Therapeutic molecules binding PSMA

• US 20200131274A1
• Filed: 07/09/2018
• Published: 04/30/2020
• Est. Priority Date: 07/10/2017
• Status: Active Grant

• Current Assignee: Crescendo Biologics Limited
• Original Assignee: Crescendo Biologics Limited
• Inventors: Royle, Nikki, Vance, Steve, Zelenay, Vivien
• Granted Patent: US 11,401,342 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/68031 the drug being an auristatin
• CPC Class Codes: A61K 47/6817 Toxins
• CPC Class Codes: A61K 47/6869 the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate
• CPC Class Codes: C07K 16/3069 Reproductive system, e.g. ovaria, uterus, testes, prostate
• CPC Class Codes: C07K 2317/14 Specific host cells or culture conditions, e.g. components, pH or temperature
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/31 multispecific
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/569 Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/77 Internalization into the cell
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 Stability, e.g. half-life, pH, temperature or enzyme-resistance
• CPC Class Codes: G01N 33/57434 of prostate
• CPC Class Codes: G01N 33/57492 involving compounds localized on the membrane of tumor or cancer cells

Abstract

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.

Claims

1. A binding molecule capable of binding human PSMA comprising a single human variable heavy chain domain (V_H) antibody selected from one of the following:

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 domain 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 or 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. A binding molecule according to claim 1 wherein said single domain V_H domain antibody comprises a sequence selected from SEQ ID NOs 4, 8, 12, 16, 20, 24, 28, 32, 36 or 40.

3. A binding molecule comprising a first single human heavy chain variable immunoglobulin (V_H) domain antibody capable of binding human PSMA according to claim 1 or 2 and a second single V_H domain antibody capable of binding human PSMA.

4. A binding molecule according to claim 3 wherein said first V_H domain and said second V_H domain bind to the same epitope on human PSMA.

5. A binding molecule according to claim 3 wherein said first single 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. A binding molecule according to claim 5 wherein said second V_H domain antibody is selected from Table 2.

7. A binding molecule according to any of claims 3 to 5 in which the first single V_H domain antibody is located C or N terminally.

8. A binding molecule according to any of claims 3 to 6 wherein said first and second V_H domain are covalently linked by a peptide.

9. A binding molecule according to claim 8 wherein the peptide is between 3 and 50 amino acids long.

10. A binding molecule according to claim 8 or 8 wherein the linker comprises glycine and serine amino acid residues.

11. A binding molecule according to any of claims 8 to 10 wherein the peptide linker consists of the formula (Gly₄Ser)_n, where n=from 1 to 10.

12. A binding molecule according to a preceding claim wherein said binding molecule is conjugated to a toxin, enzyme, radioisotope or other chemical moiety.

13. A binding molecule according to a preceding claim obtained or obtainable from a mouse that does not produce any functional endogenous light or heavy chains.

14. A pharmaceutical composition comprising a binding molecule according to any preceding claim and a pharmaceutical carrier.

15. A method for treating prostate cancer or a prostatic disorder comprising administering a therapeutically-effective amount of a binding molecule according to any of claims 1 to 13 or a pharmaceutical composition according to claim 14.

16. A binding molecule according to any of claims 1 to 13 or a pharmaceutical composition according to claim 14 for use as medicament.

17. A binding molecule according to any of claims 1 to 13 or a pharmaceutical composition according to claim 14 for use in the treatment of prostate cancer or a prostatic disorder.

18. Use of a binding molecule according to any of claims 1 to 13 or a pharmaceutical composition according to claim 14 in the manufacture of a medicament for the treatment of prostate cancer or a prostatic disorder.

19. An in vivo or in vitro method for reducing human PSMA activity comprising contacting human PSMA with a binding molecule according to any of claims 1 to 13.

20. A method for determining the presence of PSMA in a test sample by an immunoassay comprising contacting said sample with a binding molecule according to any of claims 1 to 13 and at least one detectable label.

21. A method of claim 13 wherein said method comprises diagnosing or assessing the efficacy of prophylactic or therapeutic treatment of a patient.

22. An isolated nucleic acid molecule comprising a nucleotide sequence encoding a binding molecule according to any of claims 1 to 13.

23. A construct comprising a nucleic acid according to claim 21.

24. A host cell comprising a nucleic acid according to claim 21 or a construct according to claim 23.

25. A method for producing a binding molecule according to any one of claims 1 to 13 comprising expressing a nucleic acid encoding said binding molecule in a host cell and isolating the binding molecule from the host cell culture.

26. A kit comprising a binding molecule according to any one of claims 1 to 13 or a pharmaceutical composition according to claim 14.

27. A multispecific binding molecule comprising a single V_H domain antibody according to any of claims 1 to 13.

28. A binding molecule according any one of claims 1 to 13 wherein said binding molecule is capable of being internalised by a cell.

29. An immunoconjugate comprising a single V_H domain antibody according to any of claims 1 to 13.