Bispecific antigen-binding constructs targeting HER2
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.
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 .