Antibodies that bind EGFR and cMET

Inventors: Cecilia Anna Wilhelmina Geuijen (Utrecht, NL); Robertus Cornelis Roovers (Utrecht, NL); Mark Throsby (Utrecht, NL); Cornelis Adriaan De Kruif (Utrecht, NL); Ton Logtenberg (Utrecht, NL)

Assignee: Merus B.V.

C07K16/2863 A61P35/00 C07K16/40 A61K2039/505 C07K2317/21 C07K2317/31 C07K2317/33 C07K2317/35 C07K2317/526 C07K2317/565 C07K2317/732 C07K2317/76

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Quick Facts

Patent No.: US 12668638
App. No.: 18/446,795
Granted: Jun 30, 2026
Kind: B2

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Abstract

The invention as disclosed herein relates to bispecific antibodies that comprises a first variable domain that can bind an extracellular part of epidermal growth factor receptor (EGFR) and a second variable domain that can bind an extracellular part of MET Proto-Oncogene, Receptor Tyrosine Kinase (cMET). The antibody may comprise a common light chain. It may be a human antibody. The antibody may be a full-length antibody. In some aspects, the bispecific antibody is an IgG1 format antibody having an anti-EGFR, anti-cMET stoichiometry of 1:1. In some aspects, the antibody has one variable domain that can bind EGFR and one variable domain that can bind cMET.

Claims (37)

1 . A method of treating a tumor in a subject, wherein the tumor is an EGFR positive tumor, a cMET positive tumor, or an EGFR and a cMET positive tumor, the method comprising administering to an individual in need thereof a bispecific antibody that comprises a first variable domain that can bind an extracellular part of human epidermal growth factor receptor (EGFR) and a second variable domain that can bind an extracellular part of human MET Proto-Oncogene, Receptor Tyrosine Kinase (cMET);

wherein the first variable domain comprises a heavy chain variable region with a CDR1 sequence SYGIS (SEQ ID NO: 24), a CDR2 sequence WISAYNANTNYAQKLQG (SEQ ID NO:155), and a CDR3 comprising the sequence DRHWHWWLDA (SEQ ID NO:139), and wherein the second variable domain comprises a heavy chain variable region with a CDR1 sequence TYSMN (SEQ ID NO: 152), a CDR2 sequence WINTYTGDPTYAQGFTG (SEQ ID NO:157), and a CDR3 comprising the sequence ETYFYDRGGYPFDP (SEQ ID NO: 31); or

wherein the first variable domain comprises a heavy chain variable region with a CDR1 sequence SYGIS (SEQ ID NO: 24), a CDR2 sequence WISAYSGNTNYAQKLQG (SEQ ID NO:140), and a CDR3 comprising the sequence DRHWHWWLDA (SEQ ID NO:139), and wherein the second variable domain comprises a heavy chain variable region with a CDR1 sequence TYSMN (SEQ ID NO: 152), a CDR2 sequence WINTYTGDPTYAQGFTG (SEQ ID NO:157), and a CDR3 comprising the sequence ETYFYDRGGYPFDP (SEQ ID NO: 31); or

wherein the first variable domain comprises a heavy chain variable region with a CDR1 sequence SYGIS (SEQ ID NO: 24), a CDR2 sequence WISAYSGNTNYAQKLQG (SEQ ID NO:140), and a CDR3 comprising the sequence DRHWHWWLDA (SEQ ID NO:139), and wherein the second variable domain comprises a heavy chain variable region with a CDR1 sequence SYSMN (SEQ ID NO: 28), a CDR2 sequence WINTYTGDPTYAQGFTG (SEQ ID NO: 157), and a CDR3 sequence ETYYYDRGGYPFDP (SEQ ID NO: 30); or

wherein the first variable domain comprises a heavy chain variable region with a CDR1 sequence SYGIS (SEQ ID NO: 24), a CDR2 sequence WISAYNANTNYAQKLQG (SEQ ID NO:155), and a CDR3 comprising the sequence DRHWHWWLDAFDY (SEQ ID NO: 37), and wherein the second variable domain comprises a heavy chain variable region with a CDR1 sequence SYSMN (SEQ ID NO: 28), a CDR2 sequence WINTYTGDPTYAQGFTG (SEQ ID NO: 157), and a CDR3 sequence ETYYYDRGGYPFDP (SEQ ID NO: 30); or

wherein the first variable domain comprises a heavy chain variable region with a CDR1 sequence SYGIS (SEQ ID NO: 24), a CDR2 sequence WISAYNGNTNYAQKLQG (SEQ ID NO:113), and a CDR3 comprising the sequence DRHWHWWLDAFDY (SEQ ID NO: 37), and wherein the second variable domain comprises a heavy chain variable region with a CDR1 sequence TYSMN (SEQ ID NO: 152), a CDR2 sequence WINTYTGDPTYAQGFTG (SEQ ID NO:157), and a CDR3 comprising the sequence ETYFYDRGGYPFDP (SEQ ID NO: 31); or

wherein the first variable domain comprises a heavy chain variable region with a CDR1 sequence SYGIS (SEQ ID NO: 24), a CDR2 sequence WISAYNGNTNYAQKLQG (SEQ ID NO:113), and a CDR3 comprising the sequence DRHWHWWLDAFDY (SEQ ID NO: 37), and wherein the second variable domain comprises a heavy chain variable region with a CDR1 sequence SYSMN (SEQ ID NO: 28), a CDR2 sequence WINTYTGDPTYAQGFTG (SEQ ID NO: 157), and a CDR3 sequence ETYYYDRGGYPFDP (SEQ ID NO: 30); and

wherein the first and second variable domains further comprise a common light chain variable domain comprising a CDR1 sequence QSISSY (SEQ ID NO:38), a CDR2 sequence AAS, and a CDR3 sequence QQSYSTP (SEQ ID NO: 39).

2 . The method of claim 1 , wherein the tumor is a tumor of breast cancer, colon cancer, pancreatic cancer, gastric cancer, ovarian cancer, colorectal cancer, head and neck cancer, lung cancer, or bladder cancer.

3 . The method of claim 2 , wherein the cancer is lung cancer.

4 . The method of claim 1 , wherein the tumor is resistant to treatment with an EGFR tyrosine kinase inhibitor.

5 . The method of claim 4 , wherein the EGFR tyrosine kinase inhibitor is erlotinib, gefitinib, afatinib, or a combination of thereof.

6 . The method of claim 4 , wherein the EGFR tyrosine kinase inhibitor is erlotinib.

7 . The method of claim 1 , further comprising administering erlotinib to the individual in need thereof.

8 . The method of claim 7 , wherein the said bispecific antibody is administered simultaneously, sequentially or separately with said EGFR tyrosine kinase inhibitor.

9 . The method of claim 1 , wherein the heavy chain variable region of the second variable domain comprises the amino acid sequence of SEQ ID NO:13.

10 . The method of claim 1 , wherein the heavy chain variable region of the second variable domain comprises the amino acid sequence of SEQ ID NO: 23.

11 . The method of claim 1 , wherein the first variable domain comprises a heavy chain variable region with a CDR1 sequence SYGIS (SEQ ID NO: 24), a CDR2 sequence WISAYNANTNYAQKLQG (SEQ ID NO:155), and a CDR3 comprising the sequence DRHWHWWLDA (SEQ ID NO:139), and wherein the second variable domain comprises a heavy chain variable region with a CDR1 sequence TYSMN (SEQ ID NO: 152), a CDR2 sequence WINTYTGDPTYAQGFTG (SEQ ID NO:157), and a CDR3 comprising the sequence ETYFYDRGGYPFDP (SEQ ID NO: 31).

12 . The method of claim 1 , wherein the first variable domain comprises a heavy chain variable region with a CDR1 sequence SYGIS (SEQ ID NO: 24), a CDR2 sequence WISAYNANTNYAQKLQG (SEQ ID NO:155), and a CDR3 comprising the sequence DRHWHWWLDAFDY (SEQ ID NO: 37), and wherein the second variable domain comprises a heavy chain variable region with a CDR1 sequence TYSMN (SEQ ID NO: 152), a CDR2 sequence WINTYTGDPTYAQGFTG (SEQ ID NO:157), and a CDR3 comprising the sequence ETYFYDRGGYPFDP (SEQ ID NO: 31).

13 . The method of claim 1 , wherein the first variable domain comprises a heavy chain variable region with a CDR1 sequence SYGIS (SEQ ID NO: 24), a CDR2 sequence WISAYSGNTNYAQKLQG (SEQ ID NO: 140), and a CDR3 comprising the sequence DRHWHWWLDA (SEQ ID NO: 139), and wherein the second variable domain comprises a heavy chain variable region with a CDR1 sequence TYSMN (SEQ ID NO: 152), a CDR2 sequence WINTYTGDPTYAQGFTG (SEQ ID NO:157), and a CDR3 comprising the sequence ETYFYDRGGYPFDP (SEQ ID NO: 31).

14 . The method of claim 1 , wherein the first variable domain comprises a heavy chain variable region with a CDR1 sequence SYGIS (SEQ ID NO: 24), a CDR2 sequence WISAYSGNTNYAQKLQG (SEQ ID NO: 140), and a CDR3 comprising the sequence DRHWHWWLDA (SEQ ID NO: 139), and wherein the second variable domain comprises a heavy chain variable region with a CDR1 sequence SYSMN (SEQ ID NO: 28), a CDR2 sequence WINTYTGDPTYAQGFTG (SEQ ID NO:157), and a CDR3 sequence ETYYYDRGGYPFDP (SEQ ID NO: 30).

15 . The method of claim 1 , wherein the first variable domain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:79 and the second variable domain comprises the amino acid sequence of SEQ ID NO:13.

16 . The method of claim 1 , wherein the first variable domain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:80 and the second variable domain comprises the amino acid sequence of SEQ ID NO:13.

17 . The method of claim 1 , wherein the first variable domain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 78 and the second variable domain comprises the amino acid sequence of SEQ ID NO:13.

18 . The method of claim 1 , wherein the first variable domain comprises a heavy chain variable region with a CDR1 sequence SYGIS (SEQ ID NO: 24), a CDR2 sequence WISAYSGNTNYAQKLQG (SEQ ID NO:140), and a CDR3 comprising the sequence DRHWHWWLDAFDY (SEQ ID NO:37), and wherein the second variable domain comprises a heavy chain variable region with a CDR1 sequence SYSMN (SEQ ID NO: 28), a CDR2 sequence WINTYTGDPTYAQGFTG (SEQ ID NO: 157), and a CDR3 sequence ETYYYDRGGYPFDP (SEQ ID NO: 30).

19 . The method of claim 18 , wherein the first variable domain comprises a heavy chain variable region with a CDR1 sequence SYGIS (SEQ ID NO: 24), a CDR2 sequence WISAYNANTNYAQKLQG (SEQ ID NO:155), and a CDR3 comprising the sequence DRHWHWWLDAFDY (SEQ ID NO: 37), and wherein the second variable domain comprises a heavy chain variable region with a CDR1 sequence SYSMN (SEQ ID NO: 28), a CDR2 sequence WINTYTGDPTYAQGFTG (SEQ ID NO: 157), and a CDR3 sequence ETYYYDRGGYPFDP (SEQ ID NO: 30).

20 . The method of claim 1 , wherein the first variable domain comprises a heavy chain variable region with a CDR1 sequence SYGIS (SEQ ID NO: 24), a CDR2 sequence WISAYNGNTNYAQKLQG (SEQ ID NO:113), and a CDR3 comprising the sequence DRHWHWWLDAFDY (SEQ ID NO: 37), and wherein the second variable domain comprises a heavy chain variable region with a CDR1 sequence TYSMN (SEQ ID NO: 152), a CDR2 sequence WINTYTGDPTYAQGFTG (SEQ ID NO:157), and a CDR3 comprising the sequence ETYFYDRGGYPFDP (SEQ ID NO: 31).

21 . The method of claim 1 , wherein the first variable domain comprises a heavy chain variable region with a CDR1 sequence SYGIS (SEQ ID NO: 24), a CDR2 sequence WISAYNGNTNYAQKLQG (SEQ ID NO:113), and a CDR3 comprising the sequence DRHWHWWLDAFDY (SEQ ID NO: 37), and wherein the second variable domain comprises a heavy chain variable region with a CDR1 sequence SYSMN (SEQ ID NO: 28), a CDR2 sequence WINTYTGDPTYAQGFTG (SEQ ID NO: 157), and a CDR3 sequence ETYYYDRGGYPFDP (SEQ ID NO: 30).

22 . The method of claim 1 , wherein the first variable domain comprises a heavy chain variable region with a CDR1 sequence SYGIS (SEQ ID NO: 24), a CDR2 sequence WISAYSGNTNYAQKLQG (SEQ ID NO: 140), and a CDR3 comprising the sequence DRHWHWWLDAFDY (SEQ ID NO: 37), and wherein the second variable domain comprises a heavy chain variable region with a CDR1 sequence TYSMN (SEQ ID NO: 152), a CDR2 sequence WINTYTGDPTYAQGFTG (SEQ ID NO:157), and a CDR3 comprising the sequence ETYFYDRGGYPFDP (SEQ ID NO: 31).

23 . The method of claim 1 , wherein the first variable domain comprises a heavy chain variable region with a CDR1 sequence SYGIS (SEQ ID NO: 24), a CDR2 sequence WISAYSGNTNYAQKLQG (SEQ ID NO:140), and a CDR3 comprising the sequence DRHWHWWLDAFDY (SEQ ID NO:37), and wherein the second variable domain comprises a heavy chain variable region with a CDR1 sequence SYSMN (SEQ ID NO: 28), a CDR2 sequence WINTYTGDPTYAQGFTG (SEQ ID NO: 157), and a CDR3 sequence ETYYYDRGGYPFDP (SEQ ID NO: 30).

24 . The method of claim 1 , wherein the first variable domain comprises a heavy chain variable region with a CDR1 sequence SYGIS (SEQ ID NO: 24), a CDR2 sequence WISAYNANTNYAQKLQG (SEQ ID NO:155), and a CDR3 comprising the sequence DRHWHWWLDAFDY (SEQ ID NO:37), and wherein the second variable domain comprises a heavy chain variable region with a CDR1 sequence TYSMN (SEQ ID NO: 152), a CDR2 sequence WINTYTGDPTYAQGFTG (SEQ ID NO:157), and a CDR3 comprising the sequence ETYFYDRGGYPFDP (SEQ ID NO: 31).

25 . The method of claim 1 , wherein the first variable domain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:79 and the second variable domain comprises the amino acid sequence of SEQ ID NO:23.

26 . The method of claim 1 , wherein the first variable domain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:80 and the second variable domain comprises the amino acid sequence of SEQ ID NO:23.

27 . The method of claim 1 , wherein the first variable domain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:78 and the second variable domain comprises the amino acid sequence of SEQ ID NO:23.

28 . The method of claim 1 , wherein the first variable domain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:78.

29 . The method of claim 1 , wherein the first variable domain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:79.

30 . The method of claim 1 , wherein the first variable domain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:80.