Anti-SIRPα antibodies
The present invention relates to antibodies against SIRPα that are suitable for use in anti-cancer therapy. The invention further relates to the use of the anti-SIRPα antibodies in the treatment of human solid tumours and haematological malignancies, optionally in combination with other anti-cancer therapeutics. The anti-SIRPalpha antibodies described are more specific than known anti-SIRPalpha antibodies, whereas they show excellent affinity for both SIRPalpha1 and SIRPalphaBIT. In one embodiment the anti-SIRPalpha antibodies do not bind to SIRPgamma. In a second embodiment, the anti-SIRPalpha antibodies do not bind to SIRPgamma and do not bind to SIRPbeta1v1. In a third embodiment, the anti-SIRPalpha antibodies do not bind to SIRPgamma and do not bind to SIRPeta1v2. In a fourth embodiment, the anti-SIRPalpha antibodies do not bind to SIRPbeta1v1.
1. An anti-SIRPα antibody or an antigen-binding fragment thereof comprising heavy chain (HC) and light chain (LC) variable region (VR) complementarity determining regions (CDRs) selected from the group consisting of:
(a) CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:3 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:4;
(b) CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:5 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:6;
(c) CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:7 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:8;
(d) CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:9 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:10;
(e) CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:11 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:12;
(f) CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:13 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:14;
(g) CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:15 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:16; and
(h) CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:17 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:18; and
wherein the CDRs are determined according to Kabat numbering.
2. The antibody according to claim 1 , which is chimeric, humanized or human.
3. The antibody according to claim 2 , comprising HCVR and LCVR CDRs selected from the group consisting of:
(a) CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:7 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:8; and
(b) CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:13 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:14; and
wherein the antibody is humanized.
4. The antibody according to claim 3 , comprising:
(a) CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:7, CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:8, HCVR amino acid sequence of SEQ ID NO:30 and LCVR amino acid sequence of SEQ ID NO:31;
(b) CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:7, CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:8, HCVR amino acid sequence of SEQ ID NO:32 and LCVR amino acid sequence of SEQ ID NO:33;
(c) CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:7, CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:8, HCVR amino acid sequence of SEQ ID NO:34 and LCVR amino acid sequence of SEQ ID NO:8;
(d) CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:13, CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:14, HCVR amino acid sequence of SEQ ID NO:35 and LCVR amino acid sequence of SEQ ID NO:36;
(e) CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:13, CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:14 and HCVR amino acid sequence of SEQ ID NO:35 and LCVR amino acid sequence of SEQ ID NO:37;
(f) HCVR amino acid sequence of SEQ ID NO:13, CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:14 and LCVR amino acid sequence of SEQ ID NO:38; or
(g) HCVR amino acid sequence of SEQ ID NO:13, CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO:14 and LCVR amino acid sequence of SEQ ID NO:37.
5. The anti-SIRPα antibody according to claim 1 , comprising a modified Fc region that exhibits reduced binding to a human Fcα or Fcγ receptor compared to the same anti-SIRPα antibody comprising a wild-type Fc region.
6. The anti-SIRPα antibody according to claim 1 , comprising a modified human IgG 1 Fc region comprising one or more amino acid substitutions at one or more positions selected from the group consisting of L234, L235, G237, D265, D270, N297, A327, P328, and P329 according to Eu numbering.
7. The anti-SIRPα antibody according to claim 6 , comprising the amino acid substitutions L234A and L235A; L234E and L235A; L234A, L235A and P329A; or L234A, L235A and P329G.
8. The anti-SIRPα antibody according to claim 7 , comprising the amino acid substitutions L234A and L235A; or L234E and L235A.
9. A pharmaceutical composition comprising the anti-SIRPα antibody according to claim 1 and one or more pharmaceutically acceptable excipients.
10. A pharmaceutical composition comprising the anti-SIRPα antibody according to claim 3 and one or more pharmaceutically acceptable excipients.