Therapeutic molecules binding PSMA
The invention relates to improved binding molecules that bind specifically to prostate specific membrane antigen (PSMA), in particular, single human variable heavy chain domain antibodies and related methods for treatment of cancer.
1. A binding molecule capable of binding human PSMA comprising a single human variable heavy chain domain (V H ) antibody selected from the group consisting of:
a single V H domain antibody, comprising a CDR1 sequence comprising SEQ ID NO: 1, a CDR2 sequence comprising SEQ ID NO: 2 and a CDR3 sequence comprising SEQ ID NO: 3;
a single V H domain antibody comprising a CDR1 sequence comprising SEQ ID NO: 5, a CDR2 sequence comprising SEQ ID NO: 6 and a CDR3 sequence comprising SEQ ID NO: 7;
a single V H domain antibody comprising a CDR1 sequence comprising SEQ ID NO: 9, a CDR2 sequence comprising SEQ ID NO: 10 and a CDR3 sequence comprising SEQ ID NO: 11;
a single V H domain antibody, comprising a CDR1 sequence comprising SEQ ID NO: 13, a CDR2 sequence comprising SEQ ID NO: 14 and a CDR3 sequence comprising SEQ ID NO: 15;
a single V H domain antibody comprising a CDR1 sequence comprising SEQ ID NO: 17, a CDR2 sequence comprising SEQ ID NO: 18 and a CDR3 sequence comprising SEQ ID NO: 19;
a single V H domain antibody comprising a CDR1 sequence comprising SEQ ID NO: 21, a CDR2 sequence comprising SEQ ID NO: 22 and a CDR3 sequence comprising SEQ ID NO: 23;
a single V H domain antibody, comprising a CDR1 sequence comprising SEQ ID NO: 25, a CDR2 sequence comprising SEQ ID NO: 26 and a CDR3 sequence comprising SEQ ID NO: 27;
a single V H domain antibody comprising a CDR1 sequence comprising SEQ ID NO: 29, a CDR2 sequence comprising SEQ ID NO: 30 and a CDR3 sequence comprising SEQ ID NO: 31;
a single V H domain antibody comprising a CDR1 sequence comprising SEQ ID NO: 33, a CDR2 sequence comprising SEQ ID NO: 34 and a CDR3 sequence comprising SEQ ID NO: 35; and
a single V H domain antibody comprising a CDR1 sequence comprising SEQ ID NO: 37, a CDR2 sequence comprising SEQ ID NO: 38 and a CDR3 sequence comprising SEQ ID NO: 39.
2. The binding molecule according to claim 1 wherein said single V H domain antibody comprises a sequence selected from SEQ ID Nos: 4, 8, 12, 16, 20, 24, 28, 32, 36 and 40.
3. A binding molecule comprising a first single human heavy chain variable immunoglobulin (V H ) domain antibody capable of binding human PSMA and a second single V H domain antibody capable of binding human PSMA, wherein said first single human heavy chain variable immunoglobulin (V H ) domain antibody capable of binding human PSMA is according to claim 1 .
4. The binding molecule according to claim 3 wherein said first single human heavy chain variable immunoglobulin (V H ) domain antibody and said second single V H domain antibody bind to the same epitope on human PSMA.
5. The binding molecule according to claim 3 wherein said first single human heavy chain variable immunoglobulin (V H ) domain antibody binds to a first epitope on PSMA and said second single V H domain antibody binds to a second epitope on PSMA wherein said first and said second epitope are not identical.
6. The binding molecule according to claim 5 wherein said second single V H domain antibody is selected from the group consisting of SEQ ID Nos: 71-95.
7. The binding molecule according to claim 3 wherein the first single human heavy chain variable immunoglobulin (V H ) domain antibody is located C or N terminally.
8. The binding molecule according to claim 3 wherein said first single human heavy chain variable immunoglobulin (V H ) domain antibody and said second single V H domain antibody are covalently linked by a peptide linker.
9. The binding molecule according to claim 8 wherein the peptide linker is between 3 and 50 amino acids long.
10. The binding molecule according to claim 8 wherein the peptide linker comprises glycine and serine amino acid residues.
11. The binding molecule according to claim 1 wherein said binding molecule is conjugated to a toxin, enzyme, radioisotope or other chemical moiety.
12. A pharmaceutical composition comprising the binding molecule according to claim 1 and a pharmaceutical carrier.
13. A method for treating prostate cancer or a prostatic disorder comprising administering a therapeutically-effective amount of the binding molecule according to claim 1 .
14. An in vivo or in vitro method for reducing human PSMA activity comprising contacting human PSMA with the binding molecule according to claim 1 .
15. A method for determining the presence of PSMA in a test sample by an immunoassay comprising contacting said sample with the binding molecule according to claim 1 and at least one detectable label.
16. An isolated nucleic acid molecule comprising a nucleotide sequence encoding the binding molecule according to claim 1 .
17. A construct or host cell comprising the nucleic acid according to claim 16 .
18. A method for producing the binding molecule according to claim 1 comprising expressing a nucleic acid encoding said binding molecule in a host cell and isolating the binding molecule from the host cell culture.
19. A kit comprising the binding molecule according to claim 1 or the pharmaceutical composition according to claim 12 .
20. A multispecific binding molecule comprising the binding molecule according to claim 1 .
21. The binding molecule according to claim 1 wherein said binding molecule is capable of being internalised by a cell.
22. An immunoconjugate conjugate comprising the binding molecule according to claim 1 .