Heterodimeric antibodies that bind CD3 and PSMA
The present invention is directed to heterodimeric antibodies that bind CD3 and PSMA.
1. A composition comprising a prostate specific membrane antigen (PSMA) binding domain, wherein said PSMA binding domain comprises:
a) a variable heavy domain comprising a vhCDR1 having SEQ ID NO: 111, a vhCDR2 having SEQ ID NO: 112, and a vhCDR3 having SEQ ID NO: 113; and
b) a variable light domain comprising a vlCDR1 having SEQ ID NO: 107, a vlCDR2 having SEQ ID NO: 108, and a vlCDR3 having SEQ ID NO: 109.
2. The composition according to claim 1 , wherein said variable heavy domain comprises the amino acid sequence of SEQ ID NO: 110 and said variable light domain comprises the amino acid sequence of SEQ ID NO: 106.
3. A nucleic acid composition encoding the composition of claim 1 comprising:
a) a first nucleic acid encoding said variable heavy domain; and
b) a second nucleic acid encoding said variable light domain.
4. An expression vector composition encoding the composition of claim 1 comprising:
a) a first expression vector comprising a first nucleic acid encoding said variable heavy domain; and
b) a second expression vector comprising a second nucleic acid encoding said variable light domain.
5. A host cell comprising said expression vector composition of claim 4 .
6. A heterodimeric antibody comprising:
a) a first monomer comprising a scFv-linker-CH2-CH3, wherein CH2-CH3 is a first Fc domain, and wherein scFv is a single chain Fv region that binds a first antigen;
b) a second monomer comprising a VH-CH1-hinge-CH2-CH3, wherein VH is a variable heavy domain and CH2-CH3 is a second Fc domain; and
c) a light chain comprising a variable light domain and a constant light domain;
wherein said variable heavy domain comprises a vhCDR1 having SEQ ID NO: 111, a vhCDR2 having SEQ ID NO: 112, and a vhCDR3 having SEQ ID NO: 113, and
said variable light domain comprises a vlCDR1 having SEQ ID NO: 107, a vlCDR2 having SEQ ID NO: 108, and a vlCDR3 having SEQ ID NO: 109, and
wherein said variable heavy domain and said variable light domain form a PSMA binding domain.
7. The heterodimeric antibody according to claim 6 , wherein said variable heavy domain comprises the amino acid sequence of SEQ ID NO: 110 and said variable light domain comprises the amino acid sequence of SEQ ID NO: 106.
8. The heterodimeric antibody according to claim 6 , wherein said first Fc domain and said second Fc domain comprise a set of amino acid substitutions selected from the group consisting of
a) S364K/E357Q in one of said first Fc domain and said second Fc domain and L368D/K370S in the other of said first Fc domain and said second Fc domain;
b) L368D/K370S in one of said first Fc domain and said second Fc domain and S364K in the other of said first Fc domain and said second Fc domain;
c) L368E/K370S in one of said first Fc domain and said second Fc domain and S364K in the other of said first Fc domain and said second Fc domain;
d) T411T/E360E/Q362E in one of said first Fc domain and said second Fc domain and D401K in the other of said first Fc domain and said second Fc domain;
e) L368D/K370S in one of said first Fc domain and said second Fc domain and S364K/E357L in the other of said first Fc domain and said second Fc domain; and
f) K370S in one of said first Fc domain and said second Fc domain and S364K/E357Q in the other of said first Fc domain and said second Fc domain,
wherein numbering is according to EU numbering.
9. The heterodimeric antibody according to claim 6 , wherein said scFv comprises a charged linker.
10. The heterodimeric antibody according to claim 6 , wherein said VH-CH1-hinge-CH2-CH3 of said second monomer comprises amino acid substitutions N208D/Q295E/N384D/Q418E/N421D, wherein numbering is according to EU numbering.
11. The heterodimeric antibody according to claim 6 , wherein said first and second Fc domains each comprise amino acid substitutions E233P/L234V/L235A/G236del/S267K, wherein numbering is according to EU numbering.
12. The heterodimeric antibody according to claim 6 ,
wherein said first Fc domain comprises amino acid substitutions S364K/E357Q,
wherein said second Fc domain comprises amino acid substitutions L368D/K370S,
wherein said first and second Fc domains each comprises amino acid substitutions E233P/L234V/L235A/G236del/S267K,
wherein said VH-CH1-hinge-CH2-CH3 of the second monomer comprises amino acid substitutions N208D/Q295E/N384D/Q418E/N421D, and
wherein numbering is according to EU numbering.
13. A nucleic acid composition encoding the heterodimeric antibody of claim 6 comprising:
a) a first nucleic acid encoding said first monomer;
b) a second nucleic acid encoding said second monomer; and
c) a third nucleic acid encoding said light chain.
14. An expression vector composition encoding the heterodimeric antibody of claim 6 comprising:
a) a first expression vector comprising a first nucleic acid encoding said first monomer;
b) a second expression vector comprising a second nucleic acid encoding said second monomer; and
c) a third expression vector comprising a third nucleic acid encoding said light chain.
15. A host cell comprising said nucleic acid composition of claim 13 .
16. A host cell comprising said expression vector composition of claim 14 .
17. A method of making a heterodimeric antibody comprising culturing said host cell of claim 15 or 16 under conditions wherein said antibody is expressed, and recovering said heterodimeric antibody.
18. A heterodimeric antibody comprising:
a) a first monomer comprising a VH-CH1-linker 1- scFv-linker 2-CH2-CH3,
wherein VH is a variable heavy domain, linker 1 and linker 2 are a first domain linker and a second domain linker, respectively, and CH2-CH3 is a first Fc domain;
b) a second monomer comprising a VH-CH1-hinge-CH2-CH3, wherein VH is a variable heavy domain and CH2-CH3 is a second Fc domain; and
c) a common light chain comprising a variable light domain and a constant light domain;
wherein said variable heavy domain of said first monomer and said variable light domain form a first PSMA binding domain, and said variable heavy domain of said second monomer and said variable light domain form a second PSMA binding domain,
wherein said variable heavy domain of said first monomer and said variable heavy domain of said second monomer each comprise a vhCDR1 having SEQ ID NO: 111, a vhCDR2 having SEQ ID NO: 112, and a vhCDR3 having SEQ ID NO: 113, and
said variable light domain comprises a vlCDR1 having SEQ ID NO: 107, a vlCDR2 having SEQ ID NO: 108, and a vlCDR3 having SEQ ID NO: 109.
19. The heterodimeric antibody according to claim 18 , wherein said variable heavy domain of said first monomer and said variable heavy domain of said second monomer each comprise the amino acid sequence of SEQ ID NO: 110 and said variable light domain comprises the amino acid sequence of SEQ ID NO: 106.
20. The heterodimeric antibody according to claim 18 , wherein said first Fc domain and said second Fc domain comprise a set of amino acid substitutions selected from the group consisting of
a) S364K/E357Q in one of said first Fc domain and said second Fc domain and L368D/K370S in the other of said first Fc domain and said second Fc domain;
b) L368D/K370S in one of said first Fc domain and said second Fc domain and S364K in the other of said first Fc domain and said second Fc domain;
c) L368E/K370S in one of said first Fc domain and said second Fc domain and S364K in the other of said first Fc domain and said second Fc domain;
d) T411T/E360E/Q362E in one of said first Fc domain and said second Fc domain and D401K in the other of said first Fc domain and said second Fc domain;
e) L368D/K370S in one of said first Fc domain and said second Fc domain and S364K/E357L in the other of said first Fc domain and said second Fc domain; and
f) K370S in one of said first Fc domain and said second Fc domain and S364K/E357Q in the other of said first Fc domain and said second Fc domain,
wherein numbering is according to EU numbering.
21. The heterodimeric antibody according to claim 18 , wherein said VH-CH1-hinge-CH2-CH3 of said second monomer comprises amino acid substitutions N208D/Q295E/N384D/Q418E/N421D, wherein numbering is according to EU numbering.
22. The heterodimeric antibody according to claim 18 , wherein said first and second Fc domains each comprise amino acid substitutions E233P/L234V/L235A/G236del/S267K, wherein numbering is according to EU numbering.
23. The heterodimeric antibody according to claim 18 ,
wherein said first Fc domain comprises amino acid substitutions S364K/E357Q,
wherein said second Fc domain comprises amino acid substitutions L368D/K370S,
wherein said first and second Fc domains each comprises amino acid substitutions E233P/L234V/L235A/G236del/S267K,
wherein said VH-CH1-hinge-CH2-CH3 of the second monomer comprises amino acid substitutions N208D/Q295E/N384D/Q418E/N421D, and
wherein numbering is according to EU numbering.
24. A nucleic acid composition encoding the heterodimeric antibody of claim 18 comprising:
a) a first nucleic acid encoding said first monomer;
b) a second nucleic acid encoding said second monomer; and
c) a third nucleic acid encoding said light chain.
25. An expression vector composition encoding the heterodimeric antibody of claim 18 comprising:
a) a first expression vector comprising a first nucleic acid encoding said first monomer;
b) a second expression vector comprising a second nucleic acid encoding said second monomer; and
c) a third expression vector comprising a third nucleic acid encoding said light chain.
26. A host cell comprising the nucleic acid composition of claim 24 .
27. A host cell comprising the expression vector composition of claim 25 .
28. A method of making a heterodimeric antibody comprising culturing the host cell of claim 26 or 27 under conditions wherein said antibody is expressed, and recovering said heterodimeric antibody.