KR-20260067380-A - BICYCLIC PEPTIDE LIGANDS SPECIFIC FOR NECTIN-4

Abstract

The present invention relates to a polypeptide in which two or more peptide loops are opposed between attachment points to a molecular scaffold by covalent bonding to the molecular scaffold. In particular, the present invention describes a peptide that is a high-affinity binder for Nectin-4. The present invention also relates to a drug conjugate comprising said peptide conjugated to one or more effector groups and/or action groups, a pharmaceutical composition comprising said peptide ligand and the drug conjugate, and the use of said peptide ligand and the drug conjugate in preventing, inhibiting, or treating diseases or disorders mediated by Nectin-4.

Inventors

• 베스윅 폴
• 첸 리우홍
• 머드 젬마 엘리자베스
• 박 피터
• 반 리엣슈텐 케이터린
• 릭비 마이클
• 블레이크모어 스테판
• 겔프 타라
• 킨 니콜라스

Assignees

• 바이사이클티엑스 리미티드

Dates

Publication Date

20260512

Application Date

20190621

Priority Date

20180622

Claims (20)

1. As a method for identifying or selecting cancer patients to be treated with a Nectin-4 targeted drug conjugate, i) a step of determining the number of nectin-4 copies in a sample from the patient's tumor; and ii) a step comprising identifying or selecting a patient for treatment with a nectin-4 targeted drug conjugate if it is determined in step i) that the patient has more than 2 copies of nectin-4.
2. A method for identifying or selecting a cancer patient to be treated with a nectin-4 targeted drug conjugate, comprising the step of identifying a number of nectin-4 copies greater than 2 in a sample from the patient's tumor.
3. A method according to claim 1 or 2, wherein the nectin-4 target drug conjugate comprises a peptide ligand.
4. A method according to claim 3, wherein the peptide ligand comprises a polypeptide and a molecular scaffold, the molecular scaffold forms a covalent bond with the polypeptide, the polypeptide comprises at least three amino acids, and each of the at least three amino acids comprises a reactive group that forms a covalent bond with the molecular scaffold so that at least two polypeptide loops can be formed on the molecular scaffold.
5. A method according to claim 3 or 4, wherein the nectin-4 targeted drug conjugate further comprises a cytotoxic agent.
6. In paragraph 5, the nectin-4 targeted drug conjugate is BCY8245: Person, method.
7. A method according to claim 1 or 2, wherein the nectin-4 target drug conjugate is an antibody drug conjugate.
8. In claim 7, a method in which the antibody-drug conjugate comprises a cytotoxic agent.
9. In paragraph 8, the method wherein the cytotoxic agent is monomethyl auristatin E.
10. A method according to any one of claims 1 to 9, wherein the cancer is selected from breast cancer, uterine cancer, bladder cancer, lung adenocarcinoma, lung squamous cancer, cervical cancer, head and neck cancer, pancreatic cancer, thyroid cancer, colorectal cancer, thymoma, sarcoma, renal clear cell carcinoma (RCC), prostate cancer, and stomach cancer.
11. In Clause 10, the method in which the cancer is bladder cancer.
12. A method according to any one of claims 1 to 11, wherein the sample from the tumor is a tissue sample or a hematological sample.
13. A method for preventing, inhibiting, or treating cancer in a subject, comprising the step of administering a nectin-4 targeted drug conjugate to a subject, wherein the subject is identified to have a number of nectin-4 copies greater than 2 in a sample from a tumor.
14. In paragraph 13, the method wherein the sample from the tumor is a tissue sample or a blood sample.
15. The method of claim 13 or 14, wherein the nectin-4 targeted drug conjugate comprises a peptide ligand.
16. A method according to claim 15, wherein the peptide ligand comprises a polypeptide and a molecular scaffold, the molecular scaffold forms a covalent bond with the polypeptide, the polypeptide comprises at least three amino acids, and each of the at least three amino acids comprises a reactive group that forms a covalent bond with the molecular scaffold so that at least two polypeptide loops can be formed on the molecular scaffold.
17. In paragraph 16, the nectin-4 targeted drug conjugate is BCY8245: Person, method.
18. A method according to claim 13 or 14, wherein the nectin-4 target drug conjugate is an antibody drug conjugate.
19. In paragraph 18, a method wherein the antibody-drug conjugate comprises monomethylauristatin E.
20. A method according to any one of claims 13 to 19, wherein the cancer is selected from breast cancer, uterine cancer, bladder cancer, lung adenocarcinoma, lung squamous cell carcinoma, cervical cancer, head and neck cancer, pancreatic cancer, thyroid cancer, colorectal cancer, thymoma, sarcoma, renal clear cell carcinoma, prostate cancer, and gastric cancer.

Description

Bicyclic Peptide Ligands Specific for Nectin-4 Field of invention The present invention relates to a polypeptide in which two or more peptide loops are subtended between attachment points to a molecular scaffold by covalent bonding to the scaffold. In particular, the present invention describes a peptide that is a high-affinity binder of Nectin-4. The present invention also comprises a drug conjugate comprising said peptide conjugated to one or more effectors and/or action groups, a pharmaceutical composition comprising said peptide ligand and the drug conjugate, and the use of said peptide ligand or drug conjugate in preventing, suppressing, or treating diseases or disorders mediated by Nectin-4. Background of the Invention Cyclic peptides are an attractive class of molecules for the development of therapeutics because they can bind to protein targets with high affinity and target specificity. In fact, several cyclic peptides are already being successfully used in clinical practice, such as the antibacterial peptide vancomycin, the immunosuppressive drug cyclosporine, or the anticancer drug octreotide (Driggers et al. (2008), Nat Rev Drug Discov 7 (7), 608-24). Good binding characteristics are caused by the relatively large interaction surface formed between the peptide and the target, as well as the reduced structural flexibility of the cyclic structure. Typically, macrocycles bind to surfaces of hundreds of square angstroms, such as the cyclic peptide CXCR4 antagonist CVX15 (400 Å 2 ; Wu et al. (2007), Science 330, 1066-71), the cyclic peptide with an Arg-Gly-Asp motif binding to integrin αVb3 (355 Å 2 ) (Xiong et al. (2002), Science 296 (5565), 151-5), or the cyclic peptide inhibitor Upain-1 (603 Å 2 ; Zhao et al. (2007), J Struct Biol 160 (1), 1-10) binding to a urokinase-type plasminogen activator. If present in the drawing, the error bar represents the standard error of the mean (SEM).FIGS. 1 to 7 : Tumor volumes tracked after administration of BCY7683, BCY7825, BCY7826, BCY8245, BCY8253, BCY8254, and BCY8255, respectively, to female BALB/c nude mice carrying NCI-H292 xenografts. FIGS. 8 to 10 : Tumor volumes tracked after administration of BCY8245, BCY8253, and BCY8255, respectively, to female Balb/c nude mice carrying NCI-H292 xenografts. FIGS. 11 to 15 : Tumor volumes tracked after administration of BCY7825, BCY8245, BCY8253, BCY8254, and BCY8255, respectively, to female CB17-SCID mice carrying HT-1376 xenografts. FIGS. 16 to 18 : Tumor volumes tracked after administration of BCY8245, BCY8253, and BCY8255, respectively, to female CB17-SCID mice carrying HT-1376 xenografts. FIGS. 19 to 21 : Tumor volumes tracked after administration of BCY8245, BCY8253, and BCY8255, respectively, to female Balb/c nude mice carrying Panc2.13 xenografts. FIGS. 22 to 24 : Tumor volumes tracked after administration of BCY8245, BCY8253, and BCY8255, respectively, to female Balb/c nude mice carrying MDA-MB-468 xenografts. FIGS. 25 to 28 : Tumor volumes tracked after administration of BCY8549, BCY8550, BCY8783, and BCY8784, respectively (along with BCY8245 as a control), to female BALB/c nude mice carrying NCI-H292 xenografts. Fig. 29 : Gating strategy for nectin-4 in breasts (T-47D and MDA-MB-468). Fig. 30 : Gating strategy for nectin-4 in NCI-H292 and NCI-H322. Figures 31 and 32 : Gating strategies for nectin-4 in NCI-H526 and HT1080, respectively. FIGS. 33 to 37 : Gating strategies for nectin-4 in bladder cancer (HT1376; FIG. 33), breast cancer (MDA-MB-468; FIG. 34), colorectal cancer (HT-29; FIG. 35a and HCT-116; FIG. 35b), lung cancer (A549; FIG. 36a, NCI-H292; FIG. 36b, NCI-H358; FIG. 36c and NCI-526; FIG. 36d), and pancreatic cancer (Panc02.13; FIG. 37), respectively. FIGS. 38 to 41 : Tumor volumes tracked after administration of BCY8242, BCY8245, BCY8253, and BCY8255, respectively, to female Balb/c nude mice carrying A549 xenografts. FIGS. 42 to 45 : Tumor volumes tracked after administration of BCY8242, BCY8245, BCY8253, and BCY8255, respectively, to female Balb/c nude mice carrying HCT116 xenografts. FIGS. 46 to 49 : Tumor volumes tracked after administration of BCY8242, BCY8245, BCY8253, and BCY8255, respectively, to female CB17-SCID mice carrying HT-1376 xenografts. FIGS. 50 to 53 : Tumor volumes tracked after administration of BCY8242, BCY8245, BCY8253, and BCY8255, respectively, to female Balb/c nude mice carrying MDA-MB-468 xenografts. FIGS. 54 to 57 : Tumor volumes tracked after administration of BCY8242, BCY8245, BCY8253, and BCY8255, respectively, to female Balb/c nude mice carrying NCI-H292 xenografts. FIGS. 58 to 59 : Tumor volumes tracked after administration of BCY8245 and BCY8255, respectively, to female Balb/c nude mice carrying NCI-H526 xenografts. FIGS. 60 to 63 : Tumor volumes tracked after administration of BCY8242, BCY8245, BCY8253, and BCY8255, respectively, to female Balb/c nude mice carrying Panc2.13 xenografts. Fig. 64 : Tumor volume tracked after administration of BCY8245, BCY8781, or BCY