Bicyclic peptide ligands specific for MT1-MMP
The present invention relates to polypeptides which are covalently bound to molecular scaffolds such that two or more peptide loops are subtended between attachment points to the scaffold. In particular, the invention describes peptides which are high affinity binders of membrane type 1 metalloprotease (MT1-MMP). The invention also describes drug conjugates comprising said peptides, conjugated to one or more effector and/or functional groups which have utility in imaging and targeted cancer therapy.
1. A compound which is selected from the group consisting of:
wherein Bicycle represents a peptide ligand specific for MT1-MMP comprising a polypeptide comprising at least three cysteine residues, separated by at least two loop sequences, and a molecular scaffold, which is TBMB (1,3,5-tris(bromomethyl)benzene), and which forms covalent bonds with the cysteine residues of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold, and wherein the peptide ligand comprises the amino acid sequence of:
(SEQ ID NO: 5)
(β-Ala)-Sar10-AC(D-A1a)NE(1Na1)(D-A1a)CEDFYD
(tBuGly)C,
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 which is:
or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1 which is:
or a sodium, potassium, calcium, or ammonium salt thereof.
4. The compound according to claim 1 which is:
or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1 which is:
or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 1 , wherein the pharmaceutically acceptable salt is selected from the group consisting of the sodium, potassium, calcium, and ammonium salt.
7. A pharmaceutical composition which comprises the compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients.
8. A method of treating cancer in a patient comprising administering to the patient the compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of a tumor of epithelial origin, a tumor of the central or peripheral nervous system, and a fibrosarcoma.
9. A compound which is:
or a sodium or potassium salt thereof, wherein Bicycle represents a peptide ligand specific for MT1-MMP comprising a polypeptide comprising at least three cysteine residues, separated by at least two loop sequences, and a molecular scaffold, which is TBMB (1,3,5-tris(bromomethyl)benzene), and which forms covalent bonds with the cysteine residues of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold, and wherein the peptide ligand comprises the amino acid sequence of:
(SEQ ID NO: 5)
(β-Ala)-Sar10-AC(D-A1a)NE(1Na1)(D-A1a)CEDFYD
(tBuGly)C.
10. A pharmaceutical composition which comprises the compound of claim 9 , or a sodium or potassium salt thereof, in combination with one or more pharmaceutically acceptable excipients.
11. A method of treating cancer in a patient comprising administering to the patient the compound of claim 9 , or a sodium or potassium salt thereof, wherein the cancer is selected from the group consisting of a tumor of epithelial origin, a tumor of the central or peripheral nervous system, and a fibrosarcoma.
12. The method of claim 11 , wherein the tumor of epithelial origin is selected from the group consisting of a carcinoma of the bladder and urinary tract, breast, gastrointestinal tract, liver, gall bladder and biliary system, exocrine pancreas, kidney, lung, head and neck, ovary, fallopian tubes, peritoneum, vagina, vulva, penis, cervix, myometrium, endometrium, thyroid, adrenal, prostate, skin and adnexae.
13. The method of claim 12 , wherein the carcinoma of the lung is selected from the group consisting of an adenocarcinoma, a small cell lung carcinoma, a non-small cell lung carcinoma, a bronchioalveolar carcinoma and a mesothelioma.
14. The method of claim 12 , wherein the carcinoma of the lung is a non-small cell lung carcinoma.
15. The method of claim 11 , wherein the cancer is a tumor of the central or peripheral nervous system.
16. The method of claim 11 , wherein the cancer is a fibrosarcoma.
17. The method of claim 8 , wherein the tumor of epithelial origin is selected from the group consisting of a carcinoma of the bladder and urinary tract, breast, gastrointestinal tract, liver, gall bladder and biliary system, exocrine pancreas, kidney, lung, head and neck, ovary, fallopian tubes, peritoneum, vagina, vulva, penis, cervix, myometrium, endometrium, thyroid, adrenal, prostate, skin and adnexae.
18. The method of claim 17 , wherein the carcinoma of the lung is selected from the group consisting of an adenocarcinoma, a small cell lung carcinoma, a non-small cell lung carcinoma, a bronchioalveolar carcinoma and a mesothelioma.
19. The method of claim 17 , wherein the carcinoma of the lung is a non-small cell lung carcinoma.