Bicyclic peptide ligands specific for Nectin-4
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 Nectin-4. The invention also includes drug conjugates comprising said peptides, conjugated to one or more effector and/or functional groups, to pharmaceutical compositions comprising said peptide ligands and drug conjugates and to the use of said peptide ligands and drug conjugates in preventing, suppressing or treating a disease or disorder mediated by Nectin-4.
1. A peptide ligand specific for Nectin-4 comprising a polypeptide comprising at least three cysteine residues, separated by at least two loop sequences, and a molecular scaffold which forms covalent bonds with the cysteine residues of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold, wherein the peptide ligand comprises the amino acid sequence:
(SEQ ID NO: 1)
C i P[1Nal][dD]C ii M[HArg]DWSTP[HyP]WC iii ;
wherein 1Nal represents 1-naphthylalanine, HArg represents homoarginine, HyP represents hydroxyproline and C i , C ii and C iii represent first, second and third cysteine residues, respectively, or a pharmaceutically acceptable salt thereof.
2. The peptide ligand according to claim 1 , which comprises an amino acid sequence selected from:
[B-Ala][Sar10]-(SEQ ID NO: 1) (hereinafter
referred to as BCY8234);
Ac[B-Ala][Sar 5 ]-(SEQ ID NO: 1) (hereinafter
referred to as BCY8122);
Ac-(SEQ ID NO: 1) (hereinafter referred to as
BCY8126);
(SEQ ID NO: 1) (hereinafter referred to as
BCY8116);
Fluorescein-(SEQ ID NO: 1) (hereinafter referred
to as BCY8205);
and
[PYA][B-Ala][Sar10]-(SEQ ID NO: 1) (hereinafter
referred to as BCY8846).
3. The peptide ligand according to claim 1 , which comprises an amino acid sequence selected from:
[B-Ala][Sarl0]-(SEQ ID NO: 1) (hereinafter
referred to as BCY8234);
Ac-[B-Ala][Sar 5 ]-(SEQ ID NO: 1) (hereinafter
referred to as BCY8122);
Ac-(SEQ ID NO: 1) (hereinafter referred to as
BCY8126);
(SEQ ID NO: 1) (hereinafter referred to as
BCY8116);
and
Fluorescein-(SEQ ID NO: 1) (hereinafter referred
to as BCY8205).
4. The peptide ligand according to claim 1 , which comprises an amino acid sequence selected from:
Ac-[B-Ala][Sar 5 ]-(SEQ ID NO: 1) (hereinafter
referred to as BCY8122);
Ac-(SEQ ID NO: 1) (hereinafter referred to as
BCY8126);
and
(SEQ ID NO: 1) (hereinafter referred to as
BCY8116).
5. The peptide ligand according to claim 1 , which comprises an amino acid sequence selected from:
Ac-[B-Ala][Sar 5 ]-(SEQ ID NO: 1) (hereinafter
referred to as BCY8122);
and
Ac-(SEQ ID NO: 1) (hereinafter referred to as
BCY8126).
6. The peptide ligand according to claim 1 , which comprises an amino acid sequence:
[B-Ala][Sar10]-(SEQ ID NO: 1) (hereinafter
referred to as BCY8234).
7. The peptide ligand according to claim 1 , wherein the molecular scaffold is 1,1′,1″-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one (TATA).
8. The peptide ligand according to claim 1 , wherein the pharmaceutically acceptable salt is selected from the free acid or the sodium, potassium, calcium, or ammonium salt.
9. The peptide ligand according to claim 1 , wherein the Nectin-4 is human Nectin-4.
10. A pharmaceutical composition which comprises the peptide ligand of claim 1 , in combination with one or more pharmaceutically acceptable excipients.
11. The pharmaceutical composition as defined in claim 10 , which additionally comprises one or more therapeutic agents.
12. A drug conjugate comprising a peptide ligand as defined in claim 1 , conjugated to one or more effector and/or functional groups.
13. The drug conjugate as defined in claim 12 , conjugated to one or more cytotoxic agents.
14. The drug conjugate as defined in claim 13 , wherein said cytotoxic agent is selected from Monomethyl auristatin E (MMAE) and Mertansine (DM1).
15. The drug conjugate as defined in claim 14 , wherein the cytotoxic agent is MMAE and said conjugate additionally comprises a linker selected from: -PABC-Cit-Val-Glutaryl- and -PABC-cyclobutyl-Ala-Cit-βAla-, wherein PABC represents p-aminobenzylcarbamate.
16. The drug conjugate as defined in claim 15 , wherein the cytotoxic agent is DM1 and said conjugate additionally comprises a linker which is -SPDB-(SO 3 H)—, wherein SPDB represents N-succinimidyl 3-(2-pyridyldithio)propionate.
17. The drug conjugate as defined in claim 15 , wherein the linker is -PABC-Cit-Val-Glutaryl-.
18. The drug conjugate as defined in claim 12 , which is selected from: BCY8245 and BCY8549.
19. The drug conjugate as defined in claim 18 , which is BCY8245.
20. The drug conjugate as defined in claim 14 , wherein said cytotoxic agent is MMAE.
21. A pharmaceutical composition which comprises the drug conjugate of claim 12 , in combination with one or more pharmaceutically acceptable excipients.
22. A method for suppressing or treating a disease or disorder mediated by Nectin-4, comprising administering to a patient in need thereof the drug conjugate as defined in claim 12 .
23. The method of claim 22 , wherein the disease or disorder mediated by Nectin-4 is selected from bladder cancer, breast cancer, colorectal cancer, lung cancer, ovarian cancer, and pancreatic cancer.
24. A method of suppressing or treating a cancer patient having an increased copy number variation (CNV) of Nectin-4, which comprises administering to said patient in need thereof the drug conjugate as defined in claim 12 .