# US 11,993,641 B2 · Methods for modulating an immune response

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- Number: US 11,993,641 B2
- Document ID: US11993641B2
- Status: Granted
- Kind: B2
- Application number: 18/227,057
- Filed: 2023-07-27
- Published: 2023-11-23
- Granted: 2024-05-28
- Earliest claimed: 2017-03-15
- Assignees: Cue Biopharma, Inc.
- Applicants: Cue Biopharma, Inc.
- Inventors: Ronald D. Seidel, III; Rodolfo J. Chaparro
- Web page: https://patentgrep.com/patent/US11993641B2

## CPC

- A61K 38/1774: {Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)}
- C07K 14/70539: {MHC-molecules, e.g. HLA-molecules}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 38/2013: {IL-2}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 47/644: {Transferrin, e.g. a lactoferrin or ovotransferrin}
- A61K 47/68: the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07K 14/55: IL-2
- C07K 14/79: Transferrins, e.g. lactoferrins, ovotransferrins
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- C12N 15/62: DNA sequences coding for fusion proteins
- A61K 2039/505: {comprising antibodies}
- C07K 2317/524: CH2 domain
- C07K 2317/71: Decreased effector function due to an Fc-modification
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2319/00: Fusion polypeptide
- C12N 2770/36143: viral genome or elements thereof as genetic vector
- 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)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The present disclosure provides methods of modulating an immune response in an individual. The present disclosure provides methods of treatment. The present disclosure provides methods comprising administering a multimeric polypeptide (synTac) and an immune checkpoint inhibitor to an individual. The present disclosure provides methods comprising administering a multimeric polypeptide (synTac) to an individual who is undergoing treatment with immune checkpoint inhibitor.

## Claims

### Claim 1

A method of treating an individual having a cancer that expresses a human papilloma virus-16 (HPV16) E7 antigen, the method comprising administering to the individual a combination of (i) an effective amount of an immune checkpoint inhibitor that is an anti-PD-1 antibody, and (ii) an effective amount of a protein that is a homodimer of two multimeric polypeptides, wherein each multimeric polypeptide comprises:
a) a first polypeptide comprising:
i) a peptide comprising an HPV16 E7 epitope; and
ii) a β2-microglobulin (β2M) polypeptide; and
b) a second polypeptide comprising:
i) first and second variant IL-2 polypeptides, wherein the first and second variant IL-2 polypeptides each have the amino acid sequence set forth in SEQ ID NO:49;
ii) a major histocompatibility complex (MHC) class I heavy chain polypeptide; and
iii) an immunoglobulin (Ig) Fc polypeptide, and
wherein the two multimeric polypeptides are joined to each other by one or more disulfide bonds that join the Ig Fc polypeptide of one multimeric polypeptide to the Ig Fc polypeptide of the other multimeric polypeptide, and
wherein the immune checkpoint inhibitor and the protein are administered at the same time or at different times.

### Claim 2 (depends on 1)

A method of treating according to claim 1, wherein each multimeric polypeptide comprises a peptide linker interposed between one or more of:
a) the HPV16 E7 peptide and the β2M polypeptide;
b) a first copy of the variant IL-2 polypeptide and a second copy of the variant IL-2 polypeptide;
c) one of the two copies of the variant IL-2 polypeptide and the MHC class I heavy chain polypeptide; and
d) the MHC class I heavy chain polypeptide and the Ig Fc polypeptide.

### Claim 3 (depends on 1)

A method of treating according to claim 1,
wherein the HPV16 E7 peptide is from 7 to 16 amino acids in length,
wherein the β2M polypeptide has at least 95% sequence identity to amino acids 21 to 119 of SEQ ID NO:95,
wherein the MHC class I heavy chain polypeptide has at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO:50; and
wherein the Ig Fc polypeptide comprises an amino acid sequence having at least about 95% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:21.

### Claim 4 (depends on 3)

A method of treating according to claim 3,
wherein the β2M polypeptide has at least 98% sequence identity to amino acids 21 to 119 of the amino acid sequence set forth in SEQ ID NO:95, and
wherein the MHC class I heavy chain polypeptide has at least 98% sequence identity to the amino acid sequence set forth in SEQ ID NO:50.

### Claim 5 (depends on 4)

A method of treating according to claim 4,
wherein the Ig Fc polypeptide comprises an amino acid sequence having at least about 98% amino acid sequence identity to SEQ ID NO:47, and
wherein each multimeric polypeptide comprises a disulfide bond joining a Cys residue at amino acid 12 of the β2M polypeptide and a Cys residue at amino acid 236 of the MHC class I heavy chain polypeptide.

### Claim 6 (depends on 3)

A method of treating according to claim 3, wherein:
a) the first polypeptide of each multimeric polypeptide comprises, from N-terminus to C-terminus:
i) the HPV16 E7 peptide; and
ii) the β2M polypeptide; and
b) the second polypeptide of each multimeric polypeptide comprises, from N-terminus to C-terminus:
i) the first variant IL-2 polypeptide;
ii) the second variant IL-2 polypeptide;
iii) the MHC class I heavy chain polypeptide; and
iv) the Ig Fc polypeptide,
wherein each multimeric polypeptide can include one or more peptide linkers interposed between one or more components of the first and second polypeptides.

### Claim 7 (depends on 3)

A method of treating according to claim 3, wherein:
a) the first polypeptide of each multimeric polypeptide comprises, from N-terminus to C-terminus:
i) the HPV16 E7 peptide; and
ii) the β2M polypeptide; and
b) the second polypeptide of each multimeric polypeptide comprises, from N-terminus to C-terminus:
i) the MHC class I heavy chain polypeptide;
ii) the Ig Fc polypeptide;
iii) the first variant IL-2 polypeptide; and
iv) the second variant IL-2 polypeptide;
wherein each multimeric polypeptide can include one or more peptide linkers interposed between one or more components of the first and second polypeptides.

### Claim 8 (depends on 4)

A method of treating according to claim 4, wherein:
a) the first polypeptide of each multimeric polypeptide comprises, from N-terminus to C-terminus:
i) the HPV16 E7 peptide; and
ii) the β2M polypeptide; and
b) the second polypeptide of each multimeric polypeptide comprises, from N-terminus to C-terminus:
i) the first variant IL-2 polypeptide;
ii) the second variant IL-2 polypeptide;
iii) the MHC class I heavy chain polypeptide; and
iv) the Ig Fc polypeptide,
wherein each multimeric polypeptide can include one or more peptide linkers interposed between one or more components of the first and second polypeptides.

### Claim 9 (depends on 4)

A method of treating according to claim 4, wherein:
a) the first polypeptide of each multimeric polypeptide comprises, from N-terminus to C-terminus:
i) the HPV16 E7 peptide; and
ii) the β2M polypeptide; and
b) the second polypeptide of each multimeric polypeptide comprises, from N-terminus to C-terminus:
i) the MHC class I heavy chain polypeptide;
ii) the Ig Fc polypeptide;
iii) the first variant IL-2 polypeptide; and
iv) the second variant IL-2 polypeptide,
wherein each multimeric polypeptide can include one or more peptide linkers interposed between one or more components of the first and second polypeptides.

### Claim 10 (depends on 1)

A method according to claim 1, wherein the protein is administered in an amount of from 1 mg/kg to 5 mg/kg of body weight.

### Claim 11 (depends on 3)

A method according to claim 3, wherein the protein is administered in an amount of from 1 mg/kg to 5 mg/kg of body weight.

### Claim 12 (depends on 4)

A method according to claim 4, wherein the protein is administered in an amount of from 1 mg/kg to 5 mg/kg of body weight.

### Claim 13 (depends on 5)

A method according to claim 5, wherein the protein is administered in an amount of from 1 mg/kg to 5 mg/kg of body weight.

### Claim 14 (depends on 6)

A method according to claim 6, wherein the protein is administered in an amount of from 1 mg/kg to 5 mg/kg of body weight.

### Claim 15 (depends on 7)

A method according to claim 7, wherein the protein is administered in an amount of from 1 mg/kg to 5 mg/kg of body weight.

### Claim 16 (depends on 8)

A method according to claim 8, wherein the protein is administered in an amount of from 1 mg/kg to 5 mg/kg of body weight.

### Claim 17 (depends on 9)

A method according to claim 9, wherein the protein is administered in an amount of from 1 mg/kg to 5 mg/kg of body weight.

### Claim 18 (depends on 3)

A method according to claim 3, wherein the immune checkpoint inhibitor is nivolumab or pembrolizumab.

### Claim 19 (depends on 6)

A method of treating according to claim 6, wherein:
a) the first polypeptide of each multimeric polypeptide comprises, from N-terminus to C-terminus:
i) the HPV16 E7 peptide;
ii) an optional linker; and
iii) the β2M polypeptide; and
b) the second polypeptide of each multimeric polypeptide comprises, from N-terminus to C-terminus:
i) the first variant IL-2 polypeptide;
ii) an optional linker;
iii) the second variant IL-2 polypeptide;
iv) an optional linker;
v) the MHC class I heavy chain polypeptide;
vi) an optional linker; and
vii) the Ig Fc polypeptide.