IP Library › Granted Patent US 12,440,570
Granted Patent B2
US 12,440,570 · App. 17/579,237 · Granted Oct 14, 2025

Conjugation of MCR1 ligand with cytotoxic drugs for treating skin cancer

Inventors: Minying Cai (Tucson, AZ); Victor J. Hruby (Tucson, AZ); Yang Zhou (Tucson, AZ)
Assignee: ARIZONA BOARD OF REGENTS ON BEHALF OF THE UNIVERSITY OF ARIZONA
A61K47/55A61K9/0014A61K47/545A61K47/64A61P35/00
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,440,570
App. No.
17/579,237
Granted
Oct 14, 2025
Kind
B2
Abstract

Ligand-drug conjugates for targeted melanoma therapies are disclosed herein. A ligand is conjugated to a cytotoxic cancer drug through a cleavage linker. The ligand can bind to an overexpressed receptor on a cancer cell, resulting in selectivity. This allows the drug to enter a cancer cell selectively and release the drug within that specific cancer cell. Such therapies provide selectivity to melanoma through a ligand that targets the MC1R receptor, which is highly expressed in 80% of malignant melanomas. The ligand-drug conjugates can be used to deliver a wide range of cytotoxic cancer drugs selective to melanoma cells which may solve the drug resistance problem of melanoma in current therapies.

Claims (187)

1. A pharmaceutical composition comprising a ligand-drug conjugate comprising a peptide ligand bound to a drug moiety, wherein the ligand-drug conjugate is according to the formula: L-A-B-D, wherein L is the peptide ligand, A is a spacer derived from aminohexanoic acid, B is a cleavable linker, and D is the drug moiety, wherein the peptide ligand is according to the formula:

Ac-Nle-c[Asp-His-Taa-Arg-Trp-Lys]-NH 2 (SEQ ID NO: 89), or is a derivative that has at least 50% homology to SEQ ID NO: 89, wherein Taa is DPhe or DNal(2′).

2. The composition of claim 1 , wherein the derivative has at least 60% homology, at least 70% homology, at least 80% homology, or at least 90% homology to SEQ ID NO: 89.

3. The composition of claim 1 , wherein the peptide ligand has at least one backbone residue that is N-methylated.

4. The composition of claim 1 , wherein the peptide ligand is one of the following:

Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH 2 (SEQ ID NO: 4);

Ac-Nle-c[Asp-His-DNal(2)-Arg-Trp-Lys]-NH 2 (SEQ ID NO: 5); or a derivative that has at least 50% homology to SEQ ID NO: 4 or SEQ ID NO: 5.

5. The composition of claim 4 , wherein the derivative has at least 60% homology, at least 70% homology, at least 80% homology, or at least 90% homology to SEQ ID NO: 4, or SEQ ID NO: 5.

6. The composition of claim 4 , wherein the peptide ligand has at least one backbone residue that is N-methylated.

7. The composition of claim 1 , wherein the peptide ligand is one of the following:

 (SEQ ID NO: 7)

Ac-Nle-c[Asp-His-DPhe-Arg-Trp-(NMe)Lys]-NH 2

 (SEQ ID NO: 8)

Ac-Nle-c[Asp-His-DPhe-Arg-(NMe)Trp-Lys]-NH 2

 (SEQ ID NO: 9)

Ac-Nle-c[Asp-His-DPhe-(NMe)Arg-Trp-Lys]-NH 2

 (SEQ ID NO: 10)

Ac-Nle-c[Asp-His-(NMe)DPhe-Arg-Trp-Lys]-NH 2

 (SEQ ID NO: 11)

Ac-Nle-c[Asp-(NMe)His-DPhe-Arg-Trp-Lys]-NH 2

 (SEQ ID NO: 12)

Ac-Nle-c[Asp-His-DPhe-Arg-(NMe)Trp-(NMe)Lys]-NH 2

 (SEQ ID NO: 13)

Ac-Nle-c[Asp-His-DPhe-(NMe)Arg-Trp-(NMe)Lys]-NH 2

 (SEQ ID NO: 14)

Ac-Nle-c[Asp-His-(NMe)DPhe-Arg-Trp-(NMe)Lys]-NH 2

 (SEQ ID NO: 15)

Ac-Nle-c[Asp-(NMe)His-DPhe-Arg-Trp-(NMe)Lys]-NH 2

 (SEQ ID NO: 16)

Ac-Nle-c[Asp-His-DPhe-(NMe)Arg-(NMe)Trp-Lys]-NH 2

 (SEQ ID NO: 17)

Ac-Nle-c[Asp-His-(NMe)DPhe-Arg-(NMe)Trp-Lys]-NH 2

 (SEQ ID NO: 18)

Ac-Nle-c[Asp-(NMe)His-DPhe-Arg-(NMe)Trp-Lys]-NH 2

 (SEQ ID NO: 19)

Ac-Nle-c[Asp-His-(NMe)DPhe-(NMe)Arg-Trp-Lys]-NH 2

 (SEQ ID NO: 20)

Ac-Nle-c[Asp-(NMe)His-DPhe-(NMe)Arg-Trp-Lys]-NH 2

 (SEQ ID NO: 21)

Ac-Nle-c[Asp-(NMe)His-(NMe)DPhe-Arg-Trp-Lys]-NH 2

 (SEQ ID NO: 22)

Ac-Nle-c[Asp-His-DPhe-(NMe)Arg-(NMe)Trp-(NMe)Lys]-

NH 2

 (SEQ ID NO: 23)

Ac-Nle-c[Asp-His-(NMe)DPhe-Arg-(NMe)Trp-(NMe)Lys]-

NH 2

 (SEQ ID NO: 24)

Ac-Nle-c[Asp-(NMe)His-DPhe-Arg-(NMe)Trp-(NMe)Lys]-

NH 2

 (SEQ ID NO: 25)

Ac-Nle-c[Asp-His-(NMe)DPhe-(NMe)Arg-Trp-(NMe)Lys]-

NH 2

 (SEQ ID NO: 26)

Ac-Nle-c[Asp-(NMe)His-DPhe-(NMe)Arg-Trp-(NMe)Lys]-

NH 2

 (SEQ ID NO: 27)

Ac-Nle-c[Asp-(NMe)His-(NMe)DPhe-Arg-Trp-(NMe)Lys]-

NH 2

 (SEQ ID NO: 28)

Ac-Nle-c[Asp-His-(NMe)DPhe-(NMe)Arg-(NMe)Trp-Lys]-

NH 2

 (SEQ ID NO: 29)

Ac-Nle-c[Asp-(NMe)His-DPhe-(NMe)Arg-(NMe)Trp-Lys]-

NH 2

 (SEQ ID NO: 30)

Ac-Nle-c[Asp-(NMe)His-(NMe)DPhe-Arg-(NMe)Trp-Lys]-

NH 2

 (SEQ ID NO: 31)

Ac-Nle-c[Asp-(NMe)His-(NMe)DPhe-(NMe)Arg-Trp-Lys]-

NH 2

 (SEQ ID NO: 32)

Ac-Nle-c[Asp-His-(NMe)DPhe-(NMe)Arg-(NMe)Trp-

(NMe)Lys]-NH 2

 (SEQ ID NO: 33)

Ac-Nle-c[Asp-(NMe)His-DPhe-(NMe)Arg-(NMe)Trp-

(NMe)Lys]-NH 2

 (SEQ ID NO: 34)

Ac-Nle-c[Asp-(NMe)His-(NMe)DPhe-Arg-(NMe)Trp-

(NMe)Lys]-NH 2

 (SEQ ID NO: 35)

Ac-Nle-c[Asp-(NMe)His-(NMe)DPhe-(NMe)Arg-Trp-

(NMe)Lys]-NH 2

 (SEQ ID NO: 36)

Ac-Nle-c[Asp-(NMe)His-(NMe)DPhe-(NMe)Arg-

(NMe)Trp-Lys]-NH 2

 (SEQ ID NO: 37)

Ac-Nle-c[Asp-(NMe)His-(NMe)DPhe-(NMe)Arg-

(NMe)Trp-(NMe)Lys]-NH 2

 (SEQ ID NO: 38)

Ac-Nle-c[Asp-His-DNal(2′)-Arg-Trp-(NMe)Lys]-NH 2

 (SEQ ID NO: 39)

Ac-Nle-c[Asp-His-DNal(2′)-Arg-(NMe)Trp-Lys]-NH 2

 (SEQ ID NO: 40)

Ac-Nle-c[Asp-His-DNal(2′)-(NMe)Arg-Trp-Lys]-NH 2

 (SEQ ID NO: 41)

Ac-Nle-c[Asp-His-(NMe)DNal(2′)-Arg-Trp-Lys]-NH 2

 (SEQ ID NO: 42)

Ac-Nle-c[Asp-(NMe)His-DNal(2′)-Arg-Trp-Lys]-NH 2

 (SEQ ID NO: 43)

Ac-Nle-c[Asp-His-DNal(2′)-Arg-(NMe)Trp-(NMe)Lys]-

NH 2

 (SEQ ID NO: 44)

Ac-Nle-c[Asp-His-DNal(2′)-(NMe)Arg-Trp-(NMe)Lys]-

NH 2

 (SEQ ID NO: 45)

Ac-Nle-c[Asp-His-(NMe)DNal(2′)-Arg-Trp-(NMe)Lys]-

NH 2

 (SEQ ID NO: 46)

Ac-Nle-c[Asp-(NMe)His-DNal(2′)-Arg-Trp-(NMe)Lys]-

NH 2

 (SEQ ID NO: 47)

Ac-Nle-c[Asp-His-DNal(2′)-(NMe)Arg-(NMe)Trp-Lys]-

NH 2

 (SEQ ID NO: 48)

Ac-Nle-c[Asp-His-(NMe)DNal(2′)-Arg-(NMe)Trp-Lys]-

NH 2

 (SEQ ID NO: 49)

Ac-Nle-c[Asp-(NMe)His-DNal(2′)-Arg-(NMe)Trp-Lys]-

NH 2

 (SEQ ID NO: 50)

Ac-Nle-c[Asp-His-(NMe)DNal(2′)-(NMe)Arg-Trp-Lys]-

NH 2

 (SEQ ID NO: 51)

Ac-Nle-c[Asp-(NMe)His-DNal(2′)-(NMe)Arg-Trp-Lys]-

NH 2

 (SEQ ID NO: 52)

Ac-Nle-c[Asp-(NMe)His-(NMe)DNal(2′)-Arg-Trp-Lys]-

NH 2

 (SEQ ID NO: 53)

Ac-Nle-c[Asp-His-DNal(2′)-(NMe)Arg-(NMe)Trp-

(NMe)Lys]-NH 2

 (SEQ ID NO: 54)

Ac-Nle-c[Asp-His-(NMe)DNal(2′)-Arg-(NMe)Trp-

(NMe)Lys]-NH 2

 (SEQ ID NO: 55)

Ac-Nle-c[Asp-(NMe)His-DNal(2′)-Arg-(NMe)Trp-

(NMe)Lys]-NH 2

 (SEQ ID NO: 56)

Ac-Nle-c[Asp-His-(NMe)DNal(2′)-(NMe)Arg-Trp-

(NMe)Lys]-NH 2

 (SEQ ID NO: 57)

Ac-Nle-c[Asp-(NMe)His-DNal(2′)-(NMe)Arg-Trp-

(NMe)Lys]-NH 2

 (SEQ ID NO: 58)

Ac-Nle-c[Asp-(NMe)His-(NMe)DNal(2′)-Arg-Trp-

(NMe)Lys]-NH 2

 (SEQ ID NO: 59)

Ac-Nle-c[Asp-His-(NMe)DNal(2′)-(NMe)Arg-(NMe)Trp-

Lys]-NH 2

 (SEQ ID NO: 60)

Ac-Nle-c[Asp-(NMe)His-DNal(2′)-(NMe)Arg-(NMe)Trp-

Lys]-NH 2

 (SEQ ID NO: 61)

Ac-Nle-c[Asp-(NMe)His-(NMe)DNal(2′)-Arg-(NMe)Trp-

Lys]-NH 2

 (SEQ ID NO: 62)

Ac-Nle-c[Asp-(NMe)His-(NMe)DNal(2′)-(NMe)Arg-Trp-

Lys]-NH 2

 (SEQ ID NO: 63)

Ac-Nle-c[Asp-His-(NMe)DNal(2′)-(NMe)Arg-(NMe)Trp-

(NMe)Lys]-NH 2

 (SEQ ID NO: 64)

Ac-Nle-c[Asp-(NMe)His-DNal(2′)-(NMe)Arg-(NMe)Trp-

(NMe)Lys]-NH 2

 (SEQ ID NO: 65)

Ac-Nle-c[Asp-(NMe)His-(NMe)DNal(2′)-Arg-(NMe)Trp-

(NMe)Lys]-NH 2

 (SEQ ID NO: 66)

Ac-Nle-c[Asp-(NMe)His-(NMe)DNal(2′)-(NMe)Arg-Trp-

(NMe)Lys]-NH 2

 (SEQ ID NO: 67)

Ac-Nle-c[Asp-(NMe)His-(NMe)DNal(2′)-(NMe)Arg-

(NMe)Trp-Lys]-NH 2

 (SEQ ID NO: 68)

Ac-Nle-c[Asp-(NMe)His-(NMe)DNal(2′)-(NMe)Arg-

(NMe)Trp-(NMe)Lys]-NH 2 .

8. The composition of claim 1 , wherein the cleavable linker is a biodegradable linker.

9. The composition of claim 1 , wherein the cleavable linker comprises 1,2,3-triazole, an imine, a disulfide, a thioether, a primary amide, or a secondary amide.

10. The composition of claim 1 , wherein the drug moiety is a cancer drug.

11. The composition of claim 1 , wherein the drug moiety is a topoisomerase I inhibitor.

12. The composition of claim 1 , wherein the drug moiety is camptothecin.

13. The composition of claim 1 , wherein the drug moiety is a BRAF, MEK, PD-1, PD-L1, or CTLA-4 inhibitor.

14. The composition of claim 1 , wherein the drug moiety is Atezolizumab, Avelumab, Aldesleukin, Binimetinib, Braftovi, Carboplatin, Cemiplimab-rwlc, Cisplatin, Cobimetinib, Dabrafenib Mesylate, Dacarbazine, Diclofenac, Durvalumab, Encorafenib, 5-Fluorouracil, hyaluronic acid, Imiquimod, Imlygic, Ingenol mebutate, Interleukin-2, Ipilimumab, Nivolumab, Paclitaxel, Peginterferon Alfa-2b, Pembrolizumab, Recombinant Interferon Alfa-2b, Sonidegib, Talimogene Laherparepvec, Temozolomide, Trametinib, Vemurafenib, Vinblastine, Vismodegib, or combinations thereof.

15. A pharmaceutical composition comprising a ligand-drug conjugate, wherein the ligand-drug conjugate is according to the following:

wherein MT-II is Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH 2 (SEQ ID NO: 4).

16. A pharmaceutical composition comprising a ligand-drug conjugate comprising a peptide ligand bound to a drug moiety, wherein the ligand-drug conjugate is according to the formula: L-A-B-D, wherein L is the peptide ligand, A is a spacer, B is a cleavable linker, and D is the drug moiety, wherein the peptide ligand is according to the formula:

Ac-Nle-c[Asp-His-Taa-Arg-Trp-Lys]-NH 2 (SEQ ID NO: 89), or is a derivative that has at least 50% homology to SEQ ID NO: 89, wherein Taa is DPhe or DNal(2′), wherein the peptide ligand has at least one backbone residue that is N-methylated.

Assignments (2)
CONFIRMATORY LICENSE Recorded Jan 17, 2024
From: UNIVERSITY OF ARIZONA
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 066338/0963 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 20, 2022
From: CAI, MINYING; HRUBY, VICTOR J.; ZHOU, YANG
To: ARIZONA BOARD OF REGENTS ON BEHALF OF THE UNIVERSITY OF ARIZONA
Reel/Frame 059976/0665 →
Continuity (3)
Continuation In Part PCTUS2020042769 · Jul 20, 2020
Provisional Application 62876536 · Jul 19, 2019
Related Publication 20220143196A1 · May 12, 2022
References Cited (6)
US 20140112873A1 · Gillies · 2014 [cited by examiner]
US 20170014528A1 · Sengupta et al. · 2017 [cited by applicant]
WO 2012158960A1 · 2012 [cited by applicant]
WO 2016141151A1 · 2016 [cited by applicant]
WO 2021016182A1 · 2021 [cited by applicant]
Lin et al. “Camptothecin-Loaded Liposomes with alpha-Melanocyte-Stimulating Hormone Enhance Cytotoxicity Toward and Cellular Uptake by Melanomas: An Application of Nanomedicine on Natural Product.” Journal of Traditiona… [cited by applicant]