Bispecific antibody molecules binding to CD3 and TYRP-1
The present invention generally relates to antibodies that bind to CD3, including multispecific antibodies e.g. for activating T cells. In addition, the present invention relates to polynucleotides encoding such antibodies, and vectors and host cells comprising such polynucleotides. The invention further relates to methods for producing the antibodies, and to methods of using them in the treatment of disease.
1. A method of treating a TYRP-1-expressing cancer in a human individual having a TYRP-1-expressing cancer, the method comprising administering to the individual an effective amount of a bispecific antibody molecule, wherein the bispecific antibody molecule comprises: (a) a first antigen-binding domain that binds to human CD3 and (b) a second antigen-binding domain that binds to human TYRP-1,
wherein the first antigen-binding domain comprises a heavy chain variable region (VH) comprising a heavy chain complementarity determining region (HCDR) 1 comprising the amino acid sequence SYAMN (SEQ ID NO: 2), a HCDR 2 comprising the amino acid sequence RIRSKYNNYATYYADSVKG (SEQ ID NO: 3, and a HCDR 3 comprising the amino acid sequence HTTFPSSYVSYYGY (SEQ ID NO: 5), and a light chain variable region (VL) comprising a light chain complementarity determining region (LCDR) 1 comprising the amino acid sequence GSSTGAVTTSNYAN (SEQ ID NO: 8), a LCDR 2 comprising the amino acid sequence GTNKRAP (SEQ ID NO: 9), and a LCDR 3 comprising the amino acid sequence ALWYSNLWV (SEQ ID NO: 10), and
wherein the second antigen-binding domain comprises a VH comprising a HCDR 1 comprising the amino acid sequence DYFLH (SEQ ID NO: 15), a HCDR 2 comprising the amino acid sequence WINPDNGNTVYAQKFQG (SEQ ID NO: 16), and a HCDR 3 comprising the amino acid sequence RDYTYEKAALDY (SEQ ID NO: 17), and a VL comprising a LCDR 1 comprising the amino acid sequence RASGNIYNYLA (SEQ ID NO: 19), a LCDR 2 comprising the amino acid sequence DAKTLAD (SEQ ID NO: 20, and a LCDR 3 comprising the amino acid sequence QHFWSLPFT (SEQ ID NO: 21).
2. The method of claim 1 , wherein (a) the first antigen-binding domain comprises a VH that is at least 95% identical to the amino acid sequence of SEQ ID NO: 7 and a VL that is at least 95% identical to the amino acid sequence of SEQ ID NO: 11, and/or (b) the second antigen-binding domain comprises a VH that is at least 95% identical to the amino acid sequence of SEQ ID NO: 18 and a VL that is at least 95% identical to the amino acid sequence of SEQ ID NO: 22.
3. The method of claim 1 , wherein (a) the first antigen-binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 11, and/or (b) the second antigen-binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 18 and a VL comprising the amino acid sequence of SEQ ID NO: 22.
4. The method of claim 1 , wherein the bispecific antibody molecule comprises an Fc domain comprising a first subunit and a second subunit.
5. The method of claim 4 , wherein each of the first antigen-binding domain and the second antigen-binding domain is a Fab molecule, and wherein:
(i) the second antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first antigen-binding domain, and the first antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit of the Fc domain; or
(ii) the first antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second antigen-binding domain, and the second antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit of the Fc domain.
6. The method of claim 4 , wherein the bispecific antibody molecule further comprises a third antigen-binding domain that binds to TYRP-1, and wherein the second antigen-binding domain and the third antigen-binding domain each comprises (a) a VH comprising a HCDR 1 comprising the amino acid sequence DYFLH (SEQ ID NO: 15), a HCDR 2 comprising the amino acid sequence WINPDNGNTVYAQKFQG (SEQ ID NO: 16), and a HCDR 3 comprising the amino acid sequence RDYTYEKAALDY (SEQ ID NO: 17), and (b) a VL comprising a LCDR 1 comprising the amino acid sequence RASGNIYNYLA (SEQ ID NO: 19), a LCDR 2 comprising the amino acid sequence DAKTLAD (SEQ ID NO: 20), and a LCDR 3 comprising the amino acid sequence QHFWSLPFT (SEQ ID NO: 21).
7. The method of claim 6 , wherein (a) the first antigen-binding domain comprises a VH that is at least 95% identical to the amino acid sequence of SEQ ID NO: 7 and a VL that is at least 95% identical to the amino acid sequence of SEQ ID NO: 11 and/or (b) the second antigen-binding domain and the third antigen-binding domain each comprises a VH that is at least 95% identical to the amino acid sequence of SEQ ID NO: 18 and a VL that is at least 95% identical to the amino acid sequence of SEQ ID NO: 22.
8. The method of claim 7 , wherein (a) the first antigen-binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 11; and/or (b) the second antigen-binding domain and the third antigen-binding domain each comprises a VH comprising the amino acid sequence of SEQ ID NO: 18 and a VL comprising the amino acid sequence of SEQ ID NO: 22.
9. The method of claim 6 , wherein (a) the first antigen-binding domain is a crossover Fab molecule, wherein the variable domains VL and VH or the constant domains CL and CH1 of the Fab light chain and the Fab heavy chain are replaced by each other and/or (b) each of the second antigen-binding domain and the third antigen-binding domain is a conventional Fab molecule.
10. The method of claim 9 , wherein in the constant domain CL of the second antigen-binding domain and/or the third antigen-binding domain, the amino acid at position 124 is substituted independently by lysine (K), arginine (R), or histidine (H), numbered according to Kabat numbering, and the amino acid at position 123 is substituted independently by lysine (K), arginine (R), or histidine (H), numbered according to Kabat numbering, and in the constant domain CH1 of the second antigen-binding domain and/or the third antigen-binding domain, the amino acid at position 147 is substituted independently by glutamic acid (E) or aspartic acid (D), numbered according to Kabat EU index numbering, and the amino acid at position 213 is substituted independently by glutamic acid (E) or aspartic acid (D), numbered according to Kabat EU index numbering.
11. The method of claim 6 , wherein each of the first antigen-binding domain, the second antigen-binding domain, and the third antigen-binding domain is a Fab molecule, and wherein the third antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the second subunit of the Fc domain; and
(i) the second antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first antigen-binding domain, and the first antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit of the Fc domain; or
(ii) the first antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second antigen-binding domain, and the second antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit of the Fc domain.
12. The method of claim 4 , wherein the Fc comprises a modification promoting the association of the first and the second subunit of the Fc domain.
13. The method of claim 4 , wherein the Fc domain comprises one or more amino acid substitutions that reduce binding to an Fc receptor and/or effector function.
14. The method of claim 4 , wherein the Fc domain is a human Fc domain and/or an IgG Fc domain.
15. The method of claim 1 , wherein the TYRP-1-expressing cancer is a skin cancer.
16. The method of claim 15 , wherein the skin cancer is melanoma.