# US 11,433,040 B2 · Methods for modifying endoplasmic reticulum processing of protein

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- Number: US 11,433,040 B2
- Document ID: US11433040B2
- Status: Granted
- Kind: B2
- Application number: 16/614,770
- Filed: 2018-05-18
- Published: 2020-06-11
- Granted: 2022-09-06
- Earliest claimed: 2017-05-19
- Assignees: Memorial Sloan Kettering Cancer Center
- Applicants: Memorial Sloan Kettering Cancer Center
- Inventors: Jonathan Goldberg; Elena Goldberg; Wenfu Ma
- Web page: https://patentgrep.com/patent/US11433040B2

## CPC

- A61K 31/192: having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid {(cannabinoids A61K31/658)}
- A61K 31/165: having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
- A61K 31/18: Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63)
- A61K 31/185: Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids (hydroxamic acids A61K31/16; peroxy acids A61K31/327)
- A61K 31/222: with compounds having aromatic groups, e.g. dipivefrine, ibopamine
- A61P 35/00: Antineoplastic agents
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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

The present disclosure provides compositions and methods for modifying endoplasmic reticulum trafficking of proteins. Also disclosed herein are methods for treating cancer and/or enhancing cancer or viral immunotherapy in a subject by increasing the extracellular secretion levels of GRP94 in the subject. Such methods comprise administering to the subject an effective amount of 4-PBA and/or a 4-PBA analog selected from among methoxy-PBA, 3-PPA, 5-PVA, hydroxy-PPA, hydroxy-PBA, and tolyl-BA.

## Claims

### Claim 1

A method for enhancing responsiveness of a subject infected with a virus to viral immunotherapy comprising administering to the subject 4-phenylbutyrate (4-PBA), 4-(4-methoxyphenyl)butyrate (methoxy-PBA), 3-phenylpropionate (3-PPA), 5-phenylvalerate (5-PVA), 3-(4-hydroxyphenyl)propionate (hydroxy-PPA), 4-(4-hydroxyphenyl) butyrate (hydroxy-PBA), 4-(4-tolyl) butyrate (tolyl-BA), or a compound of Formula I:
wherein R1 is H, C1-C3 alkyl, C1-C3 alkoxy, hydroxyl, thiol, C1-C3 alkylthio, —S(O)R2, —S(O)2R3, or —S(O)2OR4; R2, R3, and R4 are independently C1-C3 alkyl; and n is 2, 3, or 4, in an amount that is effective to elevate secretion of GRP94/viral antigen complexes in the subject compared to that in the subject prior to administration; and
one or more immune checkpoint inhibitors selected from the group consisting of ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, pidilizumab, AMP-224, MDX-1105, arelumab, tremelimumab, IMP321, MGA271, BMS-986016, lirilumab, urelumab, PF-05082566, IPH2101, MEDI-6469, CP-870,893, Mogamulizumab, Varlilumab, Galiximab, AMP-514, and AUNP 12.

### Claim 2 (depends on 1)

The method of claim 1, wherein the virus is selected from the group consisting of human immunodeficiency virus (HIV), herpes simplex virus (HSV), influenza virus, EBV, Ebola virus, chicken pox virus, Hepatitis B virus, Hepatitis C virus, HPV, rubeola virus, rubulavirus, rubella virus, poliovirus, Rous Sarcoma Virus, rabies virus, and rotavirus.

### Claim 3 (depends on 1)

The method of claim 1, comprising separately, sequentially or simultaneously administering one or more immune system stimulators selected from the group consisting of IL-2, IL-15, IL-15/IL-15RA complex, IL-18, IL-12, CD28, inducible costimulatory (ICOS), CD40, CD30, CD27, OX-40, 4-1BB, and a granulocyte macrophage colony-stimulating factor (GM-CSF).

### Claim 4 (depends on 1)

The method of claim 1, further comprising administering an effective amount of an adjuvant.

### Claim 5 (depends on 1)

The method of claim 1, wherein 4-PBA, methoxy-PBA, 3-PPA, 5-PVA, hydroxy-PPA, hydroxy-PBA, tolyl-BA, or the compound of Formula I is administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, iontophoretically, transmucosally, or intramuscularly.