Heterodimeric antibodies that bind somatostatin receptor 2
The present invention is directed to antibodies, including novel antigen binding domains and heterodimeric antibodies, that bind somatostatin receptor 2 (SSTR2).
1. A heterodimeric antibody comprising:
a) a first monomer comprising:
i) a first variant Fc domain; and
ii) a single chain Fv region (scFv), wherein said scFv region comprises a first variable heavy domain, a first variable light domain and a charged scFv linker, wherein said charged scFv linker covalently attaches said first variable heavy domain and said first variable light domain;
b) a second monomer comprising a VH-CH1-hinge-CH2-CH3 monomer, wherein VH is a second variable heavy domain and CH2-CH3 is a second variant Fc domain; and
c) a light chain comprising a second variable light domain and a constant light domain;
wherein said CH1-hinge-CH2-CH3 of said second monomer comprises amino acid substitutions N208D/Q295E/N384D/Q418E/N421D,
wherein said first and second variant Fc domains each comprise amino acid substitutions E233P/L234V/L235A/G236del/S267K,
wherein said first variant Fc domain comprises amino acid substitutions S364K/E357Q and said second variant Fc domain comprises amino acid substitutions L368D/K370S,
wherein said second variable heavy domain comprises SEQ ID NO: 1071 and said second variable light domain comprises SEQ ID NO: 1076, wherein numbering is according to the EU index as in Kabat.
2. A heterodimeric antibody according to claim 1 , wherein said scFv binds CD3.
3. A heterodimeric antibody according to claim 1 , wherein said first variable heavy domain and said first variable light domain are selected from the sets comprising: SEQ ID NO: 1 and SEQ ID NO: 5; SEQ ID NO: 10 and SEQ ID NO: 14; SEQ ID NO: 19 and SEQ ID NO: 23; SEQ ID NO: 28 and SEQ ID NO: 32; SEQ ID NO: 37 and SEQ ID NO: 41; and SEQ ID NO: 46 and SEQ ID NO: 50, respectively.
4. A heterodimeric antibody according to claim 3 , wherein said first variable heavy domain comprises SEQ ID NO: 1 and said first variable light domain comprises SEQ ID NO: 5.
5. A heterodimeric antibody according to claim 1 , wherein said CH1-hinge-CH2-CH3 of said second monomer comprises SEQ ID NO: 1108, said first variant Fc domain comprises SEQ ID NO: 1109 and said constant light domain comprises SEQ ID NO: 1110.
6. A heterodimeric antibody according to claim 1 , wherein said first monomer comprises SEQ ID NO: 1080, said second monomer comprises SEQ ID NO: 1070, and said light chain comprises SEQ ID NO: 1075.
7. 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 .
8. An expression vector composition comprising:
a) a first expression vector comprising said first nucleic acid of claim 7 ;
b) a second expression vector comprising said second nucleic acid of claim 7 ; and
c) a third expression vector comprising said third nucleic acid of claim 7 .
9. A host cell comprising said expression vector composition of claim 8 .
10. A method of making a heterodimeric antibody according to claim 1 comprising culturing said host cell of claim 9 under conditions wherein said antibody is expressed, and recovering said antibody.
11. A method of treating a neuroendocrine cancer in a subject in need thereof, comprising administering to said subject a heterodimeric antibody according to claim 1 .
12. A composition comprising a somatostatin receptor type 2 (SSTR2) binding domain, said SSTR2 binding domain comprising a variable heavy domain comprising SEQ ID NO: 958 and a variable light domain comprising SEQ ID NO: 962.
13. A nucleic acid composition comprising:
a) a first nucleic acid encoding said variable heavy domain of claim 12 ; and
b) a second nucleic acid encoding said variable light domain of claim 12 .
14. An expression vector composition comprising:
a) a first expression vector comprising said first nucleic acid of claim 13 ; and
b) a second expression vector comprising said second nucleic acid of claim 13 .
15. A host cell comprising said expression vector composition of claim 14 .
16. A method of making a composition according to claim 12 comprising culturing said host cell of claim 15 under conditions wherein said antibody is expressed, and recovering said antibody.
17. A method of treating a neuroendocrine cancer in a subject in need thereof, comprising administering to said subject a composition according to claim 12 .
18. A heterodimeric antibody comprising:
a) a first monomer comprising:
i) a first variant Fc domain; and
ii) a single chain Fv region (scFv), wherein said scFv region comprises a first variable heavy domain, a first variable light domain and a charged scFv linker, wherein said charged scFv linker covalently attaches said first variable heavy domain and said first variable light domain;
b) a second monomer comprising a VH-CH1-hinge-CH2-CH3 monomer, wherein VH is a second variable heavy domain and CH2-CH3 is a second variant Fc domain; and
c) a light chain comprising a second variable light domain and a constant light domain;
wherein said CH1-hinge-CH2-CH3 of said second monomer comprises amino acid substitutions N208D/Q295E/N384D/Q418E/N421D,
wherein said first and second variant Fc domains each comprise amino acid substitutions E233P/L234V/L235A/G236del/S267K,
wherein said first variant Fc domain comprises amino acid substitutions S364K/E357Q and said second variant Fc domain comprises amino acid substitutions L368D/K370S,
wherein said second variable heavy domain comprises SEQ ID NO: 1071 and said second variable light domain comprises SEQ ID NO: 1076, wherein numbering is according to the EU index as in Kabat, and
wherein said first variable heavy domain and said first variable light domain comprise SEQ ID NO: 1 and SEQ ID NO: 5, respectively.
19. A heterodimeric antibody comprising:
a) a first monomer comprising:
i) a first variant Fc domain; and
ii) a single chain Fv region (scFv), wherein said scFv region comprises a first variable heavy domain, a first variable light domain and a charged scFv linker, wherein said charged scFv linker covalently attaches said first variable heavy domain and said first variable light domain;
b) a second monomer comprising a VH-CH1-hinge-CH2-CH3 monomer, wherein VH is a second variable heavy domain and CH2-CH3 is a second variant Fc domain; and
c) a light chain comprising a second variable light domain and a constant light domain;
wherein said CH1-hinge-CH2-CH3 of said second monomer comprises amino acid substitutions N208D/Q295E/N384D/Q418E/N421D,
wherein said first and second variant Fc domains each comprise amino acid substitutions E233P/L234V/L235A/G236del/S267K,
wherein said first variant Fc domain comprises amino acid substitutions S364K/E357Q and said second variant Fc domain comprises amino acid substitutions L368D/K370S,
wherein said second variable heavy domain comprises SEQ ID NO: 1071 and said second variable light domain comprises SEQ ID NO: 1076, wherein numbering is according to the EU index as in Kabat,
wherein said first variable heavy domain and said first variable light domain comprise SEQ ID NO: 10 and SEQ ID NO: 14, respectively.
20. A heterodimeric antibody comprising:
a) a first monomer comprising:
i) a first variant Fc domain; and
ii) a single chain Fv region (scFv), wherein said scFv region comprises a first variable heavy domain, a first variable light domain and a charged scFv linker, wherein said charged scFv linker covalently attaches said first variable heavy domain and said first variable light domain;
b) a second monomer comprising a VH-CH1-hinge-CH2-CH3 monomer, wherein VH is a second variable heavy domain and CH2-CH3 is a second variant Fc domain; and
c) a light chain comprising a second variable light domain and a constant light domain;
wherein said CH1-hinge-CH2-CH3 of said second monomer comprises amino acid substitutions N208D/Q295E/N384D/Q418E/N421D,
wherein said first and second variant Fc domains each comprise amino acid substitutions E233P/L234V/L235A/G236del/S267K,
wherein said first variant Fc domain comprises amino acid substitutions S364K/E357Q and said second variant Fc domain comprises amino acid substitutions L368D/K370S,
wherein said second variable heavy domain comprises SEQ ID NO: 1071 and said second variable light domain comprises SEQ ID NO: 1076, wherein numbering is according to the EU index as in Kabat,
wherein said first variable heavy domain and said first variable light domain comprise SEQ ID NO: 19 and SEQ ID NO: 23, respectively.
21. A heterodimeric antibody comprising:
a) a first monomer comprising:
i) a first variant Fc domain; and
ii) a single chain Fv region (scFv), wherein said scFv region comprises a first variable heavy domain, a first variable light domain and a charged scFv linker, wherein said charged scFv linker covalently attaches said first variable heavy domain and said first variable light domain;
b) a second monomer comprising a VH-CH1-hinge-CH2-CH3 monomer, wherein VH is a second variable heavy domain and CH2-CH3 is a second variant Fc domain; and
c) a light chain comprising a second variable light domain and a constant light domain;
wherein said CH1-hinge-CH2-CH3 of said second monomer comprises amino acid substitutions N208D/Q295E/N384D/Q418E/N421D,
wherein said first and second variant Fc domains each comprise amino acid substitutions E233P/L234V/L235A/G236del/S267K,
wherein said first variant Fc domain comprises amino acid substitutions S364K/E357Q and said second variant Fc domain comprises amino acid substitutions L368D/K370S,
wherein said second variable heavy domain comprises SEQ ID NO: 1071 and said second variable light domain comprises SEQ ID NO: 1076, wherein numbering is according to the EU index as in Kabat, and
wherein said first variable heavy domain and said first variable light domain comprise SEQ ID NO: 28 and SEQ ID NO: 32, respectively.
22. A heterodimeric antibody comprising:
a) a first monomer comprising:
i) a first variant Fc domain; and
ii) a single chain Fv region (scFv), wherein said scFv region comprises a first variable heavy domain, a first variable light domain and a charged scFv linker, wherein said charged scFv linker covalently attaches said first variable heavy domain and said first variable light domain;
b) a second monomer comprising a VH-CH1-hinge-CH2-CH3 monomer, wherein VH is a second variable heavy domain and CH2-CH3 is a second variant Fc domain; and
c) a light chain comprising a second variable light domain and a constant light domain;
wherein said CH1-hinge-CH2-CH3 of said second monomer comprises amino acid substitutions N208D/Q295E/N384D/Q418E/N421D,
wherein said first and second variant Fc domains each comprise amino acid substitutions E233P/L234V/L235A/G236del/S267K,
wherein said first variant Fc domain comprises amino acid substitutions S364K/E357Q and said second variant Fc domain comprises amino acid substitutions L368D/K370S,
wherein said second variable heavy domain comprises SEQ ID NO: 1071 and said second variable light domain comprises SEQ ID NO: 1076, wherein numbering is according to the EU index as in Kabat, and
wherein said first variable heavy domain and said first variable light domain comprise SEQ ID NO: 37 and SEQ ID NO: 41, respectively.
23. A heterodimeric antibody comprising:
a) a first monomer comprising:
i) a first variant Fc domain; and
ii) a single chain Fv region (scFv), wherein said scFv region comprises a first variable heavy domain, a first variable light domain and a charged scFv linker, wherein said charged scFv linker covalently attaches said first variable heavy domain and said first variable light domain;
b) a second monomer comprising a VH-CH1-hinge-CH2-CH3 monomer, wherein VH is a second variable heavy domain and CH2-CH3 is a second variant Fc domain; and
c) a light chain comprising a second variable light domain and a constant light domain;
wherein said CH1-hinge-CH2-CH3 of said second monomer comprises amino acid substitutions N208D/Q295E/N384D/Q418E/N421D,
wherein said first and second variant Fc domains each comprise amino acid substitutions E233P/L234V/L235A/G236del/S267K,
wherein said first variant Fc domain comprises amino acid substitutions S364K/E357Q and said second variant Fc domain comprises amino acid substitutions L368D/K370S,
wherein said second variable heavy domain comprises SEQ ID NO: 1071 and said second variable light domain comprises SEQ ID NO: 1076, wherein numbering is according to the EU index as in Kabat, and
wherein said first variable heavy domain and said first variable light domain comprise SEQ ID NO: 46 and SEQ ID NO: 50, respectively.