# US 11,306,144 B2 · B7-H4 antibodies and methods of use thereof

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- Number: US 11,306,144 B2
- Document ID: US11306144B2
- Status: Granted
- Kind: B2
- Application number: 16/111,064
- Filed: 2018-08-23
- Published: 2019-03-21
- Granted: 2022-04-19
- Earliest claimed: 2017-08-25
- Assignees: Five Prime Therapeutics, Inc.
- Applicants: Five Prime Therapeutics, Inc.
- Inventors: Charles Kaplan; Derrick Houser; Luis Borges; Gloria Brattich; David Bellovin; Felicia Kemp; Majid Ghoddusi; Nels P. Nielson; Kathy Miller; Maike Schmidt
- Web page: https://patentgrep.com/patent/US11306144B2

## CPC

- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- A61P 35/00: Antineoplastic agents
- C07K 16/2818: {against CD28 or CD152}
- G01N 33/5759: {involving compounds localised on the membrane of tumour or cancer cells}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/40: characterized by post-translational modification
- C07K 2317/41: Glycosylation, sialylation, or fucosylation
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- C07K 2317/74: Inducing cell proliferation
- C07K 2317/75: Agonist effect on antigen
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- 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
- 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)
- 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)

## Abstract

The present disclosure provides antibodies and antigen-binding fragments thereof that specifically bind to human B7-H4 (and optionally cynomolgus monkey, mouse, and/or rat B7-H4) and compositions comprising such antibodies or antigen-binding fragments thereof. In a specific aspect, the antibodies or antigen-binding fragments thereof that specifically bind to human B7-H4 increase T cell proliferation, increase interferon-gamma production, and/or deplete B7-H4 expressing cells via ADCC activity. The present disclosure also provides methods for treating disorders, such as cancer, by administering an antibody or antigen-binding fragment thereof that specifically binds to human B7-H4.

## Claims

### Claim 1

An isolated antibody or antigen-binding fragment thereof that specifically binds to human B7-H4, comprising heavy chain variable region (VH) complementarity determining region (CDR) 1, VH CDR2, VH CDR3 and light chain variable region (VL) CDR1, CDR2, and CDR3 sequences selected from the group consisting of:
(a) SEQ ID NOs:458-463, respectively;
(b) SEQ ID NOs:5-10, respectively;
(c) SEQ ID NOs:15-20, respectively;
(d) SEQ ID NOs:25-30, respectively;
(e) SEQ ID NOs:35-40, respectively; and
(f) SEQ ID NOs:45-50, respectively.

### Claim 2

An isolated antibody or antigen-binding fragment thereof that specifically binds to human B7-H4, comprising a heavy chain variable region and a light chain variable region comprising the amino acid sequences of:
(a) SEQ ID NOs:464 and 42, respectively;
(b) SEQ ID NOs:11 and 12, respectively;
(c) SEQ ID NOs:21 and 22, respectively;
(d) SEQ ID NOs:31 and 32, respectively;
(e) SEQ ID NOs:41 and 42, respectively; or
(f) SEQ ID NOs:51 and 52, respectively.

### Claim 3 (depends on 1)

The antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment further comprises a heavy chain constant region.

### Claim 4 (depends on 3)

The antibody or antigen-binding fragment thereof of claim 3, wherein the heavy chain constant region is selected from the group consisting of human immunoglobulins IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2 heavy chain constant regions.

### Claim 5 (depends on 3)

The antibody or antigen-binding fragment thereof of claim 3, wherein the antibody or antigen-binding fragment further comprises a light chain constant region.

### Claim 6 (depends on 5)

The antibody or antigen-binding fragment thereof of claim 5, wherein the light chain constant region is selected from the group consisting of human immunoglobulins IgGκ and IgGλ, light chain constant regions.

### Claim 7 (depends on 1)

The antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain and light chain comprising the amino acid sequences of:
(a) SEQ ID NOs:469 and 44, respectively;
(b) SEQ ID NOs:13 and 14, respectively;
(c) SEQ ID NOs:23 and 24, respectively;
(d) SEQ ID NOs:33 and 34, respectively;
(e) SEQ ID NOs:43 and 44, respectively; or
(f) SEQ ID NOs:53 and 54, respectively.

### Claim 8

An isolated antibody or antigen-binding fragment thereof that specifically binds to human B7-H4, wherein the antibody or antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 of an antibody comprising a heavy chain and a light chain comprising the amino acid sequence of:
(a) SEQ ID NOs:469 and 44, respectively;
(b) SEQ ID NOs:13 and 14, respectively;
(c) SEQ ID NOs:23 and 24, respectively;
(d) SEQ ID NOs:33 and 34, respectively;
(e) SEQ ID NOs:43 and 44, respectively; or
(f) SEQ ID NOs:53 and 54, respectively.

### Claim 9 (depends on 8)

The antibody or antigen-binding fragment thereof of claim 8, wherein the CDRs are the Kabat-defined CDRs, the Chothia-defined CDRs, or the AbM-defined CDRs.

### Claim 10 (depends on 1)

The antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof is a human antibody, a chimeric antibody, or an antigen-binding fragment thereof.

### Claim 11 (depends on 1)

The antibody or antigen-binding fragment thereof of claim 1, wherein contacting a cell expressing B7-H4 with the antibody or antigen-binding fragment thereof:
(a) induces T cell proliferation when the B7-H4 cell is in a population of cells comprising T cells,
(b) induces CD4+ T cell proliferation when the B7-H4 cell is in a population of cells comprising T cells,
(c) induces CD8+ T cell proliferation when the B7-H4 cell is in a population of cells comprising T cells,
(d) is capable of inducing antibody dependent cell mediated cytotoxicity (ADCC) in a B7-H4-expressing cell,
(e) inhibits tumor growth in a murine CT26 colorectal carcinoma model, a murine breast carcinoma 4T1 model, or a melanoma cell line B16-moB7-H4/H3 model, and/or
(f) inhibits T cell checkpoint activity of B7-H4.

### Claim 12 (depends on 1)

The antibody of antigen-binding fragment thereof of claim 1, wherein contacting a cell expressing B7-H4 with the antibody or antigen-binding fragment:
(a) increases T cell proliferation by at least 5% as compared to treatment with a control antibody when the B7-H4 cell is in a population of cells comprising T cells,
(b) increases CD4+ T cell proliferation by at least 5% as compared to treatment with a control antibody when the B7-H4 cell is in a population of cells comprising T cells,
(c) increases CD8+ T cell proliferation by at least 5% as compared to treatment with a control antibody when the B7-H4 cell is in a population of cells comprising T cells,
(d) induces specific lysis in at least 20% of B7-H4 expressing cells, and/or
(e) reduces tumor growth by at least 25% as compared to treatment with a control antibody.

### Claim 13 (depends on 11)

The antibody or antigen-binding fragment thereof of claim 11, wherein the induction of T cell proliferation, the induction of CD4+ T cell proliferation, the induction of CD8+ T cell proliferation, the ADCC activity, the inhibition of tumor growth, and/or the inhibition of T cell checkpoint activity is dose-dependent.

### Claim 14 (depends on 1)

The antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof binds to cynomolgus monkey, rat, and/or mouse B7-H4.

### Claim 15 (depends on 1)

The antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof binds to the IgV domain of human B7-H4.

### Claim 16 (depends on 1)

The antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof is afucosylated.

### Claim 17 (depends on 1)

The antibody or antigen-binding fragment thereof of claim 1, further comprising a detectable label.

### Claim 18 (depends on 1)

An isolated polynucleotide comprising a nucleic acid molecule encoding the heavy chain variable region and/or the light chain variable region of claim 1.

### Claim 19 (depends on 18)

An isolated vector comprising the polynucleotide of claim 18.

### Claim 20 (depends on 18)

A host cell comprising the polynucleotide of claim 18.

### Claim 21 (depends on 20)

A method of producing an antibody or antigen-binding fragment thereof that binds to human B7-H4 comprising culturing the host cell of claim 20 so that the nucleic acid molecule is expressed and the antibody or antigen-binding fragment thereof is produced.

### Claim 22 (depends on 18)

An isolated antibody or antigen-binding fragment thereof that specifically binds to human B7-H4 and is encoded by the polynucleotide of claim 18.

### Claim 23 (depends on 1)

A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of claim 1 and a pharmaceutically acceptable excipient.

### Claim 24 (depends on 1)

A pharmaceutical composition comprising (i) antibodies or antigen-binding fragments of claim 1 and (ii) a pharmaceutically acceptable excipient, wherein at least 95% of the antibodies or antigen-binding fragments thereof in the composition are afucosylated.

### Claim 25 (depends on 23)

The pharmaceutical composition of claim 23, further comprising an anti-PD-1 antibody or an antigen-binding fragment thereof or an anti-PD-L1 antibody or an antigen-binding fragment thereof.

### Claim 26 (depends on 1)

A method for inducing T cell proliferation comprising contacting a cell expressing B7-H4 with the antibody or antigen-binding fragment thereof of claim 1, wherein the B7-H4 expressing cell is in a population of cells comprising T cells.

### Claim 27 (depends on 1)

A method for inducing CD4+ T cell proliferation comprising contacting a cell expressing B7-H4 with the antibody or antigen-binding fragment thereof of claim 1, wherein the B7-H4 expressing cell is in a population of cells comprising T cells.

### Claim 28 (depends on 1)

A method for inducing CD8+ T cell proliferation comprising contacting a cell expressing B7-H4 with the antibody or antigen-binding fragment thereof of claim 1, wherein the B7-H4 expressing cell is in a population of cells comprising T cells.

### Claim 29 (depends on 1)

A method for killing a cell expressing B7-H4 comprising contacting the cell with the antibody or antigen-binding fragment thereof of claim 1.

### Claim 30 (depends on 1)

A method for depleting B7-H4-expressing cells from a population of cells comprising contacting the population of cells with the antibody or antigen-binding fragment thereof of claim 1.

### Claim 31 (depends on 26)

The method of claim 26, further comprising contacting the cell expressing B7-H4 with an anti-PD-1 antibody or an antigen-binding fragment thereof or an anti-PD-L1 antibody or an antigen-binding fragment thereof.

### Claim 32 (depends on 1)

A method of treating a B7-H4 expressing cancer in a subject, the method comprising administering to the subject an effective amount of the antibody or antigen-binding fragment thereof of claim 1.

### Claim 33 (depends on 32)

The method of claim 32, wherein the cancer is selected from the group consisting of head and neck cancer, small cell lung cancer, gastric cancer, melanoma, breast cancer, ductal carcinoma, endometrial carcinoma, ovarian cancer, non-small cell lung cancer, pancreatic cancer, thyroid cancer, kidney cancer and bladder cancer.

### Claim 34 (depends on 32)

The method of claim 32 wherein the cancer is a PD-1 inhibitor inadequate responder, and/or wherein the cancer is a PD-L1 inhibitor inadequate responder, and/or wherein the cancer expresses a low level of PD-L1.

### Claim 35 (depends on 32)

The method of claim 32, further comprising administering to the subject an anti-PD-1 antibody or an antigen-binding fragment thereof or an anti-PD-L1 antibody or an antigen-binding fragment thereof.

### Claim 36 (depends on 1)

A method for detecting B7-H4 in a sample comprising contacting said sample with the antibody or antigen-binding fragment thereof of claim 1.

### Claim 37 (depends on 1)

A kit comprising the antibody or antigen-binding fragment thereof of claim 1, a detection reagent, and instructions for use for detection of a B7-H4 antigen.

### Claim 38 (depends on 7)

An isolated polynucleotide comprising a nucleic acid molecule encoding the heavy chain variable region or heavy chain of the antibody or antigen-binding fragment thereof of claim 7 and/or encoding the light chain variable region or light chain of the antibody or antigen-binding fragment thereof of claim 7.

### Claim 39 (depends on 2)

The antibody or antigen-binding fragment thereof of claim 2, wherein the antibody or antigen-binding fragment further comprises a heavy chain constant region.

### Claim 40 (depends on 2)

The antibody or antigen-binding fragment thereof of claim 2, wherein the antibody or antigen-binding fragment thereof is afucosylated.

### Claim 41 (depends on 7)

The antibody or antigen-binding fragment thereof of claim 7, wherein the antibody or antigen-binding fragment thereof is afucosylated.

### Claim 42 (depends on 2)

A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of claim 2 and a pharmaceutically acceptable excipient.

### Claim 43 (depends on 7)

A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of claim 7 and a pharmaceutically acceptable excipient.

### Claim 44 (depends on 24)

The pharmaceutical composition of claim 24, further comprising an anti-PD-1 antibody, an anti-PD-L1 antibody, or an antigen-binding fragment thereof.

### Claim 45 (depends on 39)

The antibody or antigen-binding fragment of claim 39, wherein the antibody or antigen-binding fragment comprises a light chain constant chain.