Bispecific antibody for ICOS and PD-L1
Multispecific antibody in mAb2 format, comprising an ICOS-binding Fab region and a PD-L1-binding Fcab region. Use of the multispecific antibody in immuno-oncology, including for treatment of solid tumours. Combination therapy including antibody to another immune checkpoint molecule such as PD-1 and CTLA-4, in addition to anti-ICOS and anti-PD-L1.
1. A multispecific antibody that binds ICOS and PD-L1 comprising a Fab and an Fc region, wherein the Fab comprises an ICOS binding site and wherein the Fc region comprises a PD-L1 binding site,
wherein the PD-L1 binding site is provided by a CH3 domain in which residues 14 to 18 are substituted by SGYW (SEQ ID NO: 617), residues 45.1 to 78 are substituted by EPQYWA (SEQ ID NO: 618), and residues 92 to 101 are substituted by SNWRWQLDD (SEQ ID NO: 619).
2. The antibody according to claim 1 , wherein the CH3 domain is a human IgG CH3 domain engineered to comprise the PD-L1 binding site.
3. The antibody according to claim 2 , wherein the Fc region is a human IgG Fc region comprising the CH3 domain engineered to comprise the PD-L1 binding site.
4. The antibody according to claim 1 , wherein the Fc region is effector positive.
5. The antibody according to claim 1 , wherein the IgG is human IgG1.
6. The antibody according to claim 1 , wherein the amino acid sequence of the CH3 domain is at least 90% identical to SEQ ID NO: 616.
7. The antibody according to claim 6 , wherein the CH3 domain comprises amino acid sequence SEQ ID NO: 616.
8. The antibody according to claim 1 , wherein the Fc region comprises an amino acid sequence at least 90% identical to SEQ ID NO: 620.
9. The antibody according to claim 8 , wherein the Fc region comprises amino acid sequence SEQ ID NO: 620.
10. The antibody according to claim 1 , wherein the Fc domain is homodimeric.
11. The antibody according to claim 1 , comprising two Fabs, each comprising an ICOS binding site.
12. The antibody according to claim 11 , wherein the two Fabs comprise identical VH-VL domain pairs.
13. The antibody according to claim 12 , which is homodimeric.
14. The antibody according to claim 1 , wherein the ICOS is human ICOS.
15. The antibody according to claim 1 , wherein the Fab binds the extracellular domain of human and mouse ICOS with an affinity (K.sub.D) of less than 5 nM as determined by surface plasmon resonance.
16. A multispecific antibody that binds ICOS and PD-L1, comprising a Fab and an Fc region, wherein
the Fab comprises an ICOS binding site comprising a VH domain amino acid sequence at least 90% identical to SEQ ID NO: 408 and a VL domain amino acid sequence at least 90% identical to SEQ ID NO: 415, and wherein
the Fc region comprises a PD-L1 binding site provided by a CH3 domain in which residues 14 to 18 are substituted by SGYW (SEQ ID NO: 617), residues 45.1 to 78 are substituted by EPQYWA (SEQ ID NO: 618), and residues 92 to 101 are substituted by SNWRWQLDD (SEQ ID NO: 619).
17. The antibody according to claim 16 , wherein the Fab comprises a VH domain amino acid sequence at least 95% identical to SEQ ID NO: 408.
18. The antibody according to claim 16 , wherein the Fab comprises a VH domain having HCDR1, HCDR2, and HCDR3 sequences wherein
HCDR1 is SEQ ID NO: 405, optionally comprising a conservative substitution at residue 28;
HCDR2 is SEQ ID NO: 406, optionally comprising a substitution at residue 59, residue 63 and/or residue 64; and
HCDR3 is SEQ ID NO: 407, optionally comprising a substitution at residue 108, residue 109 and/or residue 112.
19. The antibody according to claim 18 , comprising a VH domain having HCDR1, HCDR2, and HCDR3 sequences wherein HCDR1 is SEQ ID NO: 405, HCDR2 is SEQ ID NO: 406, and HCDR3 is SEQ ID NO: 407.
20. The antibody according to claim 16 , wherein the Fab comprises VH domain amino acid sequence SEQ ID NO: 408.
21. The antibody according to claim 16 , comprising a VL domain amino acid sequence at least 95% identical to SEQ ID NO: 415.
22. The antibody according to claim 16 , wherein the Fab comprises a VL domain having LCDR1, LCDR2, and LCDR3 sequences wherein
LCDR1 is SEQ ID NO: 412, optionally comprising a substitution at residue 36,
LCDR2 is SEQ ID NO: 413, and
LCDR3 is the SEQ ID NO 414, optionally comprising a substitution at residue 108 or residue 109.
23. The antibody according to claim 22 , comprising a VL domain having LCDR1, LCDR2, and LCDR3 sequences wherein LCDR1 is SEQ ID NO: 412, LCDR2 is SEQ ID NO: 413, and LCDR3 is the SEQ ID NO: 414.
24. The antibody according to claim 16 , comprising a VL domain amino acid sequence SEQ ID NO: 415.
25. A multispecific antibody comprising a Fab and an Fc region,
wherein the Fab comprises an ICOS binding site
wherein the Fc region comprises a PD-L1 binding site, wherein the PD-L1 binding site is provided by a CH3 domain in which residues 14 to 18 are substituted by SGYW (SEQ ID NO: 617), residues 45.1 to 78 are substituted by EPQYWA (SEQ ID NO: 618), and residues 92 to 101 are substituted by SNWRWQLDD (SEQ ID NO: 619), and
wherein the multispecific antibody comprises a heavy chain comprising amino acid sequence SEQ ID NO: 621.
26. The antibody according to claim 25 , comprising a light chain comprising amino acid sequence SEQ ID NO: 623.
27. The antibody according to claim 26 , comprising two heavy-light chain pairs, in which the heavy chain comprises amino acid sequence SEQ ID NO: 621 and the light chain comprises amino acid sequence SEQ ID NO: 623.