Bispecific antigen-binding constructs targeting HER2

Patent metadata

Field	Value
Publication number	US-10000576-B1
Application number	US-201815863464-A
Country	US
Kind code	B1
Filing date	Jan 5, 2018
Priority date	Nov 27, 2013
Publication date	Jun 19, 2018
Grant date	Jun 19, 2018

Abstract

Provided herein are biparatopic antigen-binding constructs that specifically bind HER2. The biparatopic antigen-binding constructs comprise one antigen-binding moiety that binds to ECD2 of HER2, a second antigen-binding moiety that binds to ECD4 of HER2, and an Fc. At least one of the antigen-binding moieties is an scFv. The biparatopic antigen-binding constructs can be used in the treatment of cancer.

First claim

The invention claimed is:

1. An antigen-binding construct comprising a heavy chain 1 (H1), a heavy chain 2 (H2), and a light chain 1 (L1), wherein:
a. H1 comprises the CDR sequences set forth in SEQ ID NO: 101, SEQ ID NO: 103, and SEQ ID NO: 105;
b. H2 comprises the CDR sequences set forth in SEQ ID NO: 299, SEQ ID NO: 301, SEQ ID NO: 303, SEQ ID NO: 307, SEQ ID NO: 309, and SEQ ID NO: 311; and
c. L1 comprises the CDR sequences set forth in SEQ ID NO: 73, SEQ ID NO: 75, and SEQ ID NO: 77.

2. The antigen-binding construct of claim 1 , wherein:
a. H1 comprises the VH sequence set forth in SEQ ID NO: 99;
b. H2 comprises the VH sequence set forth in SEQ ID NO: 305 and the VL sequence set forth in SEQ ID NO: 297; and
c. L1 comprises the VL sequence set forth in SEQ ID NO: 71.

3. The antigen-binding construct of claim 2 , wherein:
a. H1 comprises the sequence set forth in SEQ ID NO: 97;
b. H2 comprises the sequence set forth in SEQ ID NO: 295; and
c. L1 comprises the sequence set forth in SEQ ID NO: 69.

4. The antigen-binding construct of claim 3 , wherein:
a. H1 consists of the sequence set forth in SEQ ID NO: 97;
b. H2 consists of the sequence set forth in SEQ ID NO: 295; and
c. L1 consists of the sequence set forth in SEQ ID NO: 69.

5. The antigen-binding construct of claim 1 , wherein the construct is glycosylated.

6. The antigen-binding construct of claim 1 , wherein the construct is afucosylated.

7. The antigen-binding construct of claim 1 , wherein the construct is conjugated to a drug.

8. The antigen-binding construct of claim 7 , wherein the drug is maytansine (DM1).

9. The antigen-binding construct of claim 8 , wherein the construct is conjugated to DM1 with an SMCC linker.

10. A pharmaceutical composition comprising the construct of claim 1 and a pharmaceutical carrier.

11. The pharmaceutical composition of claim 10 , the pharmaceutical carrier comprising a buffer, an antioxidant, a low molecular weight molecule, a drug, a protein, an amino acid, a carbohydrate, a lipid, a chelating agent, a stabilizer, or an excipient.

12. A pharmaceutical composition comprising the construct of claim 2 and a pharmaceutical carrier.

13. A pharmaceutical composition comprising the construct of claim 3 and a pharmaceutical carrier.

14. A pharmaceutical composition comprising the construct of claim 4 and a pharmaceutical carrier.

15. A pharmaceutical composition comprising the construct of claim 7 and a pharmaceutical carrier.

16. A pharmaceutical composition comprising the construct of claim 8 and a pharmaceutical carrier.

17. A pharmaceutical composition comprising the construct of claim 9 and a pharmaceutical carrier.

18. An isolated polynucleotide or set of isolated polynucleotides that encode(s) the antigen-binding construct according to claim 1 .

19. A vector or set of vectors comprising the isolated polynucleotide or set of isolated polynucleotides of claim 10 .

20. An isolated cell comprising the isolated polynucleotide or set of isolated polynucleotides of claim 10 .

21. A modified construct comprising one or more antigen-binding polypeptide constructs that monovalently and specifically bind a HER2 ECD2 and comprises a VH and a VL, wherein the VH comprises three CDR sequences comprising the amino acid sequences of the three VH CDR sequences of SEQ ID NO:335, SEQ ID NO:336, and SEQ ID NO:348, and the VL comprises the three CDR sequences comprising the amino acid sequences of the three VL CDR sequences of SEQ ID NO:338, SEQ ID NO:347, and SEQ ID NO:340.

22. The modified construct of claim 21 , wherein the modified construct is monovalent, bivalent, or multivalent.

23. The modified construct of claim 21 , wherein the modified construct is (i) monovalent and comprises a Fab or an scFv, (ii) is bivalent and comprises a Fab and an scFv, or (iii) is bivalent and comprises two scFvs.

24. The modified construct of claim 21 , comprising Fc linked to the one or more antigen binding polypeptide constructs, with or without a linker.

25. The modified construct of claim 24 , comprising a polypeptide linker.

26. The modified construct of claim 25 , wherein the linker comprises an IgG1 hinge region.

27. The modified construct of claim 24 , wherein the Fc is a human Fc.

28. The modified construct of claim 27 , wherein the human Fc is a human IgG1 Fc.

29. A pharmaceutical composition comprising the modified construct of claim 21 and a pharmaceutical carrier.

30. An isolated polynucleotide or set of isolated polynucleotides that encode(s) the modified construct according to claim 21 .

Assignees

• Zymeworks Inc

Inventors

• Weisser Nina E
• Ng Gordon Yiu Kon
• Wickman Grant Raymond
• Dixit Surjit Bhimarao
• Escobar-Cabrera Eric
• Sanches Mario

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• G01N33/5759

  involving compounds localised on the membrane of tumour or cancer cells · CPC title

• C07K2317/524

  CH2 domain · CPC title

• C07K16/32 Primary

  against translation products of oncogenes · CPC title

• C07K2317/41

  Glycosylation, sialylation, or fucosylation · CPC title