# US 11,440,963 B2 · Combination PDL1 and TGF-beta blockade in patients with HPV+ malignancies

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- Number: US 11,440,963 B2
- Document ID: US11440963B2
- Status: Granted
- Kind: B2
- Application number: 16/612,495
- Filed: 2018-05-08
- Published: 2020-02-27
- Granted: 2022-09-13
- Earliest claimed: 2017-05-09
- Assignees: The United States of America, as represented by the Secretary, Department of Health and Human Services
- Applicants: The United States of America, as represented by the Secretary, Department of Health and Human Services
- Inventors: Julius Y. Strauss; James L. Gulley; Christian S. Hinrichs
- Web page: https://patentgrep.com/patent/US11440963B2

## CPC

- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- C07K 14/71: for growth factors; for growth regulators
- C07K 16/22: against growth factors {; against growth regulators}
- C12N 15/62: DNA sequences coding for fusion proteins
- C12N 15/86: Viral vectors
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- C07K 2317/31: multispecific
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- C07K 2319/32: fusions with soluble part of a cell surface receptor, "decoy receptors"
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The invention provides a method of inhibiting a malignancy associated with human papilloma virus (HPV) comprising administering to a subject an agent that blocks PD-L1 and TGF-beta pathways, thereby inhibiting a malignancy associated with HPV in the subject.

## Claims

### Claim 1

A method of inhibiting a malignancy associated with human papilloma virus (HPV) comprising administering to a subject an agent or combination of agents that blocks PD-L1 and TGF-beta pathways, thereby inhibiting a malignancy associated with HPV in the subject.

### Claim 2 (depends on 1)

The method of claim 1, wherein the agent blocks PD-1 and sequesters TGF-beta.

### Claim 3 (depends on 1)

The method of claim 1, wherein the agent is a fusion protein.

### Claim 4 (depends on 3)

The method of claim 3, wherein the fusion protein comprises (i) a PD1 inhibitor and (ii) a TGF-beta inhibitor.

### Claim 5 (depends on 4)

The method of claim 4, wherein the PD1 inhibitor is an antibody or antibody fragment.

### Claim 6 (depends on 5)

The method of claim 5, wherein the antibody or antibody fragment is a human PD-L1 antibody.

### Claim 7 (depends on 5)

The method of claim 5, wherein the antibody or antibody fragment is an IgG1 monoclonal antibody against human PD-L1.

### Claim 8 (depends on 7)

The method of claim 7, wherein the antibody or antibody fragment is avelumab.

### Claim 9 (depends on 5)

The method of claim 5, wherein the TGF-beta inhibitor is fused to the Fc region of the antibody or antibody fragment.

### Claim 10 (depends on 4)

The method of claim 4, wherein TGF-beta inhibitor is an extracellular domain of human TGF-betaRII.

### Claim 11 (depends on 10)

The method of claim 10, wherein the extracellular domain of human TGF-betaRII is a soluble extracellular domain of TGF-betaRII.

### Claim 12 (depends on 3)

The method of claim 3, wherein the fusion protein is administered as a nucleic acid encoding the fusion protein.

### Claim 13 (depends on 12)

The method of claim 12, wherein the nucleic acid encoding the fusion protein is in a vector.

### Claim 14 (depends on 13)

The method claim 13, wherein the vector is a plasmid or viral vector.

### Claim 15 (depends on 14)

The method of claim 14, wherein the vector is a viral vector selected from the group consisting of poxvirus, retrovirus, adenovirus, adeno-associated virus, herpes virus, polio virus, alphavirus, baculorvirus, and Sindbis virus.

### Claim 16 (depends on 15)

The method of claim 15, wherein the viral vector is a poxvirus selected from the group consisting of orthopox, avipox, fowlpox, raccoon pox, rabbit pox, capripox, leporipox, and suipox.

### Claim 17 (depends on 1)

The method of claim 1, wherein the agent is M7824 (MSB0011359C).

### Claim 18 (depends on 1)

The method of claim 1, wherein the agent is administered in a composition comprising the agent and a pharmaceutically acceptable carrier.

### Claim 19 (depends on 18)

The method of claim 18, wherein the composition further comprises one or more additional active agents.

### Claim 20 (depends on 19)

The method of claim 19, wherein the one or more additional active agents are selected from the group consisting of anticancer agents, antibiotics, antiviral drugs, antifungal drugs, cyclophosphamide, anti-inflammatory agents, immunotherapy, and combinations thereof.

### Claim 21 (depends on 1)

The method of claim 1, wherein the subject is a human subject.

### Claim 22 (depends on 1)

The method of claim 1, wherein the malignancy associated with HPV is selected from the group consisting of cervical cancer, oropharyngeal cancers, rectal cancer, anal cancer, vaginal cancer, vulvar cancer, penile cancer, and HPV-positive cancer.