# US 11,078,282 B2 · CD80 variant immunomodulatory proteins and uses thereof

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- Number: US 11,078,282 B2
- Document ID: US11078282B2
- Status: Granted
- Kind: B2
- Application number: 16/088,802
- Filed: 2017-04-14
- Published: 2019-05-09
- Granted: 2021-08-03
- Earliest claimed: 2016-04-15
- Assignees: Alpine Immune Sciences, Inc.
- Applicants: Alpine Immune Sciences, Inc.
- Inventors: Ryan Swanson; Michael Kornacker
- Web page: https://patentgrep.com/patent/US11078282B2

## CPC

- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- A61K 35/768: Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 40/31: Chimeric antigen receptors [CAR]
- A61K 40/421: {Immunoglobulin superfamily}
- A61K 40/4211: {CD19 or B4}
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61K 47/65: Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
- A61K 47/68: the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/02: Immunomodulators
- A61P 37/04: Immunostimulants
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07K 14/70503: {Immunoglobulin superfamily}
- C07K 14/70521: {CD28, CD152}
- C07K 14/70532: {B7 molecules, e.g. CD80, CD86}
- C07K 14/70596: {Molecules with a "CD"-designation not provided for elsewhere}
- C12N 5/0636: {T lymphocytes}
- C12N 15/62: DNA sequences coding for fusion proteins
- C12N 15/85: for animal cells
- A61K 38/1774: {Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)}
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- C07K 2319/00: Fusion polypeptide
- C07K 2319/03: containing a transmembrane segment
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- 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)

## Abstract

Provided herein are variant CD80 polypeptides, immunomodulatory proteins comprising variant CD80 polypeptides, and nucleic acids encoding such proteins. The immunomodulatory proteins provide therapeutic utility for a variety of immunological and oncological conditions. Compositions and methods for making and using such proteins are provided.

## Claims

### Claim 1

A purified CD80-Fc immunomodulatory protein consisting of a variant CD80 polypeptide, an Fc domain and a linker, wherein the variant CD80 polypeptide is linked to the Fc domain via the linker, and wherein:
the variant CD80 polypeptide comprises a sequence of amino acids that exhibits at least 90% sequence identity to an unmodified CD80 polypeptide set forth in SEQ ID NO: 28, or a portion of SEQ ID NO:28 comprising an IgV domain, wherein the IgV domain is amino acids 35-135, 35-138, 37-138 or 35-141 of SEQ ID NO:1; and
the variant CD80 polypeptide comprises the amino acid substitution V68M.

### Claim 2 (depends on 1)

The purified CD80-Fc immunomodulatory protein of claim 1, wherein the variant CD80 polypeptide comprises up to 10 amino acid substitutions.

### Claim 3 (depends on 1)

The purified CD80-Fc immunomodulatory protein of claim 1, wherein the variant CD80 polypeptide binds non-competitively to the ectodomain of CD28 and PD L1.

### Claim 4 (depends on 1)

The purified CD80-Fc immunomodulatory protein of claim 1, wherein the variant CD80 polypeptide specifically binds to the ectodomain of human PD-L1 with increased binding affinity compared to the binding of the unmodified CD80 polypeptide to the ectodomain of human PD-L1.

### Claim 5 (depends on 4)

The purified CD80-Fc immunomodulatory protein of claim 4, wherein the increased binding affinity to the ectodomain is increased more than 1.2-fold compared to the binding affinity of the unmodified CD80 polypeptide for the ectodomain.

### Claim 6 (depends on 1)

A pharmaceutical composition, comprising the purified CD80-Fc immunomodulatory protein of claim 1, wherein the pharmaceutical composition comprises a pharmaceutically acceptable excipient.

### Claim 7 (depends on 1)

The purified CD80-Fc immunomodulatory protein of claim 1, wherein the variant CD80 polypeptide comprises a sequence of amino acids that exhibits at least 90% sequence identity to amino acids 35-141 of SEQ ID NO: 1.

### Claim 8 (depends on 1)

The purified CD80-Fc immunomodulatory protein of claim 1 that is a homodimer.

### Claim 9 (depends on 8)

A pharmaceutical composition, comprising the purified CD80-Fc immunomodulatory homodimer of claim 8 and a pharmaceutically acceptable excipient.

### Claim 10 (depends on 1)

The purified CD80-Fc immunomodulatory protein of claim 1, wherein the Fc domain is a variant Fc domain with reduced effector function.

### Claim 11 (depends on 10)

The purified CD80-Fc immunomodulatory protein of claim 10, wherein the variant Fc domain is an IgG1 Fc domain comprising the amino acid substitutions R292C/N297G/V302C.

### Claim 12 (depends on 11)

The purified CD80-Fc immunomodulatory protein of claim 11 that is a homodimer.

### Claim 13 (depends on 12)

A pharmaceutical composition comprising the purified CD80-Fc immunomodulatory protein of claim 12.

### Claim 14 (depends on 11)

A pharmaceutical composition comprising the purified CD80-Fc immunomodulatory protein of claim 11.

### Claim 15 (depends on 10)

The purified CD80-Fc immunomodulatory protein of claim 10, wherein the variant Fc domain is an IgG1 Fc domain comprising the amino acid substitutions L234A/L235E/G237A.

### Claim 16 (depends on 15)

A pharmaceutical composition comprising the purified CD80-Fc immunomodulatory protein of claim 15.

### Claim 17 (depends on 15)

The purified CD80-Fc immunomodulatory protein of claim 15 that is a homodimer.

### Claim 18 (depends on 17)

A pharmaceutical composition comprising the purified CD80-Fc immunomodulatory protein of claim 17.

### Claim 19

A purified CD80-Fc immunomodulatory protein comprising a variant CD80 polypeptide linked to an Fc domain, wherein:
the variant CD80 polypeptide comprises a sequence of amino acids that exhibits at least 90% sequence identity to an unmodified CD80 polypeptide set forth in SEQ ID NO: 28, or a portion of SEQ ID NO:28 comprising an IgV domain, wherein the IgV domain is amino acids 35-135, 35-138, 37-138 or 35-141 of SEQ ID NO:1,
the variant CD80 polypeptide comprises the amino acid substitution V68M; and
the immunomodulatory protein does not comprise any additional IgSF domain.

### Claim 20 (depends on 19)

The purified CD80-Fc immunomodulatory protein of claim 19, wherein the variant CD80 polypeptide comprises up to 10 amino acid substitutions.

### Claim 21 (depends on 19)

The purified CD80-Fc immunomodulatory protein of claim 19, wherein the variant CD80 polypeptide comprises a sequence of amino acids that exhibits at least 90% sequence identity to amino acids 35-141 of SEQ ID NO: 1.

### Claim 22 (depends on 19)

A pharmaceutical composition, comprising the purified CD80-Fc immunomodulatory protein of claim 19 and a pharmaceutically acceptable excipient.

### Claim 23 (depends on 19)

The purified CD80-Fc immunomodulatory protein of claim 19 that is a homodimer.

### Claim 24 (depends on 23)

A pharmaceutical composition, comprising the purified CD80-Fc immunomodulatory homodimer of claim 23 and a pharmaceutically acceptable excipient.

### Claim 25 (depends on 19)

The purified CD80-Fc immunomodulatory protein of claim 19, wherein the Fc domain is a variant Fc domain with reduced effector function.

### Claim 26 (depends on 25)

The purified CD80-Fc immunomodulatory protein of claim 25, wherein the variant Fc domain is an IgG1 Fc domain comprising the amino acid substitutions R292C/N297G/V302C.

### Claim 27 (depends on 26)

A pharmaceutical composition comprising the purified CD80-Fc immunomodulatory protein of claim 26.

### Claim 28 (depends on 26)

The purified CD80-Fc immunomodulatory protein of claim 26 that is a homodimer.

### Claim 29 (depends on 28)

A pharmaceutical composition comprising the purified CD80-Fc immunomodulatory protein of claim 28.

### Claim 30 (depends on 25)

The purified CD80-Fc immunomodulatory protein of claim 25, wherein the variant Fc domain is an IgG1 Fc domain comprising the amino acid substitutions L234A/L235E/G237A.

### Claim 31 (depends on 30)

A pharmaceutical composition comprising the purified CD80-Fc immunomodulatory protein of claim 30.

### Claim 32 (depends on 30)

The purified CD80-Fc immunomodulatory protein of claim 30 that is a homodimer.

### Claim 33 (depends on 32)

A pharmaceutical composition comprising the purified CD80-Fc immunomodulatory protein of claim 32.