhibitors or activators, such as anti-PD-1 or anti-PD-L1 antibodies, and who do not respond positively to the administration of immune checkpoint inhibitors or activators (i.e., patients showing disease progression and / or not showing disease regression).

[0174] In one embodiment, the methods and uses described herein include monotherapy or combination therapy for treating patients as described herein.

[0175] In one embodiment, the methods and uses described herein include treating patients who have not been treated with immune checkpoint inhibitors, have not been treated with immune checkpoint inhibitors, or will not be treated with immune checkpoint inhibitors. In one embodiment, the methods and uses described herein include treating patients who have not been treated with anti-PD-1 antibodies or anti-PD-L1 antibodies, particularly anti-PD-1 antagonist antibodies or anti-PD-L1 antagonist antibodies, prior to administration of anti-SIRPα antibodies or their antigen-binding fragments.

[0176] In one embodiment, the patient has at least one SIRPα V1 allele (i.e., is homozygous and has two SIRPα V1 alleles, or is heterozygous for SIRPα and has one SIRPα V1 allele). In one embodiment, the patient is homozygous for SIRPα and is SIRPα V1 / SIRPα V1. In one embodiment, the patient is heterozygous for SIRPα and is SIRPα V1 / SIRPα V2. Combination therapy

[0177] Anti-SIRPα antibodies or their antigen-binding fragments may be administered as a monotherapy or in combination with one or more other therapeutic agents, such as currently advanced technology or standard care compounds, such as cell growth inhibitors or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids, immunomodulators / checkpoint inhibitors and the like.

[0178] Cell growth inhibitory and / or cytotoxic substances that can be administered in combination with the anti-SIRPα antibody or its antigen-binding fragment disclosed herein include, but are not limited to, hormones, hormone analogs and anti-hormones, aromatase inhibitors, LHRH agonists and antagonists, growth factor inhibitors (e.g., platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER, e.g., HER2, HER3, HER4), and hepatocyte growth factor (HGF)), including, for example, anti-growth factor antibodies or anti-growth factor receptor antibodies and tyrosine kinase inhibitors, such as cetuximab, gefitinib, etc. Afatinib, nintedanib, imatinib, lapatinib, bosutinib, and trastuzumab; antimetabolites (e.g., antifolate agents such as methotrexate, raltitrexed), pyrimidine analogs such as 5-fluorouracil (5-FU), gemcitabine, irinotecan, doxorubicin, TAS-102, capecitabine, and gemcitabine), purine and adenosine analogs such as mercaptopurine, thioguanine, cladribine, pentostatin, and cytarabine. C) Fludarabine; antitumor antibiotics (e.g., anthracycline); platinum derivatives (e.g., cisplatin, oxaliplatin, carboplatin); alkylating agents (e.g., estradiol, meclorethamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas, such as carmustine and lomustine, thiotepa); antimitotic agents (e.g., vinca alkaloids, such as vincristine, vindesine, vinorelbine, and vincristine); And taxanes, such as paclitaxel and docetaxel; angiogenesis inhibitors, including bevacizumab, ramucirumab, and aflibercept; tubulin inhibitors; DNA synthesis inhibitors; PARP inhibitors; and topoisomerase inhibitors (such as epipodophyllotoxin, such as etoposide and etopophos, teniposide, acridine, toponotecan, irinotecan, and mitoxantrone).Serine / threonine kinase inhibitors (e.g., PDK1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C-Raf inhibitors, mTOR inhibitors, mTORC1 / 2 inhibitors, PI3K inhibitors, PI3Kα inhibitors, dual mTOR / PI3K inhibitors, STK33 inhibitors, AKT inhibitors, PLK1 inhibitors (such as vorasetib), CDK inhibitors (including CDK9 inhibitors), Aurora kinase inhibitors); tyrosine kinase inhibitors (e.g., PTK2 / FAK inhibitors); proteins Inhibitors of cytokine-mass interaction; MEK inhibitors; ERK inhibitors; FLT3 inhibitors; BRD4 inhibitors; IGF-1R inhibitors; Bcl-xL inhibitors; Bcl-2 inhibitors; Bcl-2 / Bcl-xL inhibitors; ErbB receptor inhibitors; BCR-ABL inhibitors; ABL inhibitors; Src inhibitors; rapamycin analogs (e.g., everolimus, temsirolimus, ridaforolimus, sirolimus); androgen synthesis inhibitors Androgen receptor inhibitors; DNMT inhibitors; HDAC inhibitors; ANG1 / 2 inhibitors; CYP17 inhibitors; radiopharmaceuticals; immunotherapeutic agents, such as immune checkpoint inhibitors (e.g., CTLA4, PD1, PD-L1, LAG3, and TIM3 binding molecules / immunoglobulins, such as ipilimumab, nivolumab, and pembrolizumab); and various chemotherapeutic agents, such as amifostin, anagrelid, clodronate, and filgrastim. Ingredients include: tin, interferon, interferon-alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer; proteasome inhibitors (such as bortezomib); Smac and BH3 mimics; agents that restore p53 function, including MDM2-p53 antagonists; inhibitors of the Wnt / β-chain signaling pathway; and / or cyclin-dependent kinase 9 inhibitors.

[0179] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment may optionally be administered in combination with other therapeutic agents. Other therapeutic agents may be chemotherapy agents, anti-PD-1 or PD-L1 antibodies, anti-CTLA4 antibodies, T-cell conjugates, CD137-agonist-anti-FAP bispecific antibodies, tumor-targeting antibodies, VEGF-ANG2 bispecific antibodies, STING agonists, MDM2 antagonists, or radiotherapy.

[0180] In one embodiment, an anti-SIRPα antibody or its antigen-binding fragment is administered in combination with an anti-PD-1 antibody, such as nivolumab, pembrolizumab, pidilizumab, ezabenlimab, or atezolizumab. In another embodiment, an anti-SIRPα antibody or its antigen-binding fragment is administered in combination with an anti-PD-L1 antibody, including, for example, avelumab or durvalumab.

[0181] In one embodiment, the anti-SIRPα antibody or its antigen-binding fragment is administered in combination with a tumor-targeting antibody that targets HER2 (e.g., trastuzumab), EGFR (e.g., cetuximab, panitumumab), CD20 (e.g., rituximab, ofatumumab), or CD52 (e.g., alemtuzumab).

[0182] In one embodiment, an anti-SIRPα antibody or its antigen-binding fragment is administered in combination with two therapeutic agents. In another embodiment, an anti-SIRPα antibody or its antigen-binding fragment is administered in combination with an anti-PD-1 antibody (e.g., nivolumab, pembrolizumab, pildizumab, ebendizumab, or atezolizumab) or an anti-PD-L1 antibody (e.g., avelumab or duvalumab) and a tumor-targeting antibody targeting HER2 (e.g., trastuzumab), EGFR (e.g., cetuximab, panitumumab), CD20 (e.g., rituzumab, ofamumab), or CD52 (e.g., alemtuzumab).

[0183] One or more other therapeutic agents are administered to the patient in a therapeutically effective amount. In one embodiment, one or more other therapeutic agents are administered at a dose of about 0.1 mg / kg to about 50 mg / kg, such as about 1 mg / kg to about 40 mg / kg, about 5 mg / kg to about 30 mg / kg, about 5 mg / kg to about 20 mg / kg, about 5 mg / kg to about 15 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 35 mg / kg, and / or about 50 mg / kg.

[0184] Anti-SIRPα antibodies or their antigen-binding fragments can be administered to subjects in combination with pembrolizumab. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is in the form of about 800 mg to about 3600 mg (e.g., about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg), about 1600 mg to about 3600 mg. The subjects were administered doses of approximately 2400 mg to approximately 3600 mg or approximately 1600 mg to approximately 2400 mg, and pembrolizumab was administered to the subjects at a dose of approximately 400 mg. In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg, and pembrolizumab is administered to the subject at a dose of about 400 mg.

[0185] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg), and pembrolizumab is administered to the subject at a dose of about 400 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1400 mg to about 1500 mg, and pembrolizumab is administered to the subject at a dose of about 400 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1500 mg to about 1600 mg, and pembrolizumab is administered to the subject at a dose of about 400 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1600 mg to about 1700 mg, and pembrolizumab is administered to the subject at a dose of about 400 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1700 mg to about 1800 mg, and pembrolizumab is administered to the subject at a dose of about 400 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, and pembrolizumab is administered to the subject at a dose of about 400 mg.

[0186] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1400 mg, and pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg.

[0187] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of about 1500 mg, and pembrolizumab is administered intravenously to the subject at a dose of about 400 mg.

[0188] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1600 mg, and pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg.

[0189] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1700 mg, and pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg.

[0190] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1800 mg, and pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg.

[0191] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is in the form of at least 800 mg to at least 3600 mg (e.g., at least 800 mg, at least 900 mg, at least 1000 mg, at least 1100 mg, at least 1200 mg, at least 1300 mg, at least 1400 mg, at least 1500 mg, at least 1600 mg, at least 1700 mg, at least 1800 mg, at least 1900 mg, at least 2000 mg, at least 2100 mg, at least 2200 mg, at least 2300 mg, at least 2400 mg, at least 2500 mg, at least 2600 mg, at least 2700 mg, at least 2800 mg, at least 2900 mg, at least 3000 mg, at least 3100 mg, at least 3200 mg, at least 3300 mg, at least 3400 mg, at least 3500 mg, or at least 3600 mg), about 1600 mg to about 3600 mg. The subjects were administered doses of approximately 2400 mg to approximately 3600 mg or approximately 1600 mg to approximately 2400 mg, and pembrolizumab was administered to the subjects at a dose of at least 400 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of at least 800 mg, at least 900 mg, at least 1000 mg, at least 1100 mg, at least 1200 mg, at least 1300 mg, at least 1400 mg, at least 1500 mg, at least 1600 mg, at least 1700 mg, at least 1800 mg, at least 1900 mg, at least 2000 mg, at least 2100 mg, at least 2200 mg, at least 2300 mg, at least 2400 mg, at least 2500 mg, at least 2600 mg, at least 2700 mg, at least 2800 mg, at least 2900 mg, at least 3000 mg, at least 3100 mg, at least 3200 mg, at least 3300 mg, at least 3400 mg, at least 3500 mg, or at least 3600 mg, and pembrolizumab is administered to the subject at a dose of at least 400 mg.

[0192] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of at least 1400 mg to at least 1800 mg (e.g., at least 1400 mg, at least 1500 mg, at least 1600 mg, at least 1700 mg, or at least 1800 mg), and pembrolizumab is administered to the subject at a dose of at least 400 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of at least 1400 mg to at least 1500 mg, and pembrolizumab is administered to the subject at a dose of at least 400 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of at least 1500 mg to at least 1600 mg, and pembrolizumab is administered to the subject at a dose of at least 400 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of at least 1500 mg to at least 1600 mg, and pembrolizumab is administered to the subject at a dose of at least 400 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of at least 1600 mg to at least 1700 mg, and pembrolizumab is administered to the subject at a dose of at least 400 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of at least 1700 mg to at least 1800 mg, and pembrolizumab is administered to the subject at a dose of at least 400 mg. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of at least 1400 mg, at least 1500 mg, at least 1600 mg, at least 1700 mg, or at least 1800 mg, and pembrolizumab is administered to the subject at a dose of at least 400 mg.

[0193] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of at least 1400 mg, and pembrolizumab is administered intravenously to the subject at a dose of at least 400 mg.

[0194] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of at least 1500 mg, and pembrolizumab is administered intravenously to the subject at a dose of at least 400 mg.

[0195] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of at least 1600 mg, and pembrolizumab is administered intravenously to the subject at a dose of at least 400 mg.

[0196] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of at least 1700 mg, and pembrolizumab is administered intravenously to the subject at a dose of at least 400 mg.

[0197] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of at least 1800 mg, and pembrolizumab is administered intravenously to the subject at a dose of at least 400 mg.

[0198] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dosing cycle (dosing interval) of approximately once every 2 weeks (Q2W) to approximately once every 6 weeks (Q6W) (e.g., approximately once every 2 weeks (Q2W), approximately once every 3 weeks (Q3W), approximately once every 4 weeks (Q4W), approximately once every 5 weeks (Q5W), or approximately once every 6 weeks (Q6W)), and pembrolizumab is administered at a dosing cycle (dosing interval) of approximately once every 3 weeks (Q3W). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dosing cycle (dosing interval) of approximately once every 2 weeks (Q2W), approximately once every 3 weeks (Q3W), approximately once every 4 weeks (Q4W), approximately once every 5 weeks (Q5W), or approximately once every 6 weeks (Q6W), and pembrolizumab is administered at a dosing cycle (dosing interval) of approximately once every 3 weeks (Q3W).

[0199] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dosing cycle (dosing interval) of approximately once every 2 weeks (Q2W) to approximately once every 6 weeks (Q6W) (e.g., approximately once every 2 weeks (Q2W), approximately once every 3 weeks (Q3W), approximately once every 4 weeks (Q4W), approximately once every 5 weeks (Q5W), or approximately once every 6 weeks (Q6W)), and pembrolizumab is administered at a dosing cycle (dosing interval) of approximately once every 6 weeks (Q6W). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dosing cycle (dosing interval) of approximately once every 2 weeks (Q2W), approximately once every 3 weeks (Q3W), approximately once every 4 weeks (Q4W), approximately once every 5 weeks (Q5W), or approximately once every 6 weeks (Q6W), and pembrolizumab is administered at a dosing cycle (dosing interval) of approximately once every 6 weeks (Q6W).

[0200] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment and pembrolizumab are administered at a dosing cycle (dosing interval) of approximately once every 3 weeks (Q3W).

[0201] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment and pembrolizumab are administered at a dosing cycle (dosing interval) of approximately once every 6 weeks (Q6W).

[0202] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is in the form of about 800 mg to about 3600 mg (e.g., about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg), about 1600 mg to about 3600 mg, about 2400 mg, or about 3600 mg. Pembrolizumab is administered at a dose of about 3600 mg to about 3600 mg or about 1600 mg to about 2400 mg at a dosing cycle (dosing interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)), and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (dosing interval) of about once every 3 weeks (Q3W). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is in the form of about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg. The dose of pembrolizumab is administered at a dosing cycle (dosing interval) of approximately once every 2 weeks (Q2W), approximately once every 3 weeks (Q3W), approximately once every 4 weeks (Q4W), approximately once every 5 weeks (Q5W), or approximately once every 6 weeks (Q6W), and pembrolizumab is administered at a dose of approximately 400 mg at a dosing cycle (dosing interval) of approximately once every 3 weeks (Q3W).

[0203] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is in the form of about 800 mg to about 3600 mg (e.g., about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg), about 1600 mg to about 3600 mg, about 2400 mg, or about 3600 mg. Pembrolizumab is administered at a dose of about 3600 mg to about 3600 mg or about 1600 mg to about 2400 mg at a dosing cycle (dosing interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)), and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (dosing interval) of about once every 6 weeks (Q6W). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is in the form of about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg. The dose of pembrolizumab is administered at a dosing cycle (dosing interval) of approximately once every 2 weeks (Q2W), approximately once every 3 weeks (Q3W), approximately once every 4 weeks (Q4W), approximately once every 5 weeks (Q5W), or approximately once every 6 weeks (Q6W), and pembrolizumab is administered at a dose of approximately 400 mg at a dosing cycle (dosing interval) of approximately once every 6 weeks (Q6W).

[0204] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg or about 1800 mg) at a dosing cycle (dosing interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W) or about once every 6 weeks (Q6W)), and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (dosing interval) of about once every 3 weeks (Q3W). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of about 1400 mg to about 1500 mg at a dosing cycle (dosing interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)), and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (dosing interval) of about once every 3 weeks (Q3W). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of about 1500 mg to about 1600 mg at a dosing cycle (dosing interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)), and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (dosing interval) of about once every 3 weeks (Q3W). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of about 1600 mg to about 1700 mg at a dosing cycle (dosing interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)), and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (dosing interval) of about once every 3 weeks (Q3W).In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of about 1700 mg to about 1800 mg at a dosing cycle (dosing interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)), and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (dosing interval) of about once every 3 weeks (Q3W). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg or about 1800 mg at a dosing cycle (dosing interval) of about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W) or about once every 6 weeks (Q6W), and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (dosing interval) of about once every 3 weeks (Q3W).

[0205] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg or about 1800 mg) at a dosing cycle (dosing interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W) or about once every 6 weeks (Q6W)), and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (dosing interval) of about once every 6 weeks (Q6W). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of about 1400 mg to about 1500 mg at a dosing cycle (dosing interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)), and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (dosing interval) of about once every 6 weeks (Q6W). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of about 1500 mg to about 1600 mg at a dosing cycle (dosing interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)), and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (dosing interval) of about once every 6 weeks (Q6W). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of about 1600 mg to about 1700 mg at a dosing cycle (dosing interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)), and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (dosing interval) of about once every 6 weeks (Q6W).In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of about 1700 mg to about 1800 mg at a dosing cycle (dosing interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)), and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (dosing interval) of about once every 6 weeks (Q6W). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg or about 1800 mg at a dosing cycle (dosing interval) of about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W) or about once every 6 weeks (Q6W), and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (dosing interval) of about once every 6 weeks (Q6W).

[0206] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously at a dose of about 1400 mg at a dosing cycle (Q3W) of about once every 3 weeks, and pembrolizumab is administered intravenously at a dose of about 400 mg at a dosing cycle (Q3W) of about once every 3 weeks.

[0207] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously at a dose of about 1500 mg at a dosing cycle (Q3W) of about once every 3 weeks, and pembrolizumab is administered intravenously at a dose of about 400 mg at a dosing cycle (Q3W) of about once every 3 weeks.

[0208] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously at a dose of about 1600 mg at a dosing cycle (Q3W) of about once every 3 weeks, and pembrolizumab is administered intravenously at a dose of about 400 mg at a dosing cycle (Q3W) of about once every 3 weeks.

[0209] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously at a dose of about 1700 mg at a dosing cycle (Q3W) of about once every 3 weeks, and pembrolizumab is administered intravenously at a dose of about 400 mg at a dosing cycle (Q3W) of about once every 3 weeks.

[0210] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously at a dose of about 1800 mg at a dosing cycle (Q3W) of about once every 3 weeks, and pembrolizumab is administered intravenously at a dose of about 400 mg at a dosing cycle (Q3W) of about once every 3 weeks.

[0211] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously at a dose of about 1400 mg at a dosing cycle (Q6W) of about once every 6 weeks, and pembrolizumab is administered intravenously at a dose of about 400 mg at a dosing cycle (Q6W) of about once every 6 weeks.

[0212] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously at a dose of about 1500 mg at a dosing cycle (Q6W) of about once every 6 weeks, and pembrolizumab is administered intravenously at a dose of about 400 mg at a dosing cycle (Q6W) of about once every 6 weeks.

[0213] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously at a dose of about 1600 mg at a dosing cycle (Q6W) of about once every 6 weeks, and pembrolizumab is administered intravenously at a dose of about 400 mg at a dosing cycle (Q6W) of about once every 6 weeks.

[0214] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously at a dose of about 1700 mg at a dosing cycle (Q6W) of about once every 6 weeks, and pembrolizumab is administered intravenously at a dose of about 400 mg at a dosing cycle (Q6W) of about once every 6 weeks.

[0215] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously at a dose of about 1800 mg at a dosing cycle (Q6W) of about once every 6 weeks, and pembrolizumab is administered intravenously at a dose of about 400 mg at a dosing cycle (Q6W) of about once every 6 weeks.

[0216] Anti-SIRPα antibodies or their antigen-binding fragments can be administered to subjects in combination with pembrolizumab and cetuximab. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is in the form of about 800 mg to about 3600 mg (e.g., about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg), about 1600 mg to about 3600 mg, about 2400 mg, or about 3600 mg. Subjects were administered doses of approximately 3600 mg or approximately 1600 mg to approximately 2400 mg, pembrolizumab was administered at approximately 400 mg, and cetuximab at approximately 500 mg / m². 2 The anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at doses of approximately 800 mg, approximately 900 mg, approximately 1000 mg, approximately 1100 mg, approximately 1200 mg, approximately 1300 mg, approximately 1400 mg, approximately 1500 mg, approximately 1600 mg, approximately 1700 mg, approximately 1800 mg, approximately 1900 mg, approximately 2000 mg, approximately 2100 mg, approximately 2200 mg, approximately 2300 mg, approximately 2400 mg, approximately 2500 mg, approximately 2600 mg, approximately 2700 mg, approximately 2800 mg, approximately 2900 mg, approximately 3000 mg, approximately 3100 mg, approximately 3200 mg, approximately 3300 mg, approximately 3400 mg, approximately 3500 mg, or approximately 3600 mg. Pembrolizumab is administered to the subject at doses of approximately 400 mg. The subjects were administered cetuximab at a dose of approximately 500 mg / m². 2 The appropriate dose was administered to the subject.

[0217] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg), pembrolizumab is administered to the subject at a dose of about 400 mg, and cetuximab is administered at a dose of about 500 mg / m².2 The anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1400 mg to about 1500 mg, pembrolizumab is administered to the subject at a dose of about 400 mg, and cetuximab is administered to the subject at a dose of about 500 mg / m². 2 The anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1500 mg to about 1600 mg, pembrolizumab is administered to the subject at a dose of about 400 mg, and cetuximab is administered to the subject at a dose of about 500 mg / m². 2 The anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1600 mg to about 1700 mg, pembrolizumab is administered to the subject at a dose of about 400 mg, and cetuximab is administered to the subject at a dose of about 500 mg / m². 2 The anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1700 mg to about 1800 mg, pembrolizumab is administered to the subject at a dose of about 400 mg, and cetuximab is administered to the subject at a dose of about 500 mg / m². 2 The anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of approximately 1400 mg, approximately 1500 mg, approximately 1600 mg, approximately 1700 mg, or approximately 1800 mg; pembrolizumab is administered to the subject at a dose of approximately 400 mg; and cetuximab is administered to the subject at a dose of approximately 500 mg / m². 2 The appropriate dose was administered to the subject.

[0218] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1400 mg, pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg, and cetuximab is administered intravenously at a dose of approximately 500 mg / m². 2 The dose was administered intravenously to the subject.

[0219] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1500 mg, pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg, and cetuximab is administered intravenously at a dose of approximately 500 mg / m². 2 The dose was administered intravenously to the subject.

[0220] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1600 mg, pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg, and cetuximab is administered intravenously at a dose of approximately 500 mg / m². 2 The dose was administered intravenously to the subject.

[0221] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1700 mg, pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg, and cetuximab is administered intravenously at a dose of approximately 500 mg / m². 2 The dose was administered intravenously to the subject.

[0222] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1800 mg, pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg, and cetuximab is administered intravenously at a dose of approximately 500 mg / m². 2 The dose was administered intravenously to the subject.

[0223] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is in the form of about 800 mg to about 3600 mg (e.g., about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg), about 1600 mg to about 3600 mg, about 2400 mg, or about 3600 mg. Subjects were administered doses of approximately 3600 mg or approximately 1600 mg to approximately 2400 mg, pembrolizumab was administered at approximately 400 mg, and cetuximab was administered at approximately 400 mg / m². 2 The initial dose and 250 mg / m 2Subsequent doses were administered to the subject. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment was administered to the subject at doses of approximately 800 mg, approximately 900 mg, approximately 1000 mg, approximately 1100 mg, approximately 1200 mg, approximately 1300 mg, approximately 1400 mg, approximately 1500 mg, approximately 1600 mg, approximately 1700 mg, approximately 1800 mg, approximately 1900 mg, approximately 2000 mg, approximately 2100 mg, approximately 2200 mg, approximately 2300 mg, approximately 2400 mg, approximately 2500 mg, approximately 2600 mg, approximately 2700 mg, approximately 2800 mg, approximately 2900 mg, approximately 3000 mg, approximately 3100 mg, approximately 3200 mg, approximately 3300 mg, approximately 3400 mg, approximately 3500 mg, or approximately 3600 mg. Pembrolizumab was administered to the subject at doses of approximately 400 mg. The subjects were administered cetuximab at a dose of approximately 400 mg / m². 2 The initial dose and 250 mg / m 2 Subsequent doses were administered to the subjects.

[0224] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg), pembrolizumab is administered to the subject at a dose of about 400 mg, and cetuximab is administered at a dose of about 400 mg / m². 2 The initial dose and 250 mg / m 2 Subsequent doses were administered to the subject. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment was administered to the subject at a dose of about 1400 mg to about 1500 mg, pembrolizumab at a dose of about 400 mg, and cetuximab at a dose of about 400 mg / m². 2 The initial dose and 250 mg / m 2 Subsequent doses were administered to the subject. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment was administered to the subject at a dose of about 1500 mg to about 1600 mg, pembrolizumab at a dose of about 400 mg, and cetuximab at a dose of about 400 mg / m². 2 The initial dose and 250 mg / m 2 Subsequent doses were administered to the subject. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment was administered to the subject at a dose of about 1600 mg to about 1700 mg, pembrolizumab at a dose of about 400 mg, and cetuximab at a dose of about 400 mg / m².2 The initial dose and 250 mg / m 2 Subsequent doses were administered to the subject. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment was administered to the subject at a dose of about 1700 mg to about 1800 mg, pembrolizumab at a dose of about 400 mg, and cetuximab at a dose of about 400 mg / m². 2 The initial dose and 250 mg / m 2 Subsequent doses were administered to the subject. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment was administered to the subject at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, pembrolizumab was administered to the subject at a dose of about 400 mg, and cetuximab was administered to the subject at a dose of about 400 mg / m². 2 The initial dose and 250 mg / m 2 Subsequent doses were administered to the subjects.

[0225] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of approximately 1400 mg, pembrolizumab is administered to the subject at a dose of approximately 400 mg, and cetuximab is administered to the subject at a dose of approximately 400 mg / m². 2 The initial dose and 250 mg / m 2 Subsequent doses were administered to the subjects.

[0226] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of approximately 1500 mg, pembrolizumab is administered to the subject at a dose of approximately 400 mg, and cetuximab is administered to the subject at a dose of approximately 400 mg / m². 2 The initial dose and 250 mg / m 2 Subsequent doses were administered to the subjects.

[0227] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of approximately 1600 mg, pembrolizumab is administered to the subject at a dose of approximately 400 mg, and cetuximab is administered to the subject at a dose of approximately 400 mg / m². 2 The initial dose and 250 mg / m 2 Subsequent doses were administered to the subjects.

[0228] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of approximately 1700 mg, pembrolizumab is administered to the subject at a dose of approximately 400 mg, and cetuximab is administered to the subject at a dose of approximately 400 mg / m². 2 The initial dose and 250 mg / m2 Subsequent doses were administered to the subjects.

[0229] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of approximately 1800 mg, pembrolizumab at a dose of approximately 400 mg, and cetuximab at a dose of approximately 400 mg / m². 2 The initial dose and 250 mg / m 2 Subsequent doses were administered to the subjects.

[0230] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dosing interval of approximately once every 3 weeks (Q3W) or approximately once every 6 weeks (Q6W), pembrolizumab is administered to the subject at a dosing interval of approximately once every 3 weeks (Q3W) or approximately once every 6 weeks (Q6W), and cetuximab is administered to the subject at a dosing interval of approximately once every 2 weeks (Q2W) or approximately once a week (Q1W).

[0231] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dosing cycle (dosing interval) of approximately once every 3 weeks (Q3W), pembrolizumab is administered to the subject at a dosing cycle of approximately once every 3 weeks (Q3W), and cetuximab is administered to the subject at a dosing cycle of approximately once every 2 weeks (Q2W).

[0232] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dosing cycle (dosing interval) of approximately once every 6 weeks (Q6W), pembrolizumab is administered to the subject at a dosing cycle of approximately once every 6 weeks (Q6W), and cetuximab is administered to the subject at a dosing cycle of approximately once every 2 weeks (Q2W).

[0233] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dosing cycle (dosing interval) of approximately once every 3 weeks (Q3W), pembrolizumab is administered to the subject at a dosing cycle of approximately once every 3 weeks (Q3W), and cetuximab is administered to the subject at a dosing cycle of approximately once a week (Q1W).

[0234] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dosing cycle (dosing interval) of approximately once every 6 weeks (Q6W), pembrolizumab is administered to the subject at a dosing cycle of approximately once every 6 weeks (Q6W), and cetuximab is administered to the subject at a dosing cycle of approximately once a week (Q1W).

[0235] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is in the form of about 800 mg to about 3600 mg (e.g., about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg), about 1600 mg to about 3600 mg, about 2400 mg, or about 3600 mg. The subjects were administered doses of approximately 3600 mg or approximately 1600 mg or approximately 2400 mg at a dosing interval of approximately once every 3 weeks (Q3W) or approximately once every 6 weeks (Q6W); pembrolizumab was administered at a dose of approximately 400 mg at a dosing interval of approximately once every 3 weeks (Q3W) or approximately once every 6 weeks (Q6W); and cetuximab was administered at a dose of approximately 500 mg / m². 2 The dosage is administered approximately every 2 weeks (Q2W), or at approximately 400 mg / m². 2 The initial dose and approximately 250 mg / m 2 Subsequent doses are administered to the subject approximately once weekly (Q1W). In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered at doses of approximately 800 mg, approximately 900 mg, approximately 1000 mg, approximately 1100 mg, approximately 1200 mg, approximately 1300 mg, approximately 1400 mg, approximately 1500 mg, approximately 1600 mg, approximately 1700 mg, approximately 1800 mg, approximately 1900 mg, approximately 2000 mg, approximately 2100 mg, approximately 2200 mg, approximately 2300 mg, approximately 2400 mg, approximately 2500 mg, approximately 2600 mg, approximately 2700 mg, approximately 2800 mg, approximately 2900 mg, approximately 3000 mg, approximately 3100 mg, approximately 3200 mg, approximately 3300 mg, approximately 3400 mg, approximately 3500 mg, or approximately 3600 mg. The dosage of pembrolizumab was administered to the subject at a dosing interval of approximately once every 3 weeks (Q3W) or approximately once every 6 weeks (Q6W), and cetuximab was administered to the subject at a dosing interval of approximately 400 mg / m². 2The dosage is administered approximately every 2 weeks (Q2W), or at approximately 400 mg / m². 2 The initial dose and approximately 250 mg / m 2 Subsequent doses were administered to the subjects at a dosing cycle of approximately once a week (Q1W).

[0236] In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is in the form of about 800 mg to about 3600 mg (e.g., about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg), about 1600 mg to about 3600 mg, about 2400 mg, or about 3600 mg. The dosage of pembrolizumab is approximately 3600 mg or approximately 1600 mg to approximately 2400 mg, administered intravenously to the subject at a dosing cycle of approximately once every 2 weeks (Q2W). Pembrolizumab is administered intravenously to the subject at a dosage of approximately 400 mg at a dosing cycle of approximately once every 6 weeks (Q6W), and cetuximab is administered intravenously at a dosage of approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0237] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 800 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0238] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 900 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0239] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1000 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0240] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1100 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0241] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1200 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0242] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1300 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0243] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1400 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m².2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0244] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1500 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0245] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1600 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0246] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1700 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0247] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1800 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0248] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1900 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0249] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 2000 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0250] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 2100 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0251] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 2200 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0252] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 2300 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0253] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 2400 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0254] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 2500 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0255] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 2600 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0256] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 2700 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0257] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 2800 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0258] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 2900 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0259] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 3000 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0260] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 3100 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0261] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 3200 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0262] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 3300 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0263] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 3400 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0264] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 3500 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0265] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 3600 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0266] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered to the subject at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg) on ​​a dosing cycle of about once every 3 weeks (Q3W) or about once every 6 weeks (Q6W), pembrolizumab is administered to the subject at a dose of about 400 mg on a dosing cycle of about once every 3 weeks (Q3W) or about once every 6 weeks (Q6W), and cetuximab is administered at a dose of about 500 mg / m². 2 The dosage is administered approximately every 2 weeks (Q2W), or at approximately 400 mg / m². 2 The initial dose and approximately 250 mg / m 2Subsequent doses are administered to subjects at a dosing cycle of approximately once weekly (Q1W). In some embodiments, anti-SIRPα antibody or its antigen-binding fragment is administered to subjects at a dose of approximately 1400 mg to approximately 1500 mg at a dosing cycle of approximately once every 3 weeks (Q3W) or approximately once every 6 weeks (Q6W), pembrolizumab is administered to subjects at a dose of approximately 400 mg at a dosing cycle of approximately once every 3 weeks (Q3W) or approximately once every 6 weeks (Q6W), and cetuximab is administered at a dose of approximately 500 mg / m². 2 The dosage is administered approximately every 2 weeks (Q2W), or at approximately 400 mg / m². 2 The initial dose and approximately 250 mg / m 2 Subsequent doses are administered to subjects at a dosing cycle of approximately once weekly (Q1W). In some embodiments, anti-SIRPα antibody or its antigen-binding fragment is administered to subjects at a dose of approximately 1500 mg to approximately 1600 mg at a dosing cycle of approximately once every 3 weeks (Q3W) or approximately once every 6 weeks (Q6W), pembrolizumab is administered to subjects at a dose of approximately 400 mg at a dosing cycle of approximately once every 3 weeks (Q3W) or approximately once every 6 weeks (Q6W), and cetuximab is administered at a dose of approximately 500 mg / m². 2 The dosage is administered approximately every 2 weeks (Q2W), or at approximately 400 mg / m². 2 The initial dose and approximately 250 mg / m 2 Subsequent doses are administered to subjects at a dosing cycle of approximately once weekly (Q1W). In some embodiments, anti-SIRPα antibody or its antigen-binding fragment is administered to subjects at a dose of approximately 1600 mg to approximately 1700 mg at a dosing cycle of approximately once every 3 weeks (Q3W) or approximately once every 6 weeks (Q6W), pembrolizumab is administered to subjects at a dose of approximately 400 mg at a dosing cycle of approximately once every 3 weeks (Q3W) or approximately once every 6 weeks (Q6W), and cetuximab is administered at a dose of approximately 500 mg / m². 2 The dosage is administered approximately every 2 weeks (Q2W), or at approximately 400 mg / m². 2 The initial dose and approximately 250 mg / m 2Subsequent doses are administered to subjects at a dosing cycle of approximately once weekly (Q1W). In some embodiments, anti-SIRPα antibody or its antigen-binding fragment is administered to subjects at a dose of approximately 1700 mg to approximately 1800 mg at a dosing cycle of approximately once every 3 weeks (Q3W) or approximately once every 6 weeks (Q6W), pembrolizumab is administered to subjects at a dose of approximately 400 mg at a dosing cycle of approximately once every 3 weeks (Q3W) or approximately once every 6 weeks (Q6W), and cetuximab is administered at a dose of approximately 500 mg / m². 2 The dosage is administered approximately every 2 weeks (Q2W), or at approximately 400 mg / m². 2 The initial dose and approximately 250 mg / m 2 Subsequent doses are administered to subjects at a dosing cycle of approximately once weekly (Q1W). In some embodiments, anti-SIRPα antibody or its antigen-binding fragment is administered to subjects at a dose of approximately 1400 mg, approximately 1500 mg, approximately 1600 mg, approximately 1700 mg, or approximately 1800 mg at a dosing cycle of approximately once every 3 weeks (Q3W) or approximately once every 6 weeks (Q6W), pembrolizumab is administered to subjects at a dose of approximately 400 mg at a dosing cycle of approximately once every 3 weeks (Q3W) or approximately once every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dosage is administered approximately every 2 weeks (Q2W), or at approximately 400 mg / m². 2 The initial dose and approximately 250 mg / m 2 Subsequent doses were administered to the subjects at a dosing cycle of approximately once a week (Q1W).

[0267] In some implementations, the anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg) on ​​a dosing cycle of about once every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of about 400 mg on a dosing cycle of about once every 6 weeks (Q6W), and cetuximab is administered at about 500 mg / m². 2 The dosage is administered intravenously to the subject at a dosing cycle of approximately once every 2 weeks (Q2W). In some embodiments, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1400 mg at a dosing cycle of approximately once every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg at a dosing cycle of approximately once every 6 weeks (Q6W), and cetuximab is administered at a dose of approximately 500 mg / m².2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0268] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1400 mg every 3 weeks (Q3W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 3 weeks (Q3W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0269] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1400 mg every 3 weeks (Q3W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 3 weeks (Q3W), and cetuximab is administered at approximately 400 mg / m². 2 The initial dose and approximately 250 mg / m 2 Subsequent doses were administered intravenously to the subjects at a dosing cycle of approximately once a week (Q1W).

[0270] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1400 mg every 6 weeks (Q6W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0271] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1400 mg every 6 weeks (Q6W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered intravenously at approximately 400 mg / m². 2 The initial dose and approximately 250 mg / m 2 Subsequent doses were administered intravenously to the subjects at a dosing cycle of approximately once a week (Q1W).

[0272] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1500 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0273] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1500 mg every 3 weeks (Q3W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 3 weeks (Q3W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0274] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1500 mg every 3 weeks (Q3W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 3 weeks (Q3W), and cetuximab is administered at approximately 400 mg / m². 2 The initial dose and approximately 250 mg / m 2 Subsequent doses were administered intravenously to the subjects at a dosing cycle of approximately once a week (Q1W).

[0275] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1500 mg every 6 weeks (Q6W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0276] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1500 mg every 6 weeks (Q6W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 400 mg / m². 2 The initial dose and approximately 250 mg / m2 Subsequent doses were administered intravenously to the subjects at a dosing cycle of approximately once a week (Q1W).

[0277] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1600 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0278] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1600 mg every 3 weeks (Q3W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 3 weeks (Q3W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0279] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1600 mg every 3 weeks (Q3W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 3 weeks (Q3W), and cetuximab is administered at approximately 400 mg / m². 2 The initial dose and approximately 250 mg / m 2 Subsequent doses were administered intravenously to the subjects at a dosing cycle of approximately once a week (Q1W).

[0280] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1600 mg every 6 weeks (Q6W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0281] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1600 mg every 6 weeks (Q6W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 400 mg / m². 2 The initial dose and approximately 250 mg / m 2 Subsequent doses were administered intravenously to the subjects at a dosing cycle of approximately once a week (Q1W).

[0282] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1700 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0283] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1700 mg every 3 weeks (Q3W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 3 weeks (Q3W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0284] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1700 mg every 3 weeks (Q3W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 3 weeks (Q3W), and cetuximab is administered intravenously at approximately 400 mg / m². 2 The initial dose and approximately 250 mg / m 2 Subsequent doses were administered intravenously to the subjects at a dosing cycle of approximately once a week (Q1W).

[0285] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1700 mg every 6 weeks (Q6W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m².2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0286] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1700 mg every 6 weeks (Q6W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 400 mg / m². 2 The initial dose and approximately 250 mg / m 2 Subsequent doses were administered intravenously to the subjects at a dosing cycle of approximately once a week (Q1W).

[0287] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1800 mg every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0288] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1800 mg every 3 weeks (Q3W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 3 weeks (Q3W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0289] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1800 mg every 3 weeks (Q3W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 3 weeks (Q3W), and cetuximab is administered at approximately 400 mg / m². 2 The initial dose and approximately 250 mg / m 2 Subsequent doses were administered intravenously to the subjects at a dosing cycle of approximately once a week (Q1W).

[0290] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1800 mg every 6 weeks (Q6W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 500 mg / m². 2 The dose was administered intravenously to the subjects at a dosing cycle of approximately once every 2 weeks (Q2W).

[0291] In some implementations, anti-SIRPα antibody or its antigen-binding fragment is administered intravenously to the subject at a dose of approximately 1800 mg every 6 weeks (Q6W), pembrolizumab is administered intravenously to the subject at a dose of approximately 400 mg every 6 weeks (Q6W), and cetuximab is administered at approximately 400 mg / m². 2 The initial dose and approximately 250 mg / m 2 Subsequent doses were administered intravenously to the subjects at a dosing cycle of approximately once a week (Q1W).

[0292] In one embodiment, one or more other therapeutic agents are administered at doses of about 100 mg to about 1000 mg, such as about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 200 mg, about 200 mg to about 300 mg, about 300 mg to about 400 mg, about 400 mg to about 500 mg, about 500 mg to about 600 mg, about 600 mg to about 700 mg, about 700 mg to about 800 mg, about 800 mg to about 900 mg and / or about 900 mg to about 1000 mg.In one embodiment, one or more other therapeutic agents are present in doses of approximately 100 mg, approximately 110 mg, approximately 120 mg, approximately 130 mg, approximately 140 mg, approximately 150 mg, approximately 160 mg, approximately 170 mg, approximately 180 mg, approximately 190 mg, approximately 200 mg, approximately 210 mg, approximately 220 mg, approximately 230 mg, approximately 240 mg, approximately 250 mg, approximately 260 mg, approximately 270 mg, approximately 280 mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg, approximately 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg, approximately 480 mg, approximately 40 ... mg, approximately 490 mg, approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, approximately 580 mg, approximately 590 mg, approximately 600 mg, approximately 610 mg, approximately 620 mg, approximately 630 mg, approximately 640 mg, approximately 650 mg, approximately 660 mg, approximately 670 mg, approximately 680 mg, approximately 690 mg, approximately 700 mg, approximately 710 mg, approximately 720 mg, approximately 730 mg, approximately 740 mg, approximately 750 mg, approximately 760 mg, approximately 770 mg, approximately 780 mg, approximately 790 mg, approximately 800 mg, approximately 810 mg, approximately 820 mg, approximately 830 mg, approximately 840 mg, approximately 850 mg, approximately 860 mg, approximately 870 mg, approximately 880 mg, approximately 890 mg Administered at doses of approximately 1000 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg, or 1000 mg.

[0293] In one embodiment, one or more other therapeutic agents are administered to the patient more than once. In other words, one or more other therapeutic agents are administered in a prescribed dosing cycle, wherein the dosing cycle is the period between one administration of one or more other therapeutic agents and the next administration, for example, the period between the first administration of one or more other therapeutic agents and the second administration of one or more other therapeutic agents. In one embodiment, one or more other therapeutic agents are administered several times according to a regular dosing cycle, i.e., the time interval between each administration is the same, such as every 21 days. In one embodiment, one or more other therapeutic agents are administered several times according to a varying dosing cycle, i.e., the time interval between each administration may be shorter or longer than the time interval of the previous or next dosing cycle. In one embodiment, the dosing cycle is interrupted by a treatment-free period. In one embodiment, the dosing cycle is not interrupted by a treatment-free period.

[0294] In one embodiment, each dosing cycle has a period of approximately 7 days, approximately 14 days, approximately 21 days, approximately 28 days, approximately 35 days, approximately 42 days, approximately 49 days, or approximately 56 days. In one embodiment, one or more other therapeutic agents are administered to the patient on one or more of days 1, 2, 3, 4, 5, 6, or 7 of the dosing cycle, and not on the remaining days of the dosing cycle. In one embodiment, as described herein, a dose of one or more other therapeutic agents is administered to the patient on day 1 of a 21-day cycle, and not on days 2 through 21 of the 21-day cycle. In one embodiment, a dose of the anti-SIRPα antibody or its antigen-binding fragment and a dose of one or more other therapeutic agents are administered to the patient on the same day.

[0295] In one embodiment, an anti-PD1 antibody in doses of about 100 mg to about 1000 mg, such as about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 200 mg, about 200 mg to about 300 mg, about 300 mg to about 400 mg, about 400 mg to about 500 mg, about 500 mg to about 600 mg, about 600 mg to about 700 mg, about 700 mg to about 800 mg, about 800 mg to about 900 mg and / or about 900 mg to about 1000 mg, is administered to the patient on day 1 of a 21-day cycle and is not administered on days 2 through 21 of the 21-day cycle.In one embodiment, approximately 100 mg, approximately 110 mg, approximately 120 mg, approximately 130 mg, approximately 140 mg, approximately 150 mg, approximately 160 mg, approximately 170 mg, approximately 180 mg, approximately 190 mg, approximately 200 mg, approximately 210 mg, approximately 220 mg, approximately 230 mg, approximately 240 mg, approximately 250 mg, approximately 260 mg, approximately 270 mg, approximately 280 mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg, approximately 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg, approximately 480 mg, approximately 490 mg, etc. mg, approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, approximately 580 mg, approximately 590 mg, approximately 600 mg, approximately 610 mg, approximately 620 mg, approximately 630 mg, approximately 640 mg, approximately 650 mg, approximately 660 mg, approximately 670 mg, approximately 680 mg, approximately 690 mg, approximately 700 mg, approximately 710 mg, approximately 720 mg, approximately 730 mg, approximately 740 mg, approximately 750 mg, approximately 760 mg, approximately 770 mg, approximately 780 mg, approximately 790 mg, approximately 800 mg, approximately 810 mg, approximately 820 mg, approximately 830 mg, approximately 840 mg, approximately 850 mg, approximately 860 mg, approximately 870 mg, approximately 880 mg, approximately 890 mg, approximately 900 mg The anti-PD1 anti-system at doses of approximately 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg, or 1000 mg is administered to the patient on day 1 of a 21-day cycle and is not administered from day 2 to day 21 of the 21-day cycle.

[0296] In one embodiment, ebendimab in doses of about 100 mg to about 1000 mg, such as about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 200 mg, about 200 mg to about 300 mg, about 300 mg to about 400 mg, about 400 mg to about 500 mg, about 500 mg to about 600 mg, about 600 mg to about 700 mg, about 700 mg to about 800 mg, about 800 mg to about 900 mg and / or about 900 mg to about 1000 mg, is administered to the patient on day 1 of a 21-day cycle and is not administered on days 2 through 21 of the 21-day cycle.In one embodiment, approximately 100 mg, approximately 110 mg, approximately 120 mg, approximately 130 mg, approximately 140 mg, approximately 150 mg, approximately 160 mg, approximately 170 mg, approximately 180 mg, approximately 190 mg, approximately 200 mg, approximately 210 mg, approximately 220 mg, approximately 230 mg, approximately 240 mg, approximately 250 mg, approximately 260 mg, approximately 270 mg, approximately 280 mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg, approximately 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg, approximately 480 mg, approximately 490 mg, etc. mg, approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, approximately 580 mg, approximately 590 mg, approximately 600 mg, approximately 610 mg, approximately 620 mg, approximately 630 mg, approximately 640 mg, approximately 650 mg, approximately 660 mg, approximately 670 mg, approximately 680 mg, approximately 690 mg, approximately 700 mg, approximately 710 mg, approximately 720 mg, approximately 730 mg, approximately 740 mg, approximately 750 mg, approximately 760 mg, approximately 770 mg, approximately 780 mg, approximately 790 mg, approximately 800 mg, approximately 810 mg, approximately 820 mg, approximately 830 mg, approximately 840 mg, approximately 850 mg, approximately 860 mg, approximately 870 mg, approximately 880 mg, approximately 890 mg, approximately 900 mg Ebenemimab in doses of approximately 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg, or 1000 mg is administered to patients on day 1 of a 21-day cycle and is not administered on days 2 through 21 of the 21-day cycle.

[0297] In one implementation, approximately 240 mg of ebendimab is administered to the patient on day 1 of a 21-day cycle, and is not administered from day 2 to day 21 of the 21-day cycle.

[0298] In one embodiment, an anti-SIRPα antibody or its antigen-binding fragment in doses of about 200 mg, about 600 mg, about 1200 mg, about 1600 mg, about 2400 mg, or about 3500 mg, and about 240 mg of ebendimab are administered to the patient on day 1 of a 21-day cycle, and not administered on days 2 through 21 of the 21-day cycle. In another embodiment, an anti-SIRPα antibody or its antigen-binding fragment in doses of about 200 mg and about 240 mg of ebendimab are administered to the patient on day 1 of a 21-day cycle, and not administered on days 2 through 21 of the 21-day cycle. In yet another embodiment, an anti-SIRPα antibody or its antigen-binding fragment in doses of about 600 mg and about 240 mg of ebendimab are administered to the patient on day 1 of a 21-day cycle, and not administered on days 2 through 21 of the 21-day cycle. In one embodiment, approximately 1200 mg of anti-SIRPα antibody or its antigen-binding fragment and approximately 240 mg of ebendimab are administered to the patient on day 1 of a 21-day cycle, and not administered on days 2 through 21 of the 21-day cycle. In another embodiment, approximately 1600 mg of anti-SIRPα antibody or its antigen-binding fragment and approximately 240 mg of ebendimab are administered to the patient on day 1 of a 21-day cycle, and not administered on days 2 through 21 of the 21-day cycle. In yet another embodiment, approximately 2400 mg of anti-SIRPα antibody or its antigen-binding fragment and approximately 240 mg of ebendimab are administered to the patient on day 1 of a 21-day cycle, and not administered on days 2 through 21 of the 21-day cycle. In one implementation, approximately 3,500 mg of anti-SIRPα antibody or its antigen-binding fragment and approximately 240 mg of ebendimab are administered to the patient on day 1 of a 21-day cycle, and are not administered on days 2 through 21 of the 21-day cycle. Application route

[0299] Various delivery systems are known and can be used to administer anti-SIRPα antibodies or their antigen-binding fragments. Methods of administration include, but are not limited to, intravitreal, ophthalmic, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. Anti-SIRPα antibodies or their antigen-binding fragments can be administered, for example, by infusion, bolus, or injection, and can be administered together with other bioactive agents. Administration can be systemic or local. Formulations for such injections can be prepared, for example, in pre-filled syringes comprising anti-SIRPα antibodies or their antigen-binding fragments.

[0300] For use in therapy, the anti-SIRPα antibodies of this disclosure are formulated into pharmaceutical compositions suitable for administration to animals or humans. Typical formulations of the binding molecules or antibody molecules described herein can be prepared by mixing the binding molecules or antibody molecules with physiologically acceptable carriers, excipients, or stabilizers in the form of a lyophilized or otherwise dried formulation, an aqueous solution, or an aqueous or non-aqueous suspension. The carriers, excipients, modifiers, or stabilizers are non-toxic at the doses and concentrations used.

[0301] In one embodiment, the pharmaceutical composition is formulated according to standard procedures to be suitable for intravenous or subcutaneous administration to a subject. Typically, compositions intended for injection are solutions in sterile isotonic aqueous solutions. If necessary, the pharmaceutical composition may also include a solubilizer and a local anesthetic, such as lidocaine, to relieve pain at the injection site. Typically, the components of the composition are provided individually or in unit dosage forms (e.g., as dry lyophilized powders or anhydrous concentrates) in a closed, sealed container (such as an ampoule or capsule) indicating the amount of active agent. When administered by infusion, it can be prepared using an infusion bottle containing sterile pharmaceutical-grade water or physiological saline. When administered by injection, ampoules of sterile water or physiological saline for injection can be provided so that the components can be mixed prior to administration.

[0302] In addition, the pharmaceutical composition may be provided in the form of a pharmaceutical kit comprising (a) a container containing an anti-SIRPα antibody or an antigen-binding fragment thereof in lyophilized form, and (b) a second container containing a pharmaceutically acceptable diluent for injection (e.g., sterile water). The lyophilized anti-SIRPα antibody or its antigen-binding fragment may be reconstituted or diluted using the pharmaceutically acceptable diluent. Optionally, precautions may be associated with such containers in the form prescribed by a government agency that regulates the manufacture, use, or sale of the drug or biological product, reflecting that agency's approval for manufacture, use, or sale for human administration.

[0303] The present disclosure is now described with reference to the following embodiments. These embodiments are provided for illustrative purposes only, and the present disclosure should in no way be construed as limited to these embodiments, but rather as covering any and all variations that become apparent as a result of the teachings provided herein.

[0304] Without further description, it is believed that those skilled in the art can prepare and utilize the compounds of this disclosure and practice the claimed methods using the foregoing description and the following illustrative examples. Therefore, the following working examples specifically point to preferred embodiments of this disclosure and should not be construed as limiting the remainder of this disclosure in any way. Example Example 1: Pharmacometric Analysis of Anti-SIRPα Antibody

[0305] Antibody A10 was administered intravenously (iv) to each of three adult subjects at a single dose of 600 mg, 1200 mg, 1600 mg, 2400 mg, or 3600 mg. Similarly, 6 mg / kg, 12 mg / kg, 18 mg / kg, 24 mg / kg, or 36 mg / kg was administered intravenously to each of 6 to 12 adult subjects. Blood was collected from each of these subjects 0 to 504 hours after administration. Serum antibody concentrations were measured by ELISA to assess pharmacokinetics. Briefly, blood was allowed to clot at room temperature for at least 30 minutes. Samples were centrifuged at approximately 1500–2000 × g at 2–8 °C within 1 hour of collection. Collected blood was stored at -60 °C to -80 °C prior to analysis.

[0306] Serum concentration-time curve (e.g., see...) Figures 3A to 3C This is used to estimate the following PK parameters using two-compartment analysis: antibody clearance (CL), volume (V), peripheral volume, Q, and V. max and K m Individual subjects were analyzed separately, and results from each dose group were summarized as mean ± standard deviation (SD). Modeling methods included population PK-PD (serum concentration and peripheral target binding (TE)) and minimum physiological pharmacokinetics (mPBPK) (PET data - tumor lesion activity). Clinical validation was achieved through treatment with antibody X1 at 24 mg / kg. Subsequently, the mPBPK model was used to predict tumor exposure and target binding of antibody A10 at dose regimens matched to antibody X1 target binding.

[0307] Population PK model estimation results confirmed the PK findings, showing that the elimination rate of antibody A10 (linear and nonlinear components) was more than 50% higher than that of antibody X1 (Table 34). Furthermore, no significant difference in binding affinity (Kd) to peripheral targets was identified between antibody A10 and antibody X1. The data suggest that the half-life of antibody A10 is unexpectedly shorter than that of antibody X1, and that increased dosage or dosing frequency may be required to more closely match antibody X1 exposure at lower doses. Table 34 PopPK-PD model estimation results Example 2: Phase I study of antibody X1 in patients with advanced cancer

[0308] In an open-label, non-randomized, phase I study, antibody X1 was tested in four patients with advanced cancer (two with head and neck cancer, one with non-small cell lung cancer, and one with melanoma) who had no standard treatment options. The primary objective was to observe the distribution of antibody X1 in tumor lesions and normal tissues and organs in patients who were also receiving ebendimab.

[0309] All patients underwent two imaging cycles, with an injection of 37 MBq plus... 89 Zr-tagged antibody X1 was administered via PET / CT scan at 2, 24, 48, and 120 hours post-injection. This information was used to assess the injection frequency at each cycle. 89 Prior to the administration of Zr-tagged antibody X1, antibody X1 was infused, initially with a low-quality dose (tracer dose) followed by a high-quality dose (therapeutic dose) two weeks later. Venous blood samples were collected at 15, 40, 70, 130, and 250 minutes post-injection and during each PET scan for pharmacokinetic analysis.

[0310] Tumors are identified using conventional imaging methods (18F-FDG PET (for tumor glucose uptake) and CT), and in 89 Visual assessment of radioactive uptake on Zr-PET, exceeding that in tissues without target expression, was performed. Quantitative assessment was based on the net inflow rate Ki determined by Patlak linearization. This model assumes that the tumor lesion volume and background contrast remain unchanged between three PET scans within an imaging cycle. Tumors causing unreliable Patlak linearization (negative distribution volume or r < 0.9) were excluded from the analysis. Saturation was demonstrated by the reduction in Ki caused by the treatment dose compared to the tracer dose.

[0311] At tracer doses, nine out of eleven identified tumor lesions showed at least one [symptom / effect]. 89 Tracer uptake was observed in Zr-PET scans. Patlak analysis was performed in nine of the eleven tumors. The Ki values ​​for the tracer dose ranged from 1.3 × 10⁻³ [h⁻¹] to 3.7 × 10⁻³ [h⁻¹], showing a Ki higher than 0.7 × 10⁻³ [h⁻¹] (non-tumor reference Ki) for all lesions. The Ki values ​​for the therapeutic dose ranged from 0.7 × 10⁻³ [h⁻¹] to 2.1 × 10⁻³ [h⁻¹]. With the exception of one lesion, the Ki value for the therapeutic dose was lower than that for the tracer dose in all lesions.

[0312] In summary, target engagement was observed in all lesions based on Patlak linearization at tracer doses. A saturation effect was observed in eight of the eleven lesions following therapeutic infusion of antibody X1. Example 3: Phase I study of antibody A10 in patients with advanced solid tumors

[0313] In a two-step, open-label, phase I study, anti-SIRPα antibodies were tested in patients with advanced solid tumors. Part 1 investigated dose-escalation monotherapy with anti-SIRPα antibodies, and Part 2 investigated dose expansion in combination with anti-SIRPα antibodies and ebendimab.

[0314] The primary objective is to determine the maximum tolerated dose of anti-SIRPα antibody monotherapy and the combination of anti-SIRPα antibody and ebemlimab, and to determine the recommended extended dose based on all available data, including safety, preliminary efficacy, and pharmacokinetics / pharmacodynamics.

[0315] The primary endpoint was dose-limiting toxicities occurring during the maximum tolerated dose assessment period. Secondary endpoints included adverse events and dose-limiting toxicities occurring during the treatment period, as well as efficacy as assessed by the Responsive Evaluation Criteria in Solid Tumors (RECIST) v1.1 and by the investigators.

[0316] Fifteen patients received at least one dose of anti-SIRPα antibody as a monotherapy, and three patients received combination therapy with ebumab. Four patients who initially received monotherapy were subsequently treated with combination therapy. Patient demographics and disease characteristics are provided in the table below (ECOG PS: Eastern Cooperative Oncology Group Performance Score).

[0317] Of the 14 evaluable patients in the monotherapy group, 11 (73%) achieved the best response for stable disease. In the combination therapy group, 2 evaluable patients (50%) achieved the best response for progressive disease.

[0318] No dose-limiting toxicities were observed during the maximum tolerated dose assessment period, and one dose-limiting toxicity (encephalitis) was observed during the treatment period. Furthermore, adverse events were manageable during the treatment period. Dose-limiting toxicities and adverse events are provided in the table below (MTD: Maximum tolerated dose; DLT: Dose-limiting toxicity; AE: Adverse event; TRAE: Treatment-related AE; SAE: Serious AE). *One is an anti-SIRPα antibody, and the other is an ibenlimab. Example 4: Phase Ib study of antibody A10 in patients with metastatic or unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

[0319] This example describes a phase Ib open-label, randomized clinical trial to evaluate the safety and efficacy of antibody A10 in combination with pembrolizumab and cetuximab as a first-line treatment for patients with HNSCC whose tumors express PD-1. Patients will undergo a screening period, a treatment period of up to approximately 24 months, and a follow-up period of approximately one year after the last dose of antibody A10. The study will include approximately 90 participants.

[0320] Patients with histologically confirmed metastatic or unresectable HNSCC and a positive PD-L1 result (CPS ≥ 1 according to the FDA-approved test) will be included in the study. Previous biopsy results obtained no more than 6 months prior to screening are acceptable if patients have PD-L1 expression results. Patients will not be eligible for study participation if they meet the following criteria: 1. Suffering from HNSCC suitable for local treatment and with a desire for a cure; 2. Suffers from nasopharyngeal carcinoma (NPC); 3. Not suitable for pembrolizumab treatment (according to local label); 4. Not suitable for cetuximab treatment (according to local label); 5. Any tumor location requiring urgent treatment intervention (e.g., palliative care, surgery, or radiation therapy, such as spinal cord compression, other compressive masses, uncontrolled pain lesions, fractures); 6. Having progressive HNSCC within 6 months of completing curative therapy; 7. Currently receiving treatment for brain cancer metastases or LMD that may interfere with safety and / or endpoint assessment (Patients previously diagnosed with brain cancer metastases are eligible if they have completed treatment and recovered from the acute effects of radiotherapy or surgery before entering the trial, have discontinued corticosteroid treatment for these metastases, are clinically stable, have been relieved of antiepileptic drugs for at least 4 weeks, and are neurologically stable before enrollment). 8. Received systemic anticancer therapy or investigational drug treatment within 28 days or 5 half-lives (whichever is shorter) prior to the first administration of the investigational drug; 9. Previous treatment with any anti-SIRPα or anti-CD47 agents, regardless of the treatment intention; 10. Previously treated with any anti-PD-1 or anti-PD-L1 agents or with agents targeting another stimulating or co-inhibitory T-cell receptor (e.g., CTLA-4, OX40, CD137); 11. Previously received cetuximab treatment; 12. Has previously received allogeneic stem cell or solid organ transplantation; 13. Patients with an active autoimmune disease or a documented history of an autoimmune disease requiring systemic treatment, i.e., corticosteroids or immunosuppressants (patients with vitiligo, resolving childhood asthma / tonsillitis, hair loss, or any chronic skin condition that does not require systemic treatment; patients with autoimmune-related hypothyroidism taking a stable dose of thyroid replacement hormone and / or patients with controlled type 1 diabetes receiving a stable insulin or antidiabetic drug regimen are eligible); 14. The patient is receiving systemic treatment with any immunosuppressive drugs within one week prior to the first administration of the test drug; steroids at a dose equivalent to up to 10 mg prednisolone per day are permitted as alternative therapy (topical and inhaled steroids are not considered immunosuppressants); 15. Receive a live vaccine within 30 days prior to the planned start of the investigational therapy; 16. Those who have undergone major surgery within 4 weeks prior to randomization, or who plan to undergo major surgery, such as hip replacement, within 12 months after screening; 17. Have received radiation therapy within 2 weeks prior to the start of the study treatment (i.e., the trial participant must have recovered from all radiation-related toxicities, not require corticosteroids, and not have radiation pneumonitis); 18. Must or wish to continue taking restrictive medications, or any medications considered potentially interfering with the safe conduct of the trial; 19. Known history of allergy to any investigational drug or any excipient of the investigational drug; 20. History of severe allergic reactions to other mAbs and / or severe infusion-related reactions (grade ≥3 NCI CTCAEv5.0); 21. History of interstitial lung disease or active, non-infectious pneumonia within the past 5 years; 22. Having uncontrolled hyperglycemia, diabetic ketoacidosis (DKA) or other metabolic disorders, which puts them at high risk or makes them unsuitable for receiving the investigational drug; 23. Patients who have uncontrolled congestive heart failure (defined as New York Heart Association (NYHA) Class III or IV), uncontrolled hypertension, or unstable heart disease, such as coronary artery disease with unstable angina or myocardial infarction, within 6 months prior to administration of the investigational drug. 24. Significant electrocardiogram (ECG) abnormalities, defined as any cardiac arrhythmia (> grade 2, NCI CTCAE 5.0), such as significant ventricular arrhythmias, such as persistent ventricular tachycardia and / or ventricular fibrosis, or severe conduction disorders, such as atrioventricular block 2 and 3, sinoatrial block, or baseline QTcF interval > 480 milliseconds (ms); 25. Have any of the following in the past 6 months: myocardial infarction, unstable angina, coronary artery / peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack, deep vein thrombosis, arterial thrombosis, symptomatic pulmonary embolism or any other significant thromboembolism; 26. Having an active infection requiring anti-infective therapy, unless all signs and symptoms of the infection have subsided and anti-infective therapy was discontinued at least 2 weeks before the first administration of the experimental drug (except for HIV, HCV and HBV). 27. Having a pre-existing or concomitant malignancy other than the malignancy treated in this trial within the past 2 years, except for the following: non-melanoma skin cancer that has been effectively treated, cervical carcinoma in situ that has been effectively treated, ductal carcinoma in situ that has been effectively treated, or other malignancies that have been effectively treated and are considered to be cured by local treatment; 28. Individuals with a history of HIV infection who meet one or more of the following criteria: CD4+ count < 350 cells / μL or viral load > 400 copies / μL (as assessed by a local laboratory); have not received antiretroviral therapy; are receiving established antiretroviral therapy less than four weeks prior to the start of study treatment; or have a history of AIDS-defined opportunistic infection within 12 months prior to the start of study treatment (patients with an HIV history who do not meet any of the above criteria are eligible to participate, but must be under the care of an HIV / infectious disease specialist or have been diagnosed with HIV / infectious disease by an HIV / infectious disease specialist prior to enrollment). 29. History of HCV infection and currently receiving curative antiviral therapy, and / or HCV viral load above the quantitative limit (HCV RNA positive); 30. Having chronic HBV infection, having active disease that meets the criteria for anti-HBV therapy (according to local / institutional standards) and has not been treated with suppressive antiviral therapy prior to starting study treatment; 31. The results of HIV-1 and HIV-2 antibody and HIV-1 p24 antigen tests were positive during screening. 32. Positive result for hepatitis B antigen or hepatitis C antigen; 33. Those who are pregnant, in care of others, or planning to become pregnant during the trial; 34. The participant is not expected to comply with the trial protocol or is not expected to complete the trial as scheduled (e.g., chronic alcoholism or substance abuse, or any other condition that the researchers believe would make the participant an unreliable trial participant). 35. Students were previously randomly assigned to groups in this trial; 36. Currently enrolled in another investigational program or drug trial, or less than 90 days since the end of another investigational program or drug trial or the receipt of other investigational treatments; 37. Having unstable medical (including surgical) or psychological (including alcoholism or substance abuse) conditions that may affect the completion of the trial and / or compliance and / or the ability to provide informed consent; or 38. Any condition not covered by any other exclusion criteria that, in the researcher's opinion, may jeopardize its safety or compliance.

[0321] Patients meeting the inclusion criteria will receive either antibody A10 in combination with pembrolizumab (Group 1), antibody A10 in combination with pembrolizumab and cetuximab (Group 2), or pembrolizumab monotherapy (Group 3). Antibody A10 will be administered intravenously at a dose of 3600 mg every 3 weeks (Q3W), pembrolizumab at a dose of 200 mg intravenously every 3 weeks (Q3W), and cetuximab at a dose of 500 mg / m² every 2 weeks (Q2W). 2 The dose or at 400 mg / m 2 The initial dose, followed by weekly (Q1W) 250 mg / m². 2 Subsequent doses were administered intravenously.

[0322] The primary objective of this trial is to investigate whether antibody A10 alone and the combination of antibody A10 with pembrolizumab and cetuximab demonstrate preliminary efficacy compared to pembrolizumab alone and the combination of antibody A10 with pembrolizumab. Preliminary comparisons will be made in all treated patients, regardless of protocol adherence or early discontinuation of trial treatment, but excluding the influence of any subsequent anticancer therapies initiated before disease progression. The efficacy of antibody A10 will be assessed by evaluating tumor response according to RECIST v1.1 and iRECIST. The primary endpoint includes a confirmed objective response (OR), defined as the best overall response of complete response (CR) or partial response (PR), where the best overall response is determined by researchers from randomization according to RECIST v1.1 until disease progression, death, or the earliest of the last evaluable tumor assessments before initiation of subsequent anticancer therapies, when follow-up is not possible, or when consent is withdrawn.

[0323] Secondary trial objectives include assessing the safety and tolerability of antibody A10, as measured by the proportion of patients experiencing at least one adverse event (AE) and the efficacy of antibody A10, as determined by overall survival (OS12) at 12 months of treatment, progression-free survival (PFS), and PFS at 6 months (PFS6), disease control (DC), and duration of response (DOR). The pharmacokinetics, pharmacodynamics, and immunogenicity of antibody A10 will also be assessed.

[0324] In addition, the study will include exploratory biomarker analyses to examine potential biomarkers for future patient selection. Such analyses may include DNA / RNA sequencing and / or immunohistochemistry of tumor tissue sections to determine SIRPα or CD47 expression or T cell and macrophage infiltration.

[0325] The specific embodiments provided herein may be further limited in the claims using the language of "consisting of..." or "substantially consisting of...". When used in the claims, whether as submitted or added according to amendments, the transitional term "consisting of..." excludes any element, step, or component not specified in the claims. The transitional term "substantially consisting of..." limits the scope of the claims to the specified materials or steps, and does not substantially affect the essential and novel features. The embodiments thus claimed are inherently or explicitly described and implemented herein.

[0326] Where numerical values ​​are indicated herein, those skilled in the art will understand that the technical effect of the features under discussion is guaranteed within a certain accuracy range, which typically covers a deviation of ±10% or ±5% of the given numerical value. At least, and without attempting to limit the application of equivalence to the scope of the claims, each numerical parameter should at least take into account the number of significant figures reported and be interpreted by applying common rounding techniques.

[0327] Unless otherwise indicated, all numerical values ​​used in this specification and claims to represent the amount, characteristics (such as molecular weight and median size), reaction conditions, etc., of components should be understood to be modified by the term "about" in all cases. Therefore, unless indicated to the contrary, the numerical parameters set forth in the following specification and appended claims are approximate values ​​that may vary depending on the desired characteristics obtained.

[0328] Unless otherwise indicated herein or expressly contradicted by the context, the terms “a / an,” “the,” and similar designations used in the context of the description herein (particularly in the context of the claims) shall be construed as encompassing both the singular and the plural. The description of ranges of values ​​herein is intended only as a way of individually referring to each individual value belonging to that range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were described separately herein. Unless otherwise indicated herein or expressly contradicted by the context, all methods described herein may be performed in any suitable order. The use of any and all illustrative or exemplary language provided herein (e.g., “such as”) is intended only to better describe this specification and does not constitute a limitation on the scope of the claims. No language in this specification should be construed as indicating any unclaimed element necessary for the implementation of this specification.

[0329] Unless explicitly stated or obvious in the context, the term “or” as used herein should be understood as inclusive and encompassing both “or” and “and”.

[0330] The grouping of alternative components or embodiments provided herein should not be construed as limiting. Members of a group may be referred to and claimed individually or in any combination with other members of the group or other components found herein. It is contemplated that one or more members of a group may be included in or removed from the group for convenience and / or patentability reasons. When any such inclusion or removal occurs, this specification is deemed to contain the modified group and thus satisfy the written description of all Markush groups as used in the appended claims.

[0331] This document describes certain embodiments, including the best known mode for implementing the methods provided herein. Of course, variations of these described embodiments will become apparent upon reading the foregoing description. Such variations are to be expected where appropriate and can be practiced in ways different from those specifically described herein. Therefore, this specification includes all modifications and equivalents of the object set forth in the claims appended herein, where permitted by applicable law. Furthermore, unless otherwise indicated herein or otherwise clearly contradicted by the context, the invention covers any combination of the elements described above in all their possible variations.

[0332] It should be understood that the embodiments provided herein illustrate the principles described herein. Other modifications may be made within the scope of this specification. Therefore, alternative configurations may be utilized, by way of example but not limitation, based on the teachings herein. Thus, the information presented is not limited to the precise information shown and described.

[0333] Although this specification has been described and illustrated herein with reference to various specific materials, procedures, and embodiments, it should be understood that this specification is not limited to the specific combination of materials and procedures chosen for this purpose. As will be appreciated, many variations in such details may be implied. The specification and embodiments are intended to be illustrative only, and the true scope and spirit of the specification are indicated by the appended claims. All references, patents, and patent applications mentioned in this application are incorporated herein by reference in their entirety.

[0334] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood. While other probes, compositions, methods, and kits similar to or equivalent to those described herein may be used in the practices described herein, the materials and methods described herein are specific. It should be understood that the terminology used herein is for descriptive purposes only and is not intended to be limiting.

[0335] Unless the context explicitly states or is obvious, as used herein, the term “about” should be understood as being within normal tolerances, such as within two standard deviations of the mean. “About” is understood as being within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless the context explicitly states otherwise, all numerical values ​​provided herein are modified by the term “about”.

[0336] The stated range should be understood as any value between the stated ranges and as a limit of the stated ranges. For example, the range between 1 and 5 includes 1, 2, 3, 4, and 5; the range between 1 and 10 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and the range between 1 and 100 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19. 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 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, 99 and 100.

[0337] Any aspect or implementation described herein may be combined with any other aspect or implementation described herein.

Claims

1. A method of treating cancer in a subject in need, comprising administering to the subject a dose of about 800 mg to about 3600 mg of an anti-SIRPα antibody or an antigen-binding fragment thereof; The anti-SIRPα antibody or its antigen-binding fragment contains: a) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 34 (H-CDR2); and the amino acid sequence of SEQ ID NO: 35 (H-CDR3), and The light chain variable region comprises the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 37 (L-CDR1); the amino acid sequence of SEQ ID NO: 38 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3). or b) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 223 (H-CDR1); the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 or SEQ ID NO: 224 (H-CDR2); and the amino acid sequence of SEQ ID NO: 6 (H-CDR3); and The light chain variable region comprises the amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 225 (L-CDR1); the amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11 or SEQ ID NO: 226 (L-CDR2); and the amino acid sequence of SEQ ID NO: 12 or SEQ ID NO: 227 (L-CDR3). or c) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 52 (H-CDR1); the amino acid sequence of SEQ ID NO: 53 (H-CDR2); and the amino acid sequence of SEQ ID NO: 54 (H-CDR3); and The light chain variable region comprises the amino acid sequence of SEQ ID NO: 55 (L-CDR1); the amino acid sequence of SEQ ID NO: 56 (L-CDR2); and the amino acid sequence of SEQ ID NO: 57 (L-CDR3). or d) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 70 (H-CDR2); and the amino acid sequence of SEQ ID NO: 71 (H-CDR3); and The light chain variable region comprises the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3). or e) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 243 (H-CDR1); the amino acid sequence of SEQ ID NO: 87 (H-CDR2); and the amino acid sequence of SEQ ID NO: 88 (H-CDR3); and The light chain variable region comprises the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 89 (L-CDR3).

2. A method of treating cancer in a subject of need, comprising administering to the subject a dose of about 800 mg to about 3600 mg of an anti-SIRPα antibody or an antigen-binding fragment thereof. The anti-SIRPα antibody or its antigen-binding fragment contains: a) Heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 34 (H-CDR2); the amino acid sequence of SEQ ID NO: 35 (H-CDR3); and The light chain variable region contains the amino acid sequence of SEQ ID NO: 233, wherein amino acid X1 = D or G and X2 = L or A (L-CDR1); the amino acid sequence of SEQ ID NO: 38 (L-CDR2); the amino acid sequence of SEQ ID NO: 39 (L-CDR3), or b) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 228 (H-CDR1), wherein amino acid X1 = N or D; the amino acid sequence of SEQ ID NO: 229, wherein X1 = Y or D, X2 = N or T, X3 = N or Q and X4 = S or P (H-CDR2); the amino acid sequence of SEQ ID NO: 6 (H-CDR3); and The light chain variable region comprises the amino acid sequence of SEQ ID NO: 230, wherein X1=K or R, X2=N or T, X3=G or A and X4=N, A or T (L-CDR1); the amino acid sequence of SEQ ID NO: 231, wherein X1=L, Q or G and X2=N or S (L-CDR2); and the amino acid sequence of SEQ ID NO: 232, wherein X1=M or G (L-CDR3).

3. The method of claim 1 or 2, wherein the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg.

4. The method of claim 1 or 2, wherein the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of about 1400 mg to about 1800 mg.

5. The method of claim 1 or 2, wherein the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg.

6. The method of claim 1 or 2, wherein the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of about 1400 mg.

7. The method of claim 1 or 2, wherein the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of about 1500 mg.

8. The method of claim 1 or 2, wherein the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of about 1600 mg.

9. The method of claim 1 or 2, wherein the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of about 1700 mg.

10. The method of claim 1 or 2, wherein the anti-SIRPα antibody or its antigen-binding fragment is administered at a dose of about 1800 mg.

11. The method of any of the preceding claims, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof is administered at a dose of about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), about once every 6 weeks (Q6W), about once every 7 weeks (Q7W), or about once every 8 weeks (Q8W).

12. The method of any one of claims 1 to 10, wherein the dose of the anti-SIRPα antibody or the antigen-binding fragment thereof is administered at a dosing cycle of about once every 2 weeks (Q2W).

13. The method of any one of claims 1 to 10, wherein the dose of the anti-SIRPα antibody or the antigen-binding fragment thereof is administered at a dosing cycle of approximately once every 3 weeks (Q3W).

14. The method of any one of claims 1 to 10, further comprising administering pembrolizumab to the subject.

15. The method of claim 14, wherein pembrolizumab is administered at a dose of about 400 mg.

16. The method of claim 15, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof and pembrolizumab are administered at a dosing cycle of approximately once every 3 weeks (Q3W).

17. The method of claim 15, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof and pembrolizumab are administered at a dosing cycle of approximately once every 6 weeks (Q6W).

18. The method of any one of claims 14 to 17, further comprising administering cetuximab to the subject.

19. The method of claim 18, wherein cetuximab is administered at approximately 500 mg / m². 2 Dosage administration.

20. The method of claim 18, wherein cetuximab is administered at approximately 400 mg / m². 2 The initial dose and approximately 250 mg / m 2 Subsequent doses should be administered.

21. The method of any one of claims 19 or 20, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof is administered at a dosing cycle of about every 2 weeks (Q2W), pembrolizumab is administered at a dosing cycle of about every 6 weeks (Q6W), and cetuximab is administered at a dosing cycle of about every 2 weeks (Q2W).

22. The method of claim 19, wherein cetuximab is administered at a dosing cycle of approximately once every 2 weeks (Q2W).

23. The method of claim 20, wherein the subsequent dose is administered at a dosing cycle of approximately once a week (Q1W).

24. The method of claim 1, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof comprises: The heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 34 (H-CDR2); and the amino acid sequence of SEQ ID NO: 35 (H-CDR3), and The light chain variable region comprises the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 37 (L-CDR1); the amino acid sequence of SEQ ID NO: 38 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3).

25. The method of claim 1, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof comprises: The heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 223 (H-CDR1); the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 or SEQ ID NO: 224 (H-CDR2); and the amino acid sequence of SEQ ID NO: 6 (H-CDR3); and The light chain variable region comprises the amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 225 (L-CDR1); the amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11 or SEQ ID NO: 226 (L-CDR2); and the amino acid sequence of SEQ ID NO: 12 or SEQ ID NO: 227 (L-CDR3).

26. The method of claim 1, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof comprises: The heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 52 (H-CDR1); the amino acid sequence of SEQ ID NO: 53 (H-CDR2); and the amino acid sequence of SEQ ID NO: 54 (H-CDR3); and The light chain variable region comprises the amino acid sequence of SEQ ID NO: 55 (L-CDR1); the amino acid sequence of SEQ ID NO: 56 (L-CDR2); and the amino acid sequence of SEQ ID NO: 57 (L-CDR3).

27. The method of claim 1, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof comprises: The heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 70 (H-CDR2); and the amino acid sequence of SEQ ID NO: 71 (H-CDR3); and The light chain variable region comprises the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3).

28. The method of claim 1, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof comprises: The heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 243 (H-CDR1); the amino acid sequence of SEQ ID NO: 87 (H-CDR2); and the amino acid sequence of SEQ ID NO: 88 (H-CDR3); and The light chain variable region comprises the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 89 (L-CDR3).

29. The method of claim 1, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence of any one of SEQ ID NO: 100, 110, 111, 112, 113, 114, 115, 116 or 117; and a light chain variable region comprising an amino acid sequence of any one of SEQ ID NO: 105, 125 or 126.

30. The method of claim 1, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence of any one of SEQ ID NO: 104, 118, 119, 120, 121, 122, 123, 124 or 221; and a light chain variable region comprising an amino acid sequence of any one of SEQ ID NO: 109, 127, 128, 129, 130 or 222.

31. The method of claim 1, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence of any one of SEQ ID NO: 100, 101, 102, 103 or 104; and a light chain variable region comprising an amino acid sequence of any one of SEQ ID NO: 105, 106, 107, 108 or 109.

32. The method of claim 29, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof comprises: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 105; or b) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 110; and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 125; or c) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 111; and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 125; or d) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 112; and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 125; or e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 113; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 125; or f) Containing the amino acid sequence of SEQ ID NO: 114; and a light chain variable region containing the amino acid sequence of SEQ ID NO: 125; or g) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 115; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 125; or h) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 116; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 125; or i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 117; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 125; or j) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 110; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 126; or k) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 111; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 126; or l) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 112; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 126; or m) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 113; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 126; or n) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 114; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 126; or o) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 115; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 126; or p) The heavy chain variable region contains the amino acid sequence of SEQ ID NO: 117; and the light chain variable region contains the amino acid sequence of SEQ ID NO:

126.

33. The method of claim 30, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof comprises: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 104; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 109; or b) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 118; and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 127; or c) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 118; and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 128; or d) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119; and the amino acid sequence of SEQ ID NO: 127; or e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 129; or f) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 120; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 127; or g) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 120; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 129; or h) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 121; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 127; or i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 122; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 127; or j) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 118; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 130; or k) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 121; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 129; or l) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 122; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 129; or m) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 130; or n) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 123; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 127; or o) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 120; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 130; or p) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 123; and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 129; or q) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 121; and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 130; or r) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 122; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 130; or s) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 124; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 129; or t) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 124; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 127; or u) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 123; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 130; or v) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 124; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 130; or w) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 221; and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

222.

34. The method of claim 31, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof comprises: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 105; or b) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 101; and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 106; or c) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 102; and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 107; or d) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 103; and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 108; or e) The heavy chain variable region, which contains the amino acid sequence of SEQ ID NO: 104; and the light chain variable region, which contains the amino acid sequence of SEQ ID NO:

109.

35. The method of claim 29, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof comprises: a heavy chain comprising the amino acid sequence of any one of SEQ ID NO: 131, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152 or 217; and a light chain comprising the amino acid sequence of any one of SEQ ID NO: 174, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195 or 218.

36. The method of claim 35, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof comprises: a) a heavy chain containing the amino acid sequence of SEQ ID NO: 131; and a light chain containing the amino acid sequence of SEQ ID NO: 174; or b) A heavy chain containing the amino acid sequence of SEQ ID NO: 138; and a light chain containing the amino acid sequence of SEQ ID NO: 181; or c) A heavy chain containing the amino acid sequence of SEQ ID NO: 139; and a light chain containing the amino acid sequence of SEQ ID NO: 182; or d) A heavy chain containing the amino acid sequence of SEQ ID NO: 140; and a light chain containing the amino acid sequence of SEQ ID NO: 183; or e) a heavy chain containing the amino acid sequence of SEQ ID NO: 141; and a light chain containing the amino acid sequence of SEQ ID NO: 184; or f) a heavy chain containing the amino acid sequence of SEQ ID NO: 142; and a light chain containing the amino acid sequence of SEQ ID NO: 185; or g) a heavy chain containing the amino acid sequence of SEQ ID NO: 143; and a light chain containing the amino acid sequence of SEQ ID NO: 186; or h) a heavy chain containing the amino acid sequence of SEQ ID NO: 144; and a light chain containing the amino acid sequence of SEQ ID NO: 187; or i) a heavy chain containing the amino acid sequence of SEQ ID NO: 145; and a light chain containing the amino acid sequence of SEQ ID NO: 188; or j) A heavy chain containing the amino acid sequence of SEQ ID NO: 146; and a light chain containing the amino acid sequence of SEQ ID NO: 189; or k) a heavy chain containing the amino acid sequence of SEQ ID NO: 147; and a light chain containing the amino acid sequence of SEQ ID NO: 190; or l) a heavy chain containing the amino acid sequence of SEQ ID NO: 148; and a light chain containing the amino acid sequence of SEQ ID NO: 191; or m) a heavy chain containing the amino acid sequence of SEQ ID NO: 149; and a light chain containing the amino acid sequence of SEQ ID NO: 192; or n) a heavy chain containing the amino acid sequence of SEQ ID NO: 150; and a light chain containing the amino acid sequence of SEQ ID NO: 193; or o) a heavy chain containing the amino acid sequence of SEQ ID NO: 151; and a light chain containing the amino acid sequence of SEQ ID NO: 194; or p) a heavy chain containing the amino acid sequence of SEQ ID NO: 152; and a light chain containing the amino acid sequence of SEQ ID NO: 195; or q) a heavy chain containing the amino acid sequence of SEQ ID NO: 217; and a light chain containing the amino acid sequence of SEQ ID NO:

218.

37. The method of claim 30, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of any one of SEQ ID NO: 135, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173 or 219; and a light chain comprising the amino acid sequence of any one of SEQ ID NO: 178, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216 or 220.

38. The method of claim 37, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof comprises: a) a heavy chain containing the amino acid sequence of SEQ ID NO: 135; and a light chain containing the amino acid sequence of SEQ ID NO: 178; or b) A heavy chain containing the amino acid sequence of SEQ ID NO: 153; and a light chain containing the amino acid sequence of SEQ ID NO: 196; or c) A heavy chain containing the amino acid sequence of SEQ ID NO: 154; and a light chain containing the amino acid sequence of SEQ ID NO: 197; or d) A heavy chain containing the amino acid sequence of SEQ ID NO: 155; and a light chain containing the amino acid sequence of SEQ ID NO: 198; or e) a heavy chain containing the amino acid sequence of SEQ ID NO: 156; and a light chain containing the amino acid sequence of SEQ ID NO: 199; or f) a heavy chain containing the amino acid sequence of SEQ ID NO: 157; and a light chain containing the amino acid sequence of SEQ ID NO: 200; or g) a heavy chain containing the amino acid sequence of SEQ ID NO: 158; and a light chain containing the amino acid sequence of SEQ ID NO: 201; or h) a heavy chain containing the amino acid sequence of SEQ ID NO: 159; and a light chain containing the amino acid sequence of SEQ ID NO: 202; or i) a heavy chain containing the amino acid sequence of SEQ ID NO: 160; and a light chain containing the amino acid sequence of SEQ ID NO: 203; or j) A heavy chain containing the amino acid sequence of SEQ ID NO: 161; and a light chain containing the amino acid sequence of SEQ ID NO: 204; or k) a heavy chain containing the amino acid sequence of SEQ ID NO: 162; and a light chain containing the amino acid sequence of SEQ ID NO: 205; or l) a heavy chain containing the amino acid sequence of SEQ ID NO: 163; and a light chain containing the amino acid sequence of SEQ ID NO: 206; or m) a heavy chain containing the amino acid sequence of SEQ ID NO: 164; and a light chain containing the amino acid sequence of SEQ ID NO: 207; or n) a heavy chain containing the amino acid sequence of SEQ ID NO: 165; and a light chain containing the amino acid sequence of SEQ ID NO: 208; or o) a heavy chain containing the amino acid sequence of SEQ ID NO: 166; and a light chain containing the amino acid sequence of SEQ ID NO: 209; or p) a heavy chain containing the amino acid sequence of SEQ ID NO: 167; and a light chain containing the amino acid sequence of SEQ ID NO: 210; or q) A heavy chain containing the amino acid sequence of SEQ ID NO: 168; and a light chain containing the amino acid sequence of SEQ ID NO: 211; or r) a heavy chain containing the amino acid sequence of SEQ ID NO: 169; and a light chain containing the amino acid sequence of SEQ ID NO: 212; or s) a heavy chain containing the amino acid sequence of SEQ ID NO: 170; and a light chain containing the amino acid sequence of SEQ ID NO: 213; or t) a heavy chain containing the amino acid sequence of SEQ ID NO: 171; and a light chain containing the amino acid sequence of SEQ ID NO: 214; or u) a heavy chain containing the amino acid sequence of SEQ ID NO: 172; and a light chain containing the amino acid sequence of SEQ ID NO: 215; or v) a heavy chain containing the amino acid sequence of SEQ ID NO: 173; and a light chain containing the amino acid sequence of SEQ ID NO: 216; or w) a heavy chain containing the amino acid sequence of SEQ ID NO: 219; and a light chain containing the amino acid sequence of SEQ ID NO:

220.

39. The method of claim 31, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of any one of SEQ ID NO: 131, 133, 134, 137 or 135; and a light chain comprising the amino acid sequence of any one of SEQ ID NO: 174, 176, 177, 180 or 178.

40. The method of claim 39, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof comprises: a) a heavy chain containing the amino acid sequence of SEQ ID NO: 131; and a light chain containing the amino acid sequence of SEQ ID NO: 174; or b) A heavy chain containing the amino acid sequence of SEQ ID NO: 133; and a light chain containing the amino acid sequence of SEQ ID NO: 176; or c) A heavy chain containing the amino acid sequence of SEQ ID NO: 134; and a light chain containing the amino acid sequence of SEQ ID NO: 177; or d) A heavy chain containing the amino acid sequence of SEQ ID NO: 137; and a light chain containing the amino acid sequence of SEQ ID NO: 180; or e) a heavy chain containing the amino acid sequence of SEQ ID NO: 135; and a light chain containing the amino acid sequence of SEQ ID NO: 178; or f) a heavy chain containing the amino acid sequence of SEQ ID NO: 132; and a light chain containing the amino acid sequence of SEQ ID NO: 175; or g) a heavy chain containing the amino acid sequence of SEQ ID NO: 136; and a light chain containing the amino acid sequence of SEQ ID NO:

179.

41. The method as described in any of the preceding claims, wherein the subject has been diagnosed with cancer having a solid tumor, particularly an advanced solid tumor.

42. The method of any of the preceding claims, wherein the subject has been diagnosed with SIRPα-positive cancer, CD47-positive cancer, PD-1-positive cancer, or PD-L1-positive cancer.

43. The method as described in any of the preceding claims, wherein the cancer is a solid tumor exhibiting or overexpressing SIRPα, CD47, PD-1 and / or PD-L1.

44. The method of any of the preceding claims, wherein the subject has not been treated with an anti-PD-1 antibody or an anti-PD-L1 antibody prior to administration of the anti-SIRPα antibody or its antigen-binding fragment.

45. The method of any one of claims 1 to 40, wherein the subject has been treated with an anti-PD-1 antibody or an anti-PD-L1 antibody and has shown disease progression prior to administration of the anti-SIRPα antibody or its antigen-binding fragment.

46. ​​An anti-SIRPα antibody or an antigen-binding fragment thereof for treating cancer in a subject in need, wherein the subject is administered a dose of the anti-SIRPα antibody or an antigen-binding fragment thereof of about 800 mg to about 3600 mg. The anti-SIRPα antibody or its antigen-binding fragment contains: a) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 34 (H-CDR2); and the amino acid sequence of SEQ ID NO: 35 (H-CDR3), and The light chain variable region comprises the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 37 (L-CDR1); the amino acid sequence of SEQ ID NO: 38 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3). or b) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 223 (H-CDR1); the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 or SEQ ID NO: 224 (H-CDR2); and the amino acid sequence of SEQ ID NO: 6 (H-CDR3); and The light chain variable region comprises the amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 225 (L-CDR1); the amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11 or SEQ ID NO: 226 (L-CDR2); and the amino acid sequence of SEQ ID NO: 12 or SEQ ID NO: 227 (L-CDR3). or c) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 52 (H-CDR1); the amino acid sequence of SEQ ID NO: 53 (H-CDR2); and the amino acid sequence of SEQ ID NO: 54 (H-CDR3); and The light chain variable region comprises the amino acid sequence of SEQ ID NO: 55 (L-CDR1); the amino acid sequence of SEQ ID NO: 56 (L-CDR2); and the amino acid sequence of SEQ ID NO: 57 (L-CDR3). or d) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 70 (H-CDR2); and the amino acid sequence of SEQ ID NO: 71 (H-CDR3); and The light chain variable region comprises the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3). or e) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 243 (H-CDR1); the amino acid sequence of SEQ ID NO: 87 (H-CDR2); and the amino acid sequence of SEQ ID NO: 88 (H-CDR3); and The light chain variable region comprises the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 89 (L-CDR3).

47. Use of an anti-SIRPα antibody or an antigen-binding fragment thereof in the manufacture of a medicament for treating cancer, wherein the anti-SIRPα antibody or the antigen-binding fragment thereof is formulated for administration at a dose of about 800 mg to about 3600 mg. The anti-SIRPα antibody or its antigen-binding fragment contains: a) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 34 (H-CDR2); and the amino acid sequence of SEQ ID NO: 35 (H-CDR3), and The light chain variable region comprises the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 37 (L-CDR1); the amino acid sequence of SEQ ID NO: 38 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3). or b) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 223 (H-CDR1); the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 or SEQ ID NO: 224 (H-CDR2); and the amino acid sequence of SEQ ID NO: 6 (H-CDR3); and The light chain variable region comprises the amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 225 (L-CDR1); the amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11 or SEQ ID NO: 226 (L-CDR2); and the amino acid sequence of SEQ ID NO: 12 or SEQ ID NO: 227 (L-CDR3). or c) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 52 (H-CDR1); the amino acid sequence of SEQ ID NO: 53 (H-CDR2); and the amino acid sequence of SEQ ID NO: 54 (H-CDR3); and The light chain variable region comprises the amino acid sequence of SEQ ID NO: 55 (L-CDR1); the amino acid sequence of SEQ ID NO: 56 (L-CDR2); and the amino acid sequence of SEQ ID NO: 57 (L-CDR3). or d) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 70 (H-CDR2); and the amino acid sequence of SEQ ID NO: 71 (H-CDR3); and The light chain variable region comprises the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3). or e) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 243 (H-CDR1); the amino acid sequence of SEQ ID NO: 87 (H-CDR2); and the amino acid sequence of SEQ ID NO: 88 (H-CDR3); and The light chain variable region comprises the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 89 (L-CDR3).

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