JP-2022514255-A5 -

Dates

Publication Date

20221219

Application Date

20191213

Description

The peptide ligand of the present invention was tested using the PSMA binding and enzyme inhibition assays described above. The results are shown in Table 1: Table 1: Biological assay data of the peptide ligand of the present invention This application provides the invention in the following embodiments. (Aspect 1) A PSMA-specific peptide ligand comprising a polypeptide containing at least three cysteine residues separated by at least two loop sequences, and a molecular scaffold that forms covalent bonds with the cysteine residues of the polypeptide, thereby forming at least two polypeptide loops on the molecular scaffold. (Aspect 2) The peptide ligand according to embodiment 1, wherein the loop sequence comprises two or seven amino acids. (Aspect 3) The peptide ligand according to embodiment 1 or embodiment 2, wherein the loop sequence comprises three cysteine residues separated by two loop sequences, one of which consists of two amino acids and the other of which consists of seven amino acids. (Aspect 4) (Chem.1) (Here, X represents any amino acid residue, and Ci , Ci ii , and Ci iii represent the first, second, and third cysteine residues, respectively.) A peptide ligand according to any one of embodiments 1 to 3, comprising an amino acid sequence selected from : or a pharmaceutically acceptable salt thereof. (Aspect 5) (Case 2) (Here, X represents any amino acid residue, Nle represents norleucine, and C i , C ii , and C iii represent the first, second, and third cysteine residues, respectively.) A peptide ligand according to any one of embodiments 1 to 4, comprising an amino acid sequence selected from : or a pharmaceutically acceptable salt thereof. (Aspect 6) Sequence IDs 1-14: (Case 3) A peptide ligand according to embodiment 4 or embodiment 5, comprising an amino acid sequence selected from any one of the following (wherein Ci , Ci ii , and Ci iii represent the first, second, and third cysteine residues, respectively, and Nle represents norleucine) or a pharmaceutically acceptable salt thereof. (Aspect 7) A-(Sequence ID 1)-A (referred to herein as 21-31-N002); Ac-(Sequence ID 1) (referred to as 21-31-N003 herein); (Case 4) (referred to as 21-31-N004 in this specification); (Sequence ID 2)-A (referred to herein as 21-31-01-N001); (Sequence ID 3)-A (referred to herein as 21-31-02-N001); (Sequence ID 4)-A (referred to herein as 21-31-03-N001); EV-(Sequence ID 5)-A (referred to herein as 21-31-04-T01-N001)); (D-Gln)V-(Sequence ID 5)-A-Sar 6 -K (referred to herein as 21-31-04-T01-N002)); β-Ala-Sar 5 -EV-(Sequence ID 5) (referred to as 21-31-04-T01-N003 in this specification)); Ac-(D-Gln)-V-(Sequence ID 5)-A-Sar 6 -K-Ac (referred to herein as 21-31-04-T01-N004)); Ac-(D-Gln)-V-(Sequence ID 6)-A-Sar 6 -K (referred to herein as 21-31-04-T01-N005)); Ac-(D-Gln)-V-(Sequence ID 5)-A-Sar 6- (D-Lys) (referred to as 21-31-04-T01-N007 in this specification)); Ac-(D-Gln)-V-(Sequence ID 7)-A-Sar 6- (D-Lys) (referred to as 21-31-04-T01-N008 in this specification)); Ac-(D-Gln)-V-(Sequence ID 8)-A-Sar 6- (D-Lys) (referred to as 21-31-04-T01-N009 in this specification)); Ac-(D-Gln)-V-(Sequence ID 9)-A-Sar 6- (D-Lys) (referred to herein as 21-31-04-T01-N010); SV-(Sequence ID 10)-A (referred to herein as 21-31-07-T01-N001); F-(Sequence ID 11)-A (referred to herein as 21-31-11-T01-N001); L-(Sequence ID 12)-A (referred to herein as 21-31-12-T01-N001); (D-Val)-(Sequence ID 13)-A-Sar 6 -K (referred to herein as 21-31-14-T01-N002); β-Ala-Sar 5 -V-(SEQ ID NO: 13)-A-Sar 6 -K (referred to herein as 21-31-14-T01-N003); Ac-(Sequence ID 1)-A-Sar 6 -K (referred to herein as 21-31-N005); β-Ala-Sar 5 -A-(Sequence ID 1) (referred to as 21-31-N006 in this specification); Ac-(SEQ ID NO: 14)-A-Sar 6 -K (referred to herein as 21-31-N007); and β-Ala-Sar 5 -A-(SEQ ID NO: 14) (referred to as 21-31-N008 in this specification) A peptide ligand according to any one of embodiments 4 to 6, comprising an amino acid sequence selected from: (Appendix 8) EV-(Sequence ID 5)-A (referred to herein as 21-31-04-T01-N001)); Ac-(D-Gln)-V-(Sequence ID 8)-A-Sar 6- (D-Lys) (referred to as 21-31-04-T01-N009 in this specification)); F-(Sequence ID 11)-A (referred to herein as 21-31-11-T01-N001); and L-(Sequence ID 12)-A (referred to herein as 21-31-12-T01-N001) A peptide ligand according to any one of embodiments 4 to 7, comprising an amino acid sequence selected from: (Aspect 9) The peptide ligand according to any one of embodiments 1 to 8, wherein the pharmaceutically acceptable salt is selected from free acids or sodium, potassium, calcium, and ammonium salts. (Aspect 10) The peptide ligand according to any one of embodiments 1 to 9, wherein the PSMA is human PSMA. (Aspect 11) A drug conjugate comprising a peptide ligand according to any one of embodiments 1 to 10, conjugated to one or more effectors and/or functional groups. (Aspect 12) A pharmaceutical composition comprising a peptide ligand according to any one of embodiments 1 to 10 or a drug conjugate accor