Heterotandem bicyclic peptide complex
The present invention relates to a heterotandem bicyclic peptide complex which comprises a first peptide ligand, which binds to EphA2, conjugated via a linker to two second peptide ligands, which bind to CD137. The invention also relates to the use of said heterotandem bicyclic peptide complex in preventing, suppressing or treating cancer.
1. A heterotandem bicyclic peptide complex comprising:
(a) a first peptide ligand which binds to EphA2 and which has the sequence A-[HArg]-D-C i [HyP]LVNPLC ii LEP[d1Nal]WTC iii (SEQ ID NO: 1); conjugated via an N-(acid-PEG 3 )-N-bis(PEG 3 -azide) linker to
(b) two second peptide ligands which bind to CD137 both of which have the sequence Ac—C i [tBuAla]PE[D-Lys(PYA)]PYC ii FADPY[Nle]C iii -A (SEQ ID NO: 2);
or a pharmaceutically acceptable salt thereof,
wherein each of said peptide ligands comprise a polypeptide comprising three reactive cysteine groups (C i , C ii and C iii ), separated by two loop sequences, and a molecular scaffold which is 1,1′,1″-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one (TATA) and which forms covalent bonds with the reactive cysteine groups of the polypeptide such that two polypeptide loops are formed on the molecular scaffold;
wherein Ac represents acetyl, HArg represents homoarginine, HyP represents trans-4-hydroxy-L-proline, 1Nal represents 1-naphthylalanine, tBuAla represents t-butyl-alanine, PYA represents 4-pentynoic acid and Nle represents norleucine.
2. The heterotandem bicyclic peptide complex according to claim 1 which is:
or a pharmaceutically acceptable salt thereof.
3. The heterotandem bicyclic peptide complex as defined in claim 1 , wherein the pharmaceutically acceptable salt is selected from the free acid or the sodium, potassium, calcium, or ammonium salt.
4. A pharmaceutical composition which comprises the heterotandem bicyclic peptide complex of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients.
5. A heterotandem bicyclic peptide complex which is:
or a pharmaceutically acceptable salt thereof.
6. The heterotandem bicyclic peptide complex of claim 5 , wherein the pharmaceutically acceptable salt is selected from the free acid or the sodium, potassium, calcium, or ammonium salt.
7. A pharmaceutical composition comprising the heterotandem bicyclic peptide complex of claim 5 , or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients.
8. A method of binding an EphA2 receptor in a subject in need thereof, comprising administering to the subject the heterotandem bicyclic peptide complex as defined in claim 1 , or a pharmaceutically acceptable salt thereof.
9. The method of claim 8 , wherein the subject has an EphA2 associated cancer.
10. The method of claim 9 , wherein the cancer is lung cancer.
11. The method of claim 9 , wherein the cancer is colon cancer.
12. The method of claim 9 , wherein the cancer is bladder cancer.
13. The method of claim 9 , wherein the cancer is breast cancer.
14. The method of claim 8 , wherein the heterotandem bicyclic peptide complex, or a pharmaceutically acceptable salt thereof, is administered via an intravenous administration.
15. A method of binding an EphA2 receptor in a subject in need thereof, comprising administering to the subject the heterotandem bicyclic peptide complex as defined in claim 5 , or a pharmaceutically acceptable salt thereof.
16. The method of claim 15 , wherein the subject has an EphA2 associated cancer.
17. The method of claim 16 , wherein the cancer is lung cancer.
18. The method of claim 16 , wherein the cancer is colon cancer.
19. The method of claim 16 , wherein the cancer is bladder cancer.
20. The method of claim 16 , wherein the cancer is breast cancer.
21. The method of claim 15 , wherein the heterotandem bicyclic peptide complex, or a pharmaceutically acceptable salt thereof, is administered via an intravenous administration.