A delta-opioid receptor targeted agent for molecular imaging and immunotherapy of cancer

Patent metadata

Field	Value
Publication number	US-2024181095-A1
Application number	US-202218548724-A
Country	US
Kind code	A1
Filing date	Mar 1, 2022
Priority date	Mar 1, 2021
Publication date	Jun 6, 2024
Grant date	—

Abstract

This invention provides a molecular conjugate of anticancer compounds and imaging agents, generally as a cancer therapy comprising an antagonist of a cell surface opioid receptor such as a delta opioid receptor, specific to a target cell, an imaging agent, and an immune modulatory molecule, such as a T cell modulator, conjugated to the opioid receptor antagonist. The target cell can be a cell responsible for development of a disease in a subject, for example, a cancer cell. In certain embodiments, the immune modulatory molecule is an immune effector antibody. A method of treating a disease is provided comprising administering to a patient a therapeutically effective amount of the compounds or compositions of this invention to the patient. The disease may be treating cancer.

First claim

1 . A composition comprising at least one delta-opioid receptor targeting ligand and an immunomodulatory molecule, wherein said delta-opioid receptor targeting ligand is a fluorescent moiety tagged delta-opioid receptor antagonist or a rare earth compound labeled delta-opioid receptor antagonist, and wherein said delta-opioid receptor targeting ligand is covalently conjugated to said immunomodulatory molecule.

2 . The composition of claim 1 wherein said delta-opioid receptor antagonist is naltrindole or an analog of naltrindole.

3 . The composition of claim 1 wherein said rare earth compound is a compound of a lanthanide series of Group IIIB of the Periodic Table.

4 . The composition of claim 3 wherein said rare earth compound is selected from the group consisting of lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, and lutetium.

5 . The composition of claim 1 wherein a dodecane tetraacetic acid (DOTA) is conjugated with said rare earth compound.

6 . The composition of claim 5 wherein said delta-opioid receptor targeting ligand is naltrindole-DOTA-rare earth compound.

7 . The composition of claim 6 that is naltrindole-DOTA-rare earth compound-anti-PD1.

8 . The composition of claim 1 wherein said immunomodulatory molecule is selected from the group consisting of an antibody or a fragment of an antibody that specifically acts as an adaptive immune effector.

9 . The composition of claim 8 wherein said antibody is selected from the group of (i) PD-1 antibody of a human, a rabbit, or a murine PD-1, (ii) an antibody that is specific for programed cell death protein 1 (anti-PD1), and (iii) one or more of a CD28, a CD137, an OX40, and a CD40 agonistic antibodies.

10 . The composition of claim 8 wherein said immunomodulatory molecule is an anti-PD1 checkpoint inhibitor antibody.

11 . The composition of claim 2 wherein said delta-opioid receptor targeting ligand is a fluorescent moiety tagged naltrindole conjugated to an anti-PD1 antibody.

12 . The composition of claim 1 wherein said immunomodulatory molecule targets extracellular juxtacrine receptors.

13 . The composition of claim 2 wherein said immunomodulatory molecule is scFv anti-TGIT, anti-TGFb, or a TFGb signal inhibitor.

14 . (canceled)

15 . A compound of Formula I:

wherein
X is a delta opioid receptor targeting ligand;
Z is a linker fragment;
and Ab is an antibody; and
wherein said linker fragment Z is a single atom or is selected from the group consisting of a substituted carbon, an oxygen, a substituted or an unsubstituted sulphur, a substituted nitrogen, a substituted phosphorous, a substituted or an unsubstituted alkyl, a substituted or an unsubstituted alkylene, a substituted alkenyl, a substituted alkynyl chain, a substituted or an unsubstituted alkyne chain, a substituted or an unsubstituted alkoxyl chain, an ether, an amine, an amide, a sulfonamide, an alkylamine, a thioether, a carboxylate, a polyethylene, a polypropylene, and a derivative or a combination thereof.

16 . The compound of claim 15 wherein the ratio of X to Ab is about 4 to 1.

17 . The compound of claim 15 wherein the Ab moiety is an antibody or fragment thereof that specifically acts as an adaptive immune effector, wherein said antibody is one selected from the group of (i) a PD-1 antibody of a human, a rabbit, or a murine PD-1, (ii) an antibody that is specific for programed cell death protein 1 (anti-PD1), and (iii) one or more of a CD28, a CD137, an OX40, and a CD40 agonistic antibody.

18 . The compound of claim 15 wherein said X is (X),, wherein n is 4, 9 or 12.

19 . A compound of Formula II:

wherein
Y is a delta opioid receptor targeting ligand;
Z is a linker fragment;
M is any metal of the lanthanide series of the Periodic Table;
Ab is an antibody; and
wherein aid linker fragment Z is a single atom or is selected form the group consisting a substituted carbon, an oxygen, a substituted or an unsubstituted sulphur, a substituted nitrogen, a substituted phosphorous, a substituted or an unsubstituted alkyl, a substituted alkenyl, a substituted alkynyl chain, a substituted or an unsubstituted alkylene, a substituted or an unsubstituted alkyne chain, a substituted or an unsubstituted alkoxyl chain, an ether, an amine, an amide, a sulfonamide, an alkylamine, a thioether, a carboxylate, a polyethylene, a polypropylene, and a derivative or a combination thereof.

20 . The compound of claim 19 wherein the ratio of Y to Ab is approximately 4 to 1.

21 . The compound of claim 19 wherein said Y is (Y) n wherein said n is 4, 9, or 12.

22 . The compound of claim 19 wherein the Ab moiety is an antibody or fragment thereof that specifically acts as an immune effector, wherein said antibody is one selected from the group of (i) a PD-1 antibody of a human, a rabbit, or a murine PD-1, (ii) an antibody that is specific for programed cell death protein 1 (anti-PD1), and (iii) one or more of a CD28, a CD137, an OX40, and a CD40 agonistic antibody.

23 . A compound of Formula III:

wherein
Z is a linker fragment, wherein said linker fragment Z is a single atom or is selected from the group consisting of a substituted carbon, an oxygen, a substituted or an unsubstituted sulphur, a substituted nitrogen, a substituted phosphorous, a substituted or an unsubstituted alkyl, a substituted or an unsubstituted alkylene, a substituted or an unsubstituted alkyne chain, a substituted or an unsubstituted alkoxyl chain, a substituted alkenyl, a substituted alkynyl chain, an ether, an amine, an amide, a sulfonamide, an alkylamine, a thioether, a carboxylate, a polyethylene, a polypropylene, and a derivative or a combination thereof.

24 . A compound of Formula IV:

wherein
Z is a linker fragment;
M is any metal of the lanthanide series; and
wherein said linker fragment Z is a single atom or is selected from the group consisting of a substituted carbon, an oxygen, a substituted or an unsubstituted sulphur, a substituted nitrogen, a substituted phosphorous, a substituted or an unsubstituted alkyl, a substituted or an unsubstituted alkylene, a substituted or an unsubstituted alkyne chain, a substituted or an unsubstituted alkoxyl chain, a substituted alkenyl, a substituted alkynyl chain, an ether, an amine, an amide, a sulfonamide, an alkylamine, a thioether, a carboxylate, a polyethylene, a polypropylene, and a derivative or a combination thereof.

25 . The compound of claim 15 wherein Ab is specific for programed cell death protein 1 (anti-PD1).

26 . The compound of claim 19 wherein Ab is specific for programmed cell death protein 1 (anti-PD1).

27 . The compound of claim 15 wherein Ab is a PD-L1 antagonist, or a CD137, an OX40, or a CD40 agonist antibody.

28 . The compound

Assignees

• West Virginia Univ Board Of Governors On Behalf Of West Virginia Univ

Inventors

• Garcia Jose Gabriel
• Mclaughlin Mark

Classifications

• A61K51/1093 Primary

  conjugates with carriers being antibodies · CPC title

• A61K47/6803

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title

• C07K16/2818 Primary

  against CD28 or CD152 · CPC title

• A61K47/68037

  the drug being a camptothecin [CPT] or derivatives · CPC title

• A61K31/485

  Morphinan derivatives, e.g. morphine, codeine · CPC title