Antibody variable domains targeting the NKG2D receptor

Patent metadata

Field	Value
Publication number	US-12264200-B2
Application number	US-202318501427-A
Country	US
Kind code	B2
Filing date	Nov 3, 2023
Priority date	Feb 8, 2018
Publication date	Apr 1, 2025
Grant date	Apr 1, 2025

Abstract

Antibody heavy chain variable domains that can be paired with antibody light chain variable domains to form an antigen-binding site targeting the NKG2D receptor on natural killer cells are described. Proteins comprising an NKG2D antigen-binding site, pharmaceutical compositions and therapeutic methods thereof, including for the treatment of cancer, are also described.

First claim

What is claimed is:

1. An antigen-binding site that binds NKG2D, comprising:
an antibody heavy chain variable domain comprising a complementarity-determining region 1 (CDR1) amino acid sequence of SEQ ID NO: 48, a complementarity-determining region 2 (CDR2) amino acid sequence of SEQ ID NO: 30, and a complementarity-determining region 3 (CDR3) amino acid sequence of SEQ ID NO: 71; and
an antibody light chain variable domain comprising a CDR1 amino acid sequence of SEQ ID NO: 32, a CDR2 amino acid sequence of SEQ ID NO: 33, and a CDR3 amino acid sequence of SEQ ID NO: 34.

2. The antigen-binding site of claim 1 , wherein the antibody heavy chain variable domain comprises CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NOs: 29, 30, and 31, respectively, and the antibody light chain variable domain comprises CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NOs: 32, 33, and 34, respectively.

3. The antigen-binding site of claim 1 , wherein the antibody heavy chain variable domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 7, and the antibody light chain variable domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 8.

4. The antigen-binding site of claim 1 , wherein the antibody heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 7, and the antibody light chain variable domain comprises the amino acid sequence of SEQ ID NO: 8.

5. A protein comprising the antigen-binding site of claim 1 and an additional antigen-binding site.

6. The protein of claim 5 , wherein the additional antigen-binding site binds a tumor-associated antigen.

7. The protein of claim 5 , wherein the additional antigen-binding site comprises an antibody heavy chain variable domain, and
wherein the antibody heavy chain variable domain of the antigen-binding site that binds NKG2D is present on a first polypeptide that further comprises a first antibody constant region, and the antibody heavy chain variable domain of the additional antigen-binding site is present on a second polypeptide that further comprises a second antibody constant region.

8. The protein of claim 7 , wherein the first antibody constant region and the second antibody constant region form a complex that binds CD16.

9. The protein of claim 8 , wherein the first antibody constant region and the second antibody constant region each comprise hinge, CH2, and CH3 domains.

10. The protein of claim 8 , wherein the first antibody constant region and the second antibody constant region are human IgG1 Fc regions.

11. The protein of claim 10 , wherein the first antibody constant region comprises a Y349C substitution and the second antibody constant region comprises an S354C substitution, numbered according to the EU index as in Kabat.

12. The protein of claim 10 , wherein the first antibody constant region comprises K360E and K409W substitutions, and the second antibody constant region comprises Q347R, D399V and F405T substitutions, numbered according to the EU index as in Kabat.

13. The protein of claim 5 , further comprising an antigen-binding site that binds CD16.

14. A pharmaceutical composition comprising the protein of claim 5 and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising the protein of claim 6 and a pharmaceutically acceptable carrier.

16. A pharmaceutical composition comprising the protein of claim 8 and a pharmaceutically acceptable carrier.

17. A pharmaceutical composition comprising the protein of claim 10 and a pharmaceutically acceptable carrier.

18. A pharmaceutical composition comprising the protein of claim 13 and a pharmaceutically acceptable carrier.

Assignees

• Dragonfly Therapeutics Inc

Inventors

• Chang Gregory P
• Cheung Ann F
• Grinberg Asya
• Haney William
• Lunde Bradley M
• Prinz Bianka

Classifications

• A61K2039/505

  comprising antibodies · CPC title

• C07K2317/732

  Antibody-dependent cellular cytotoxicity [ADCC] · CPC title

• C07K2317/622

  Single chain antibody (scFv) · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title