Antibody that binds to GPRC5D

Abstract

To provide novel antibodies comprising bispecific antibodies that specifically bind to human GPRC5D.SOLUTION: Provided is a bispecific antigen binding molecule, comprising: (a) a first antigen binding moiety that binds to a first antigen, the first antigen being GPRC5D, and the first antigen binding moiety comprising: a heavy chain variable region (VH) comprising a heavy chain complementary determining region (HCDR) of specific sequences; and a light chain variable region (VL) comprising a light chain complementary determining region (LCDR) of other specific sequences; and (b) a second antigen binding moiety that binds to a second antigen, the second antigen being CD3, and the second antigen binding moiety comprising: a heavy chain variable region (VH) comprising a heavy chain complementary determining region (HCDR) of other specific sequences; and a light chain variable region (VL) comprising a light chain complementarity determining region (LCDR) of other specific sequences. Also provided are a method for producing the antibody and a method of use thereof in treating diseases.SELECTED DRAWING: None

Claims

1. 1. A bispecific antigen-binding molecule comprising: (a) a first antigen-binding moiety that binds to a first antigen, wherein the first antigen is GPRC5D, and the first antigen-binding moiety comprises: A heavy chain variable region (VH) comprising a heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO: 83, a HCDR 2 of SEQ ID NO: 85, and a HCDR 3 of SEQ ID NO: 86, and a light chain variable region (VL) comprising a light chain complementarity determining region (LCDR) 1 of SEQ ID NO: 87, a LCDR 2 of SEQ ID NO: 88, and a LCDR 3 of SEQ ID NO:

89. and a first antigen-binding portion comprising: (b) a second antigen-binding portion that binds to a second antigen, wherein the second antigen is CD3, and the second antigen-binding portion comprises: A heavy chain variable region (VH) comprising a heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO: 98, a HCDR 2 of SEQ ID NO: 99, and a HCDR 3 of SEQ ID NO: 100, and a light chain variable region (VL) comprising a light chain complementarity determining region (LCDR) 1 of SEQ ID NO: 101, a LCDR 2 of SEQ ID NO: 102, and a LCDR 3 of SEQ ID NO:

103. and a second antigen-binding moiety comprising the VH of the first antigen-binding portion comprises an amino acid sequence at least about 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:48, and the VL of the first antigen-binding portion comprises an amino acid sequence at least about 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:53; the VH of the second antigen-binding portion comprises an amino acid sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 104, and the VL of the second antigen-binding portion comprises an amino acid sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 105; Bispecific antigen binding molecules.

2. The bispecific antigen-binding molecule of claim 1 , wherein the first and / or second antigen-binding portion is a Fab molecule.

3. 3. The bispecific antigen-binding molecule of claim 1 or 2, wherein the second antigen-binding portion is a Fab molecule in which the variable domains VL and VH, or the constant domains CL and CH1, in particular the variable domains VL and VH, of the Fab light chain and the Fab heavy chain are replaced by each other.

4. 4. The bispecific antigen-binding molecule of claim 1, wherein the first antigen-binding moiety is a Fab molecule in which in the constant domain the amino acid at position 124 is independently substituted by lysine (K), arginine (R) or histidine (H) (Kabat numbering), the amino acid at position 123 is independently substituted by lysine (K), arginine (R) or histidine (H) (Kabat numbering), and in the constant domain CH1 the amino acid at position 147 is independently substituted by glutamic acid (E) or aspartic acid (D) (Kabat EU index numbering) and the amino acid at position 213 is independently substituted by glutamic acid (E) or aspartic acid (D) (Kabat EU index numbering).

5. 5. The bispecific antigen-binding molecule of claim 1 , wherein the first and second antigen-binding moieties are fused to each other, optionally via a peptide linker.

6. 6. The bispecific antigen-binding molecule of claim 1 , wherein the first and second antigen-binding moieties are each a Fab molecule and (i) the second antigen-binding moiety 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 moiety, or (ii) the first antigen-binding moiety 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 moiety.

7. 7. The bispecific antigen-binding molecule of claim 1 , further comprising a third antigen-binding moiety.

8. The bispecific antigen-binding molecule of claim 7, wherein the third antigen-binding portion is identical to the first antigen-binding portion.

9. 9. A bispecific antigen-binding molecule according to any one of claims 1 to 8, comprising an Fc domain composed of a first and a second subunit.

10. the first, second and, if present, third antigen-binding moieties are each Fab molecules, and (i) the second antigen-binding moiety 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 moiety and the first antigen-binding moiety 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 moiety 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 moiety and the second antigen-binding moiety is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit of the Fc domain; 10. The bispecific antigen-binding molecule of claim 9, wherein, if present, the third antigen-binding portion is fused at the C-terminus of the Fab heavy chain to the N-terminus of the second subunit of the Fc domain.

11. The bispecific antigen-binding molecule of claim 9 or 10, wherein the Fc domain is an IgG Fc domain.

12. Fc domain is IgG １ 12. The bispecific antigen-binding molecule of claim 11, which is an Fc domain.

13. 13. The bispecific antigen-binding molecule of claim 9, wherein the Fc domain is a human Fc domain.

14. 14. The bispecific antigen-binding molecule of claim 9, wherein an amino acid residue in the CH3 domain of a first subunit of the Fc domain is replaced with an amino acid residue having a larger side chain volume, thereby creating a protuberance within the CH3 domain of the first subunit that can be positioned within a cavity within the CH3 domain of the second subunit, and an amino acid residue in the CH3 domain of a second subunit of the Fc domain is replaced with an amino acid residue having a smaller side chain volume, thereby creating a cavity within the CH3 domain of the second subunit into which the protuberance within the CH3 domain of the first subunit can be positioned.

15. 15. The bispecific antigen-binding molecule of claim 9, wherein the Fc domain comprises one or more amino acid substitutions that reduce binding to an Fc receptor and / or effector function.

16. 16. The bispecific antigen-binding molecule of any one of claims 1 to 15, comprising a polypeptide comprising an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO: 122, a polypeptide comprising an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO: 123, a polypeptide comprising an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO: 124, and a polypeptide comprising an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO:

125.

17. 17. The bispecific antigen-binding molecule of any one of claims 1 to 16, comprising a polypeptide comprising the amino acid sequence of SEQ ID NO: 122, a polypeptide comprising the amino acid sequence of SEQ ID NO: 123, a polypeptide comprising the amino acid sequence of SEQ ID NO: 124, and a polypeptide comprising the amino acid sequence of SEQ ID NO:

125.

18. 18. One or more isolated polynucleotides encoding the bispecific antigen-binding molecule of any one of claims 1 to 17.

19. 19. One or more vectors, in particular expression vectors, comprising the polynucleotide of claim 18.

20. 20. A host cell comprising the polynucleotide of claim 18 or the vector of claim 19.

21. 21. A method for producing a bispecific antigen-binding molecule that binds to GPRC5D, comprising the steps of: a) culturing a host cell according to claim 20 under conditions suitable for expression of the bispecific antigen-binding molecule; and b) optionally recovering the bispecific antigen-binding molecule.

22. 20. A pharmaceutical composition comprising the bispecific antigen-binding molecule of any one of claims 1 to 17 and a pharma- ceutically acceptable carrier.

23. 23. A bispecific antigen-binding molecule according to any one of claims 1 to 17 or a pharmaceutical composition according to claim 22 for use as a medicament.

24. 23. A bispecific antigen-binding molecule according to any one of claims 1 to 17 or a pharmaceutical composition according to claim 22 for use in the treatment of a disease.

25. 25. The bispecific antigen-binding molecule or pharmaceutical composition of claim 24, wherein the disease is cancer or an autoimmune disease.

26. 25. The bispecific antigen-binding molecule or pharmaceutical composition of claim 24, wherein the disease is multiple myeloma.

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