Heterodimeric antibodies that bind CD3 and tumor antigens
The present invention is directed to novel heterodimeric antibodies.
1. A heterodimeric antibody comprising:
a) a first monomer comprising, from N- to C-terminus, a VH1-CH1-linker 1-VL2-scFv linker-VH2-linker 2-CH2-CH3,
wherein VL2-scFv linker-VH2 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, from N- to C-terminus, 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 (VL1) comprising a first variable light domain (VL1); and
wherein the first variable heavy domain (VH1) on the first monomer and the first variable light domain (VL1) form a first binding domain, and the first variable heavy domain (VH1) on the second monomer and the first variable light domain (VL1) form a second binding domain, and
wherein the second variable heavy domain (VH2) and second variable light domain (VL2) have the amino acid sequence SEQ ID NO: 10 and SEQ ID NO: 14, or SEQ ID NO: 19 and SEQ ID NO: 23, respectively.
2. The heterodimeric antibody of claim 1 , wherein VH2 has the amino acid sequence of SEQ ID NO: 10, and VL2 has the amino acid sequence of SEQ ID NO: 14.
3. The heterodimeric antibody of claim 1 , wherein VH2 has the amino acid sequence of SEQ ID NO: 19, and VL2 has the amino acid sequence of SEQ ID NO: 23.
4. A heterodimeric antibody according to claim 1 , wherein the first and second IgG Fc domains are variants of a human IgG Fc domain.
5. A heterodimeric antibody according to claim 1 , wherein the first IgG Fc domain comprises amino acid substitutions S364K/E357Q and the second IgG Fc domain comprises amino acid substitutions L368D/K370S, wherein numbering is according to EU numbering.
6. A heterodimeric antibody according to claim 1 , wherein the CH1-hinge-CH2-CH3 of the second monomer comprises amino acid substitutions N208D/Q295E/N384D/Q418E/N421D, wherein numbering is according to EU numbering.
7. A heterodimeric antibody according to claim 1 , wherein the first and second IgG Fc domains comprise amino acid substitutions E233P/L234V/L235A/G236del/S267K, wherein numbering is according to EU numbering.
8. A heterodimeric antibody according to claim 1 , wherein the scFv linker is a charged linker.
9. A heterodimeric antibody according to claim 1 , wherein the first IgG Fc domain comprises amino acid substitutions S364K/E357Q and the second Fc domain comprises amino acid substitutions L368D/K370S,
wherein the first and second IgG Fc domains each comprise amino acid substitutions E233P/L234V/L235A/G236del/S267K, and
wherein the CH1-hinge-CH2-CH3 of the second monomer comprises amino acid substitutions N208D/Q295E/N384D/Q418E/N421D, wherein numbering is according to EU numbering.
10. A polynucleotide composition comprising:
a) a first polynucleotide encoding the first monomer of claim 1 ;
b) a second polynucleotide encoding the second monomer of claim 1 ; and
c) a third polynucleotide encoding the common light chain of claim 1 .
11. An expression vector composition comprising:
a) a first expression vector comprising a first polynucleotide encoding the first monomer of claim 1 ;
b) a second expression vector comprising a second polynucleotide encoding the second monomer of claim 1 ; and
c) a third expression vector comprising a third polynucleotide encoding the common light chain of claim 1 .
12. A host cell comprising the expression vector composition of claim claim 11 .
13. A method of making a heterodimeric antibody comprising culturing the host cell of claim 12 under conditions wherein the heterodimeric antibody is expressed, and recovering the heterodimeric antibody.