# US 11,998,521 B2 · Use of an RXR agonist in treating drug resistant HER2+ cancers

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- Number: US 11,998,521 B2
- Document ID: US11998521B2
- Status: Granted
- Kind: B2
- Application number: 18/076,997
- Filed: 2022-12-07
- Published: 2023-06-08
- Granted: 2024-06-04
- Earliest claimed: 2021-12-07
- Assignees: Io Therapeutics, Inc.; Board of Regents, The University of Texas System
- Applicants: Io Therapeutics, Inc.; Board of Regents, The University of Texas System
- Inventors: Martin E. Sanders; Powel H. Brown; Cassandra Moyer; Abhijit Mazumdar
- Web page: https://patentgrep.com/patent/US11998521B2

## CPC

- A61K 31/216: of acids having aromatic rings, e.g. benactizyne, clofibrate
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 31/215: of carboxylic acids
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61P 35/00: Antineoplastic agents
- C07K 16/32: against translation products of oncogenes
- A61K 2039/505: {comprising antibodies}
- 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
- 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)

## Abstract

The present specification provides combinations of active agents for the improved treatment of Her2+ cancers and associated methods of treatments. The combinations comprise an RXR agonist and a Her2-targeted therapeutic agent and may optionally further comprise thyroid hormone.

## Claims

### Claim 1

A method of treating a patient with Her2+ cancer resistant to at least one Her2-targeted therapeutic agent, the method comprising administering a retinoid X receptor (RXR) agonist of Formula I
wherein R is H, or lower alkyl of 1 to 6 carbons, or a pharmaceutically-acceptable salt thereof, to the patient;
wherein the Her2+ cancer resistant to a Her2-targeted therapeutic agent is also resistant to the RXR agonist of Formula I; and
the patient has received or is receiving the Her2-targeted therapeutic agent.

### Claim 2 (depends on 1)

The method of claim 1, wherein the patient is receiving the Her2-targeted therapeutic agent.

### Claim 3 (depends on 1)

The method of claim 1, further comprising administering thyroid hormone in conjunction with the RXR agonist.

### Claim 4 (depends on 1)

The method of claim 1, wherein the RXR agonist is a compound of Formula II

### Claim 5 (depends on 1)

The method of claim 1, wherein the Her2-targeted therapeutic agent comprises an anti-Her2 therapeutic antibody.

### Claim 6 (depends on 5)

The method of claim 5, wherein the therapeutic antibody is trastuzumab or pertuzumab.

### Claim 7 (depends on 1)

The method of claim 1, wherein the Her2-targeted therapeutic agent comprises an antibody-drug conjugate wherein the antibody is an anti-Her2 antibody.

### Claim 8 (depends on 1)

The method of claim 1, wherein the Her2-targeted therapeutic agent comprises a Her2 kinase inhibitor.

### Claim 9 (depends on 8)

The method of claim 8, wherein the Her2 kinase inhibitor is lapatinib, neratinib or tucatinib.

### Claim 10 (depends on 8)

The method of claim 8, wherein the Her2 kinase inhibitor comprises afatinib, dacomitinib, canertinib, sapitinib, CP-724714, or CUDC-101.

### Claim 11 (depends on 1)

The method of claim 1, wherein the Her2+ cancer is Her2+ breast cancer.

### Claim 12 (depends on 1)

The method of claim 1, wherein tumor cell growth is inhibited by a combination of the Her2-targeted therapeutic and the RXR agonist, and the inhibition of tumor cell growth by the combination is greater than additive inhibitory effects of each of the Her2-targeted therapeutic and the RXR agonist alone.

### Claim 13

A method of treating a patient with Her2+ cancer undergoing treatment with a Her2-targeted therapeutic agent, wherein the cancer has become resistant to the Her2-targeted therapeutic agent, the method comprising continuing treatment with the Her2-targeted therapeutic agent and initiating treatment with an RXR agonist of Formula I,
wherein R is H, or lower alkyl of 1 to 6 carbons, or a pharmaceutically-acceptable salt thereof; and
wherein the Her2+ cancer resistant to a Her2-targeted therapeutic agent is also resistant to the RXR agonist of Formula I.

### Claim 14 (depends on 13)

The method of claim 13, further comprising administering thyroid hormone in conjunction with the RXR agonist.

### Claim 15 (depends on 13)

The method of claim 13, wherein the RXR agonist is a compound of Formula II

### Claim 16 (depends on 13)

The method of claim 13, wherein the Her2-targeted therapeutic agent comprises an anti-Her2 therapeutic antibody.

### Claim 17 (depends on 16)

The method of claim 16, wherein the therapeutic antibody is trastuzumab or pertuzumab.

### Claim 18 (depends on 13)

The method of claim 13, wherein the Her2-targeted therapeutic agent comprises an antibody-drug conjugate wherein the antibody is an anti-Her2 antibody.

### Claim 19 (depends on 13)

The method of claim 13, wherein the Her2-targeted therapeutic agent comprises a Her2 kinase inhibitor.

### Claim 20 (depends on 19)

The method of claim 19, wherein the Her2 kinase inhibitor is lapatinib, neratinib or tucatinib.

### Claim 21 (depends on 19)

The method of claim 19, wherein the Her2 kinase inhibitor comprises afatinib, dacomitinib, canertinib, sapitinib, CP-724714, or CUDC-101.

### Claim 22 (depends on 13)

The method of claim 13, wherein the Her2+ cancer is Her2+ breast cancer.

### Claim 23 (depends on 13)

The method of claim 13, wherein tumor cell growth is inhibited by a combination of the Her2-targeted therapeutic and the RXR agonist, and the inhibition of tumor cell growth by the combination is greater than additive inhibitory effects of each of the Her2-targeted therapeutic and the RXR agonist alone.