# US 2024/0189441 A1 · A delta-opioid receptor targeted agent for molecular imaging and immunotherapy of cancer

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- Number: US 2024/0189441 A1
- Document ID: US20240189441A1
- Status: Published application
- Kind: A1
- Application number: 18/548,729
- Filed: 2022-03-01
- Published: 2024-06-13
- Earliest claimed: 2021-03-01
- Assignees: West Virginia University Board of Governors on behalf of West Virginia University; Tuhura Biopharma Inc.
- Applicants: West Virginia University Board of Governors On Behalf of West Virginia University; Tuhura Biopharma Inc.
- Inventors: Jose Gabriel GARCIA; Mark MCLAUGHLIN; James A. BIANCO
- Web page: https://patentgrep.com/patent/US20240189441A1

## CPC

- C07K 16/2818: {against CD28 or CD152}
- A61K 47/6803: {Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 49/0032: {Methine dyes, e.g. cyanine dyes}
- A61K 49/0052: {Small organic molecules (oligomers, polymers, dendrimers A61K49/0054)}
- A61K 49/0058: {Antibodies}
- A61K 51/0455: {having six-membered rings with one nitrogen as the only ring hetero atom}
- A61K 51/0497: {conjugates with a carrier being an organic compounds}
- A61K 51/1027: {against receptors, cell-surface antigens or cell-surface determinants}
- A61K 51/1093: {conjugates with carriers being antibodies}
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

A composition comprising at least one kinase inhibitor or JAK/STAT3 inhibitor and an immunomodulatory molecule, wherein said kinase inhibitor or JAK/STAT3 inhibitor comprises a fluorescent moiety tagged kinase inhibitor or JAK/STAT3 inhibitor or a rare earth compound labeled kinase inhibitor or JAK/STAT3 inhibitor, and wherein said kinase inhibitor or JAK/STAT3 inhibitor is covalently conjugated to said immunomodulatory molecule.

### Claim 2

(canceled)

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 3)

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.

### Claim at position 5

5-7. (canceled)

### Claim 8 (depends on 1)

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.

### Claim 9 (depends on 8)

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.

### Claim 10 (depends on 8)

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

### Claim 11

(canceled)

### Claim 12 (depends on 1)

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

### Claim 13 (depends on 2)

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

### Claim 14

(canceled)

### Claim 15

A compound of Formula I:
wherein
X is a kinase inhibitor or JAK/STAT3 inhibitor;
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.

### Claim 16 (depends on 15)

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

### Claim 17 (depends on 15)

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.

### Claim 18 (depends on 15)

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

### Claim 19

A compound of Formula II:
wherein
Y is a kinase inhibitor or JAK/STAT3 inhibitor;
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.

### Claim 20 (depends on 19)

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

### Claim 21 (depends on 19)

The compound of claim 19 wherein said Y is (Y) 11 wherein said n is 4, 9, or 12.

### Claim 22 (depends on 19)

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.

### Claim at position 21

23-24. (canceled)

### Claim 25 (depends on 15)

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

### Claim 26 (depends on 19)

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

### Claim 27 (depends on 15)

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

### Claim 28 (depends on 19)

The compound of claim 19 wherein Ab is a PD-L1 antagonist, or a CD137, an OX40, or a CD40 agonist antibody.

### Claim 29 (depends on 15)

The compound of claim 15 wherein the compound has the Formula I wherein Ab is an antibody and X is (X)n wherein n is an integer of from 1 to 50.

### Claim 30 (depends on 19)

The compound of claim 19 wherein the compound has the Formula II wherein Ab is an antibody and Y is (Y)n wherein n is an integer of from 1 to 50.

### Claim 31

An antibody conjugated to one or more moieties of X:
wherein
X is a kinase inhibitor or JAK/STAT3 inhibitor;
Z is a linker fragment;
Ab is an antibody;
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; and
X is (X)n wherein n is an integer of from 1 to 50.

### Claim 32 (depends on 31)

The antibody of claim 31 that is specific for programed cell death protein 1 (anti-PD1).

### Claim 33

An antibody conjugated to one or more moieties of Y:
wherein
Y is a kinase inhibitor or JAK/STAT3 inhibitor;
Z is a linker fragment;
M is any metal of the lanthanide series of the Periodic Table;
wherein said 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;
Y is (Y)n wherein n is an integer of from 1 to 50; and
Ab is an antibody.

### Claim 34 (depends on 33)

The antibody of claim 33 that is specific for programed cell death protein 1 (anti-PD1).

### Claim 35 (depends on 31)

The antibody of claim 31 wherein the antibody is specific for a programed cell death protein 1 (PD1), a PD-L1 antagonist, or a CD137, an OX40, or a CD40 agonist antibody.

### Claim 36 (depends on 33)

The antibody of claim 33 wherein the antibody is specific for programed cell death protein 1 (PD!), a PD-L1 antagonist, or a CD137, an OX40, or a CD40 agonist antibody.

### Claim 37 (depends on 1)

A method of treating cancer in a patient comprising administering to a patient a therapeutically effective amount of a composition of claim 1.

### Claim 38 (depends on 37)

The method of claim 37 wherein said cancer is colon cancer.

### Claim 39 (depends on 37)

The method of claim 37 wherein said cancer is lung cancer.

### Claim 40 (depends on 18)

The method of claim 18, wherein the cancer is liver cancer.

### Claim 41 (depends on 39)

The method of claim 39 wherein said lung cancer is small cell lung cancer and non-small cell lung cancer.

### Claim 42 (depends on 1)

A method of decreasing peritoneal metastasis formation in a patient comprising: administering to a patient a therapeutically effective amount of a compound of claim 1.

### Claim 43 (depends on 42)

The method of claim 42 wherein said metastasis is distal metastasis.

### Claim 44

(canceled)