Cross-species-specific PSMAxCD3 bispecific single chain antibody
The present invention relates to a bispecific single chain antibody molecule comprising a first binding domain capable of binding to an epitope of human and non-chimpanzee primate CD3 epsilon chain, wherein the epitope is part of an amino acid sequence comprised in the group consisting of SEQ ID NOs. 2, 4, 6, and 8, and a second binding domain capable of binding to prostate-specific membrane antigen (PSMA). The invention also provides nucleic acids encoding said bispecific single chain antibody molecule as well as vectors and host cells and a process for its production. The invention further relates to pharmaceutical compositions comprising said bispecific single chain antibody molecule and medical uses of said bispecific single chain antibody molecule.
1. A method for treating prostate cancer in a subject having prostate cancer expressing prostate-specific membrane antigen (PSMA) comprising administering to the subject an effective amount of a bispecific single chain antibody molecule, wherein the bispecific single chain antibody molecule comprises a first binding domain that specifically binds to human CD3 epsilon chain and a second binding domain that specifically binds to human PSMA, wherein the first binding domain comprises a light chain variable (VL CD3) region comprising complementarity determining regions CDR-L1, CDR-L2, and CDR-L3 and a heavy chain variable (VH CD3) region comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3, and wherein CDR-L1 has the sequence of SEQ ID NO: 171, CDR-L2 has the sequence of SEQ ID NO: 172, CDR-L3 has the sequence of SEQ ID NO: 173, CDR-H1 has the sequence of SEQ ID NO: 174, CDR-H2 has the sequence of SEQ ID NO: 175, and CDR-H3 has the sequence of SEQ ID NO: 176.
2. The method of claim 1 , wherein at least one of the first binding domain and the second binding domain is a humanized binding domain.
3. The method of claim 1 , wherein both the first binding domain and the second binding domain are humanized binding domains.
4. The method of claim 1 , wherein the VL CD3 of the first binding domain comprises the sequence of SEQ ID NO: 179 and the VH CD3 of the first binding domain comprises the sequence of SEQ ID NO: 177.
5. The method of claim 1 , wherein the first binding domain is a single chain variable fragment (scFv) and the VH CD3 and the VL CD3 are connected by a peptide linker.
6. The method of claim 5 , wherein the VH CD3 and VL CD3 are arranged in an amino to carboxyl terminal order of VH-VL.
7. The method of claim 5 , wherein the first binding domain comprises the sequence of SEQ ID NO: 185.
8. The method of claim 5 , wherein the first binding domain is positioned toward the carboxyl terminus of the molecule relative to the second binding domain.
9. The method of claim 1 , wherein the second binding domain is a single chain variable fragment (scFv) comprising a VH region and a VL region connected by a peptide linker.
10. The method of claim 1 , wherein the second binding domain comprises a VH region (VH PSMA) and VL region (VL PSMA), and wherein the variable regions in the bispecific single chain antibody molecule are arranged in an amino to carboxyl terminal order of VH PSMA-VL PSMA-VH CD3-VL CD3 or VL PSMA-VH PSMA-VH CD3-VL CD3.
11. The method of claim 1 , wherein the bispecific single chain antibody molecule is administered in a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
12. The method of claim 1 , wherein the bispecific single chain antibody molecule is administered intravenously.
13. The method of claim 12 , wherein the bispecific single chain antibody molecule is administered by intravenous infusion.