# US 11,078,295 B2 · Use of semaphorin-4D inhibitory molecules with an immune modulating therapy to inhibit tumor growth and metastases

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 11,078,295 B2
- Document ID: US11078295B2
- Status: Granted
- Kind: B2
- Application number: 16/392,451
- Filed: 2019-04-23
- Published: 2019-08-15
- Granted: 2021-08-03
- Earliest claimed: 2013-06-25
- Assignees: Vaccinex, Inc.
- Applicants: Vaccinex, Inc.
- Inventors: Elizabeth Evans; Ernest S. Smith; Maurice Zauderer
- Web page: https://patentgrep.com/patent/US11078295B2

## CPC

- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 35/15: Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells (presenting a specific antigen A61K39/00; therapeutic combinations of antibodies, or fragments thereof, and blood-derived cells A61K39/00)
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61P 35/00: Antineoplastic agents
- A61P 37/04: Immunostimulants
- C12N 5/0638: {Cytotoxic T lymphocytes [CTL] or lymphokine activated killer cells [LAK]}
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 38/2013: {IL-2}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- A61K 2039/54: {characterised by the route of administration}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- A61K 2039/572: {cytotoxic response}
- C07K 14/4705: {stimulating, promoting or activating activity}
- C07K 14/70596: {Molecules with a "CD"-designation not provided for elsewhere}
- C07K 16/18: against material from animals or humans
- C07K 16/2803: {against the immunoglobulin superfamily}
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/2863: {against receptors for growth factors, growth regulators}
- C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere}
- C07K 16/30: from tumour cells
- C07K 16/32: against translation products of oncogenes
- C07K 16/40: against enzymes
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C12N 2501/2302: Interleukin-2 (IL-2)
- C12N 2501/998: Proteins not provided for elsewhere
- G01N 33/5094: {for blood cell populations (red blood cells G01N33/80)}
- 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)
- 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)
- 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

Provided herein are methods for inhibiting, delaying, or reducing tumor growth and metastases of Plexin-B1-expressing cancer cells in a subject, comprising administering to the subject an effective amount of an isolated binding molecule which specifically binds to semaphorin-4D (SEMA4D) in combination with an effective amount of at least one other immune modulating therapy.

## Claims

### Claim 1

A method for inhibiting, delaying, or reducing solid tumor growth in a subject with cancer, comprising
(a) determining the levels of B cells and/or T cells in a subject with cancer; and
(b) administering to the subject an effective amount of an isolated antibody or antigen-binding fragment thereof that specifically binds to semaphorin-4D (SEMA4D) if the levels of B cells and/or T cells per microliter of blood in the subject are at least 1.5 times the mean number of B cells and/or T cells in circulation in other cancer patients with solid tumors, thereby treating the subject with cancer,
wherein the antibody or antigen-binding fragment thereof that specifically binds to SEMA4D comprises a variable heavy chain (VH) comprising VHCDRs 1-3 comprising SEQ ID NOs 6, 7, and 8, respectively, and a variable light chain (VL) comprising VLCDRs 1-3 comprising SEQ ID NOs 14, 15, and 16, respectively.

### Claim 2 (depends on 1)

The method of claim 1, wherein the levels of B cells, and/or T cells are measured as a percentage of total blood cells or as the mean number per microliter of blood.

### Claim 3 (depends on 1)

The method of claim 1, wherein the T cells are CD8+ T cells.

### Claim 4 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment thereof that specifically binds to SEMA4D inhibits SEMA4D interaction with its receptor.

### Claim 5 (depends on 4)

The method of claim 4, wherein the receptor is Plexin-B1, Plexin-B2, CD72, or a combination thereof.

### Claim 6 (depends on 5)

The method of claim 5, wherein the antibody or antigen-binding fragment thereof that specifically binds to SEMA4D inhibits SEMA4D-mediated Plexin-B1 signal transduction.

### Claim 7 (depends on 1)

The method of claim 1, wherein the VH and VL comprise, respectively, SEQ ID NO: 9 and SEQ ID NO: 17 or SEQ ID NO: 10 and SEQ ID NO: 18.

### Claim 8 (depends on 1)

The method of claim 1, further comprising administering to the subject an effective amount of at least one other immune modulating therapy if the levels of B cells, and/or T cells per microliter of blood in the subject is at least 1.5 times the mean number of B cells and/or T cells in circulation in other cancer patients with solid tumors,
wherein the at least one other immune modulating therapy comprises adoptive T cell therapy, an immune checkpoint blockade inhibitor selected from an anti-Programmed Cell Death 1 (PD-1) antibody, an anti-Programmed Death-Ligand 1 (PD-L1) antibody, an anti-Lymphocyte Activation Gene 3 (LAG3) antibody, an anti-B7-H3 antibody, an antigen-binding fragment thereof, or a combination thereof, a regulatory T cell (Treg) modulator comprising cyclophosphamide, or a combination thereof.

### Claim 9 (depends on 8)

The method of claim 8, wherein the antibody or antigen-binding fragment thereof that specifically binds to SEMA4D and the at least one immune modulating therapy are administered separately or concurrently.

### Claim 10 (depends on 8)

The method of claim 8, wherein the adoptive T cell therapy comprises tumor-infiltrating lymphocytes (TIL) recovered from resected patient tumor, T cells transduced with a chimeric antigen receptor, or a combination thereof.

### Claim 11 (depends on 10)

The method of claim 10, wherein the recovered TIL have been expanded in vitro.

### Claim 12 (depends on 11)

The method of claim 11, wherein the in vitro expansion comprises incubating the recovered TIL with allo-reactive feeder cells, interleukin-2 (IL-2), anti-CD3 antibody, or any combination thereof.

### Claim 13 (depends on 12)

The method of claim 12, wherein the in vitro expansion enriches for cytotoxic CD8+ T cells.

### Claim 14 (depends on 8)

The method of claim 8, wherein administration of the combination of the antibody or antigen-binding fragment thereof that specifically binds to SEMA4D and the at least one immune modulating therapy results in enhanced therapeutic efficacy relative to administration of either agent alone.

### Claim 15 (depends on 2)

The method of claim 2, wherein the levels of B cells and/or T cells per microliter of blood in the subject are about 1.5 to about 5 times the mean number of B cells and/or T cells in circulation in other cancer patients.

### Claim 16 (depends on 15)

The method of claim 15, wherein the levels of B cells and/or T cells per microliter of blood in the subject range from about 147 to about 588 and from about 1173 to about 3910, respectively.

### Claim 17 (depends on 2)

The method of claim 2, wherein the levels of B cells and/or T cells per microliter of blood in the subject fall within or above the range of B cells and/or T cells of healthy, non-cancer patients.

### Claim 18 (depends on 15)

The method of claim 15, wherein the levels of B cells and/or T cells per microliter of blood in the subject range from about 225 to about 275 or more and from about 1350 to about 1650 and more, respectively.

### Claim 19 (depends on 1)

The method of claim 1, wherein the cancer is carcinoma, lymphoma, blastoma, sarcoma, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, gastric cancer, pancreatic cancer, neuroendocrine cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, brain cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, esophageal cancer, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, head and neck cancer, or a combination thereof.

### Claim 20 (depends on 1)

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