Heterodimeric antibodies that bind CD3 and tumor antigens

Patent metadata

Field	Value
Publication number	US-10259887-B2
Application number	US-201615141350-A
Country	US
Kind code	B2
Filing date	Apr 28, 2016
Priority date	Nov 26, 2014
Publication date	Apr 16, 2019
Grant date	Apr 16, 2019

Abstract

The present invention is directed to novel heterodimeric antibodies.

First claim

What is claimed is:

1. A heterodimeric antibody comprising:
a) a first monomer comprising an anti-CD3 scFv-linker-CH2-CH3, wherein CH2-CH3 is a first IgG Fc domain and said anti-CD3 scFv comprises a first variable heavy chain having the amino acid sequence of SEQ ID NO: 10, a first variable light chain having the amino acid sequence of SEQ ID NO: 14, and a scFv linker that attaches said first variable heavy chain with said first variable light chain;
b) a second monomer comprising a VH-CH1-hinge-CH2-CH3, wherein VH is a second variable heavy chain and CH2-CH3 is a second IgG Fc domain; and
c) a light chain comprising a second variable light chain.

2. A heterodimeric antibody according to claim 1 , wherein said first and second IgG Fc domains are variants of a human IgG Fc domain.

3. A heterodimeric antibody according to claim 1 wherein said first IgG Fc domain comprises amino acid substitutions S364K/E357Q and said second Fc domain comprises amino acid substitutions L368D/K370S.

4. A heterodimeric antibody according to claim 1 , wherein said second variant IgG Fc domain comprises amino acid substitutions N208D/Q295E/N384D/Q418E/N421D.

5. A heterodimeric antibody according to claim 1 , wherein said first and second IgG Fc domains each comprise amino acid substitutions E233P/L234V/L235A/G236del/S267K.

6. A heterodimeric antibody according to claim 1 , wherein said linker is a charged linker.

7. A heterodimeric antibody according to claim 1 , wherein said anti-CD3 scFv comprises the amino acid sequence of SEQ ID NO: 18.

8. A heterodimeric antibody according to claim 1 , wherein said first IgG Fc domain comprises amino acid substitutions S364K/E357Q and said second Fc domain comprises amino acid substitutions L368D/K370S,
wherein said first and second IgG Fc domains each comprise amino acid substitutions E233P/L234V/L235A/G236del/S267K,
wherein said first and second IgG Fc domains each comprise amino acid substitutions E233P/L234V/L235A/G236del/S267K, and
wherein said second IgG Fc domain comprises amino acid substitutions N208D/Q295E/N384D/Q418E/N421D.

9. A heterodimeric antibody according to claim 1 , wherein said linker-CH2-CH3 of said first monomer has the amino acid sequence of SEQ ID NO: 472 and said CH1-hinge-CH2-CH3 of said second monomer has the amino acid sequence of SEQ ID NO: 471.

10. A heterodimeric antibody comprising:
a) a first monomer comprising a VH1-CH1-linker1-VH2-scFv linker-VL2-linker2-CH2-CH3,
wherein VH2-scFv linker-VL2 is an anti-CD3 scFV, linker 1 and linker 2 are a first linker and second linker, respectively, and CH2-CH3 is a first IgG Fc domain;
b) a second monomer comprising a VH1-CH1-hinge-CH2-CH3, wherein VH1 is a first variable heavy domain and CH2-CH3 is a second IgG Fc domain;
c) a common light chain comprising a first variable light domain (VL1); and
wherein said first variable heavy domain on said first monomer and said first variable light domain form a first binding domain, and said first variable heavy domain on said second monomer and said first variable light domain form a second binding domain, and
wherein said VH2 is a second variable heavy domain having the amino acid sequence of SEQ ID NO: 10 and said VL2 is a second variable light domain having the amino acid sequence of SEQ ID NO: 14.

11. A heterodimeric antibody according to claim 10 , wherein said first and second IgG Fc domains are variants of a human IgG Fc domain.

12. A heterodimeric antibody according to claim 10 , wherein said first IgG Fc domain comprises amino acid substitutions S364K/E357Q and said second IgG Fc domain comprises amino acid substitutions L368D/K370S.

13. A heterodimeric antibody according to claim 10 , wherein said second IgG Fc domain comprises amino acid substitutions N208D/Q295E/N384D/Q418E/N421D.

14. A heterodimeric antibody according to claim 10 , wherein said first and second IgG Fc domains comprise amino acid substitutions E233P/L234V/L235A/G236del/S267K.

15. A heterodimeric antibody according to claim 10 , wherein said scFv linker is a charged linker.

16. A heterodimeric antibody according to claim 10 , wherein said first IgG Fc domain comprises amino acid substitutions S364K/E357Q and said second Fc domain comprises amino acid substitutions L368D/K370S,
wherein said first and second IgG Fc domains each comprise amino acid substitutions E233P/L234V/L235A/G236del/S267K, and
wherein said second IgG Fc domain comprises amino acid substitutions N208D/Q295E/N384D/Q418E/N421D.

17. A heterodimeric antibody according to claim 10 , wherein said anti-CD3 scFv comprises the amino acid sequence of SEQ ID NO: 18.

18. A nucleic acid composition comprising:
a) a first nucleic acid encoding said first monomer of claim 1 ;
b) a second nucleic acid encoding said second monomer of claim 1 ; and
c) a third nucleic acid encoding said light chain of claim 1 .

19. An expression vector composition comprising:
a) a first expression vector comprising a first nucleic acid encoding said first monomer of claim 1 ;
b) a second expression vector comprising a second nucleic acid encoding said second monomer of claim 1 ; and
c) a third expression vector comprising a third nucleic acid encoding said light chain of claim 1 .

20. A host cell comprising said expression vector composition of claim 19 .

21. A method of making a heterodimeric antibody comprising culturing the host cell of claim 20 under conditions wherein said heterodimeric antibody is expressed, and recovering said heterodimeric antibody.

22. A nucleic acid composition comprising:
a) a first nucleic acid encoding said first monomer of claim 10 ;
b) a second nucleic acid encoding said second monomer of claim 10 ; and
c) a third nucleic acid encoding said common light chain of claim 10 .

23. An expression vector composition comprising:
a) a first expression vector comprising a first nucleic acid encoding said first monomer of claim 10 ;
b) a second expression vector comprising a second nucleic acid encoding said second monomer of claim 10 ; and
c) a third expression vector comprising a third nucleic acid encoding said common light chain of claim 10 .

24. A host cell comprising said expression vector composition of claim 23 .

25. A method of making a heterodimeric antibody comprising culturing the host cell of claim 24 under conditions wherein said heterodimeric antibody is expressed, and recovering said heterodimeric antibody.

Assignees

• Xencor Inc

Inventors

• Bernett Matthew J
• Moore Gregory
• Desjarlais John
• Chu Seung
• Rashid Rumana
• Muchhal Umesh
• Lee Sung-Hyung

Classifications

• C07K16/468 Primary

  Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies · CPC title

• C07K2317/64

  comprising a combination of variable region and constant region components · CPC title

• C07K2317/52

  Constant or Fc region; Isotype · CPC title

• C07K2317/31

  multispecific · CPC title

• C07K2317/73

  Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation · CPC title