Bispecific antigen binding molecules that bind HER2, and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11958910-B2
Application number	US-202117187511-A
Country	US
Kind code	B2
Filing date	Feb 26, 2021
Priority date	Feb 28, 2020
Publication date	Apr 16, 2024
Grant date	Apr 16, 2024

Abstract

Provided herein are bispecific antigen-binding molecules that bind HER2 and methods of use thereof. The bispecific antigen-binding molecules comprise a first and a second antigen-binding domain, wherein the first and second antigen-binding domains bind to two different (preferably non-overlapping) epitopes of the extracellular domain of human HER2. The bispecific antigen-binding molecules cluster on the surface of HER2 IHC2+ and IHC3+ cells, and are internalized into the cellular lysosomes. Also included are antibody-drug conjugates (ADCs) comprising the antibodies or bispecific antigen-binding molecules provided herein linked to a cytotoxic agent, radionuclide, or other moiety, as well as methods of treating cancer in a subject by administering to the subject a bispecific antigen-binding molecule or an ADC thereof.

First claim

What is claimed is:

1. A bispecific antigen-binding molecule comprising:
a first antigen-binding domain (D1); and
a second antigen-binding domain (D2);
wherein D1 specifically binds a first epitope of human HER2; and
wherein D2 specifically binds a second epitope of human HER2; and
wherein D1 comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 18, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 4; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 6; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 8; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 20; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 22; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 24; and
wherein D2 comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 10 and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 18, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 12; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 14; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 16; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 20; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 22; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 24.

2. The bispecific antigen-binding molecule of claim 1 , wherein the bispecific antigen-binding molecule is conjugated to a cytotoxin.

3. The bispecific antigen-binding molecule of claim 2 , wherein the cytotoxin is a tubulysin, a camptothecin, or a maytansinoid.

4. The bispecific antigen-binding molecule of claim 1 , wherein the bispecific antigen-binding molecule is conjugated to a cytotoxin through a linker.

5. The bispecific antigen-binding molecule of claim 4 , wherein the cytotoxin is a tubulysin.

6. The bispecific antigen-binding molecule of claim 5 , wherein the tubulysin is:

7. The bispecific antigen-binding molecule of claim 4 , wherein the bispecific antigen-binding molecule is conjugated to

or a regioisomer thereof, wherein

is a bond to a heavy chain glutamine.

8. The bispecific antigen-binding molecule of claim 5 , wherein the bispecific antigen-binding molecule comprises a heavy chain conjugated to tubulysin through Q295.

9. The bispecific antigen-binding molecule of claim 5 , wherein the bispecific antigen-binding molecule comprises a heavy chain comprising an N297Q mutation (EU index numbering), and wherein the bispecific antigen-binding molecule is (1) conjugated to a tubulysin through the glutamine residue of the heavy chain Q295, and (2) conjugated to a tubulysin through the glutamine residue of the N297Q mutation.

10. The bispecific antigen-binding molecule of claim 4 , wherein the cytotoxin is a maytansinoid.

11. The bispecific antigen-binding molecule of claim 10 wherein the maytansinoid is:

wherein the

is the bond to the linker.

12. The bispecific antigen-binding molecule of claim 11 , wherein the linker is:

wherein the bond noted with

represents the bond to the bispecific antigen-binding molecule and the bond noted with

represents the bond to the maytansinoid.

13. The bispecific antigen-binding molecule of claim 10 , wherein the maytansinoid is

wherein the

is the bond to the linker.

14. The bispecific antigen-binding molecule of claim 13 , wherein the linker is:

wherein the bond noted with

represents the bond to the bispecific antigen-binding molecule and the bond noted with

represents the bond to the maytansinoid.

15. A pharmaceutical composition comprising the bispecific antigen-binding molecule of claim 1 , and a pharmaceutically acceptable carrier.

16. A method of treating a cancer in a subject suffering from a tumor overexpressing HER2, the method comprising administering to the subject the bispecific antigen-binding molecule of claim 2 .

17. The method of claim 16 , wherein the cancer is selected from the group consisting of a breast cancer, lung cancer, gastric cancer, cervical cancer, gastric cancer, endometrial cancer, and ovarian cancer.

18. The bispecific antigen-binding molecule of claim 4 , wherein the cytotoxin is a camptothecin.

19. The bispecific antigen-binding molecule of claim 1 , wherein the bispecific antigen-binding molecule comprises a heavy chain comprising an N297Q mutation (EU index numbering).

20. A bispecific antigen-binding molecule comprising:
a first antigen-binding domain (D1); and
a second antigen-binding domain (D2);
wherein D1 specifically binds a first epitope of human HER2; and
wherein D2 specifically binds a second epitope of human HER2; and
wherein D1 comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 18; and
wherein D2 comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 10 and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 18.

21. The bispecific antigen-binding molecule of claim 20 , wherein D1 comprises an HCDR1 amino acid sequence as set forth in SEQ ID NO: 4; an HCDR2 amino acid sequence as set forth in SEQ ID NO: 6; an HCDR3 amino acid sequence as set forth in SEQ ID NO: 8; an LCDR

Assignees

• Regeneron Pharma

Inventors

• Andreev Julian
• Perez Bay Andres
• Daly Christopher
• Delfino Frank
• Han Amy
• Nittoli Thomas
• Olson William
• Thurston Gavin

Classifications

• A61K39/39558

  against tumor tissues, cells, antigens · CPC title

• A61K47/6803 Primary

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title

• A61K47/68033

  the drug being a maytansine · CPC title

• C07K16/32 Primary

  against translation products of oncogenes · CPC title

• C07K5/021

  containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds · CPC title