Bispecific antibody containing an NRP1-binding domain and method of use thereof

Abstract

The present disclosure provides a bispecific antibody, and a composition and method for treating cancer incorporating the bispecific antibody.The bispecific antibody comprises a polypeptide comprising an EGFR binding domain and a C-terminal neuropilin (NRP1) specific binding domain.A monoclonal antibody that specifically binds to NRP1 is also provided.

Claims

1. A bispecific antibody comprising a first binding domain that binds to the human neuropilin-1 receptor (NRP1) and a second binding domain that binds to the epidermal growth factor receptor (EGFR), wherein the first binding domain is: (i) an antibody heavy chain variable (VH) domain comprising CDR1, CDR2, and CDR3 regions (HCDR1, HCDR2, and HCDR3, respectively), where HCDR1 consists of the sequence shown in SEQ ID NO: 79, HCDR2 consists of the sequence shown in SEQ ID NO: 80, and HCDR3 consists of the sequence shown in SEQ ID NO: 81; and (ii) A variable antibody light chain (VL) domain comprising CDR1, CDR2, and CDR3 regions (LCDR1, LCDR2, and LCDR3, respectively), where LCDR1 consists of the sequence shown in SEQ ID NO: 85, LCDR2 consists of the sequence shown in SEQ ID NO: 88, and LCDR3 consists of the sequence shown in SEQ ID NO: 89 The second binding domain includes: (i) an antibody heavy chain variable (VH) domain comprising CDR1, CDR2, and CDR3 regions (HCDR1, HCDR2, and HCDR3, respectively), where HCDR1 consists of the sequence shown in SEQ ID NO: 71, HCDR2 consists of the sequence shown in SEQ ID NO: 72, and HCDR3 consists of the sequence shown in SEQ ID NO: 73; and (ii) A variable antibody light chain (VL) domain comprising CDR1, CDR2, and CDR3 regions (LCDR1, LCDR2, and LCDR3, respectively), where LCDR1 consists of the sequence shown in SEQ ID NO: 74, LCDR2 consists of the sequence shown in SEQ ID NO: 75, and LCDR3 consists of the sequence shown in SEQ ID NO: 76 A bispecific antibody containing [specific antibody].

2. The bispecific antibody according to claim 1, wherein the second binding domain is composed of an N-terminal EGFR-binding heavy chain variable domain (VH) and a heavy chain constant 1 domain (CH1), and the first binding domain is composed of a C-terminal NRP1-binding single-chain variable fragment (scFv), and the N-terminal variable heavy chain (VH) and the C-terminal scFv-binding domain are located at opposite ends of the continuous sequence.

3. The bispecific antibody according to claim 2, wherein the second binding domain further comprises a heavy chain constant 2 domain (CH2) and a heavy chain constant 3 domain (CH3).

4. The bispecific antibody according to claim 3, wherein the C-terminal NRP1-bound scFv comprises a light chain variable domain (VL) to which the heavy chain variable domain (VH) is connected by a flexible linker peptide.

5. The bispecific antibody according to claim 4, further comprising a corresponding EGFR-binding light chain variable domain (VL) and a light chain constant domain (CL), wherein the bispecific antibody is composed of two polypeptides.

6. A bispecific antibody comprising a first binding domain for binding to human neuropilin-1 receptor (NRP1) and a second binding domain for binding to epidermal growth factor receptor (EGFR), wherein the first binding domain for binding to human NRP1 comprises a VH domain containing the sequence shown in SEQ ID NO: 77 and a VL domain containing the sequence shown in SEQ ID NO: 78, and the second binding domain for binding to EGFR comprises a VH domain containing the sequence shown in SEQ ID NO: 69 and a VL domain containing the sequence shown in SEQ ID NO:

70.

7. The bispecific antibody according to claim 1, wherein the first binding domain comprises a VH domain containing the sequence shown in SEQ ID NO: 77 and a VL domain containing the sequence shown in SEQ ID NO: 78; and the second binding domain comprises a VH domain containing the sequence shown in SEQ ID NO: 69 and a VL domain containing the sequence shown in SEQ ID NO:

70.

8. The bispecific antibody according to claim 1, wherein the first binding domain and the second binding domain each contain a heavy chain having the amino acid sequence shown in SEQ ID NO:

11.

9. The bispecific antibody according to claim 8, wherein the heavy chain is paired with a light chain having the amino acid sequence shown in SEQ ID NO:

12.

10. A pharmaceutical composition comprising the bispecific antibody described in claim 1.

11. A polynucleotide encoding the bispecific antibody described in claim 1.

12. The polynucleotide according to claim 11, wherein the bispecific antibody comprises a heavy chain polypeptide encoded by the polynucleotide sequence described in SEQ ID NO:

24.

13. The polynucleotide according to claim 12, wherein the polynucleotide sequence is inserted into a protein expression vector.

14. A pharmaceutical composition for treating cancer associated with abnormal NRP1 expression, comprising the bispecific antibody described in claim 1.

15. A pharmaceutical composition for treating cancer associated with abnormal EGFR expression, comprising the bispecific antibody described in claim 1.

16. The pharmaceutical composition according to claim 15, wherein the cancer is non-small cell lung cancer.

17. The pharmaceutical composition according to claim 14 or 15, wherein for combination therapy, the pharmaceutical composition further comprises at least one additional chemotherapeutic agent, or the pharmaceutical composition is administered in combination with at least one additional chemotherapeutic agent.

18. Use of the bispecific antibody according to claim 1 in the manufacture of a pharmaceutical product for use in the treatment of cancer.

19. The use according to claim 18, wherein the treatment of cancer further comprises the administration of another drug.

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