# US 12,109,266 B2 · Modulating gabarap to modulate immunogenic cell death

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- Number: US 12,109,266 B2
- Document ID: US12109266B2
- Status: Granted
- Kind: B2
- Application number: 17/518,272
- Filed: 2021-11-03
- Published: 2022-07-07
- Granted: 2024-10-08
- Earliest claimed: 2020-11-13
- Assignees: Dana-Farber Cancer Institute, Inc.
- Applicants: Dana-Farber Cancer Institute, Inc.
- Inventors: Kenneth C. Anderson; Annamaria Gullà
- Web page: https://patentgrep.com/patent/US12109266B2

## CPC

- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 31/136: having the amino group directly attached to the aromatic ring, e.g. benzeneamine
- A61K 31/555: containing heavy metals, e.g. hemin, hematin, melarsoprol
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 38/05: Dipeptides
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/04: specific for metastasis
- C07K 14/4705: {stimulating, promoting or activating activity}
- C07K 14/4725: {Proteoglycans, e.g. aggreccan}
- C07K 14/575: Hormones (derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695)
- C07K 14/705: Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)}
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/2866: {against receptors for cytokines, lymphokines, interferons}
- C12N 5/0639: {Dendritic cells, e.g. Langherhans cells in the epidermis}
- C12N 5/0694: {Cells of blood, e.g. leukemia cells, myeloma cells}
- G01N 33/575: for cancer
- A61K 35/13: Tumour cells, irrespective of tissue of origin (tumour vaccines A61K39/00)
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61K 2039/505: {comprising antibodies}
- A61K 2039/572: {cytotoxic response}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C12N 2501/22: Colony stimulating factors (G-CSF, GM-CSF)
- C12N 2502/1114: T cells
- C12N 2502/1121: Dendritic cells
- C12N 2506/115: from monocytes, from macrophages
- C12N 2510/00: Genetically modified cells
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present invention relates, in part, to methods of inducing immunogenic cell death to treat a cancer in a subject comprising administering to the subject a therapeutically effective amount of an agent that increases one or more biomarkers listed in Table 1 in combination with an inducer of immunogenic cell death (ICD).

## Claims

### Claim 1

A method of identifying a compound that induces immunogenic cell death (ICD) of a multiple myeloma cancer cell comprising an increase in an amount of STC1, wherein the STC1 comprises an amino acid sequence of SEQ ID NOs: 14, 16, or 18, the method comprising:
a) contacting the multiple myeloma cancer cell comprising an increase in the amount of STC1, relative to the amount of STC1 in a non-cancerous cell, with (i) a test compound and (ii) an inducer of ICD; and
b) determining the level of calreticulin trapped in the mitochondria of the multiple myeloma cancer cell, wherein the decrease in the level of calreticulin trapped in the mitochondria of the multiple myeloma cancer cell in the presence of the test compound as compared to the level of calreticulin trapped in the mitochondria of the multiple myeloma cancer cell in the absence of the test compound indicates that the test compound induces ICD of the multiple myeloma cancer cell comprising the increase in the amount of STC1.

### Claim 2 (depends on 1)

The method of claim 1, wherein the multiple myeloma cancer cell is from a relapsed cancer.

### Claim 3 (depends on 1)

The method of claim 1, wherein the inducer of ICD is selected from the group consisting of chemotherapeutic agents, radiation therapy, and proteasome inhibitors.

### Claim 4 (depends on 3)

The method of claim 3, wherein the chemotherapeutic agent is selected from the group consisting of oxazophorines, platinum-based compounds, anthracyclines, and anthracenediones.

### Claim 5 (depends on 1)

The method of claim 1, wherein the inducer of ICD is selected from the group consisting of bortezomib, carfilzomib, cyclophosphamide, idarubicin, doxorubicin, mitoxantrone, epirubicin, and oxaliplatin.

### Claim 6

A method of identifying a compound that induces immunogenic cell death (ICD) of a multiple myeloma cancer cell comprising an increase in an amount of a nucleic acid encoding STC1, wherein the STC1 comprises an amino acid sequence of SEQ ID NOs: 14, 16, or 18, the method comprising:
a) contacting the multiple myeloma cancer cell comprising an increase in the amount of the nucleic acid encoding STC1, relative to the amount of nucleic acid encoding STC1 in a non-cancerous cell, with (i) a test compound and (ii) an inducer of ICD; and
b) determining the level of calreticulin trapped in the mitochondria of the multiple myeloma cancer cell, wherein the decrease in the level of calreticulin trapped in the mitochondria of the multiple myeloma cancer cell in the presence of the test compound as compared to the level of calreticulin trapped in the mitochondria of the multiple myeloma cancer cell in the absence of the test compound indicates that the test compound induces ICD of the multiple myeloma cancer cell comprising the increase in the amount of nucleic acid encoding STC1.

### Claim 7 (depends on 6)

The method of claim 6, wherein the multiple myeloma cancer cell is from a relapsed cancer.

### Claim 8 (depends on 6)

The method of claim 6, wherein the inducer of ICD is selected from the group consisting of chemotherapeutic agents, radiation therapy, and proteasome inhibitors.

### Claim 9 (depends on 8)

The method of claim 8, wherein the chemotherapeutic agent is selected from the group consisting of oxazophorines, platinum-based compounds, anthracyclines, and anthracenediones.

### Claim 10 (depends on 6)

The method of claim 6, wherein the inducer of ICD is selected from the group consisting of bortezomib, carfilzomib, cyclophosphamide, idarubicin, doxorubicin, mitoxantrone, epirubicin, and oxaliplatin.