# US 2020/0079842 A1 · Novel anti-netrin-1 antibody

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- Number: US 2020/0079842 A1
- Document ID: US20200079842A1
- Status: Published application
- Kind: A1
- Application number: 16/657,200
- Filed: 2019-10-18
- Published: 2020-03-12
- Earliest claimed: 2014-01-10
- Assignees: Netris Pharma
- Applicants: Netris Pharma
- Inventors: Jean-Guy DELCROS; Yann DEAN
- Web page: https://patentgrep.com/patent/US20200079842A1

## CPC

- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/22: against growth factors {; against growth regulators}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- 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 2317/76: 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
- 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
- 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)

## Abstract

The application discloses method of treatment of cancer utilizing a linear or substantially linear epitope on netrin-1 that likely corresponds to the specific binding region of netrin-1 to receptor, in particular of the UNC5 class, especially UNC5B and UNC5A, or alternatively corresponds to a region nearby the specific binding region of netrin-1 to receptor that when bound to an antibody prevents netrin-1/receptor interaction. This determination of a linear epitope allows for the production of antibodies binding to netrin-1 and interfering with netrin-1/receptor interaction, thereby inducing apoptosis or cell death of tumour cells expressing or overexpressing netrin-1 and at least one netrin-1 receptor, owing the fact that this interaction inhibits netrin-1 binding to a receptor and the multimerization of the receptor. The application also discloses a murine monoclonal antibody directed against this epitope and various humanized forms thereof.

## Claims

### Claim 1

A method of treatment of cancer comprising administering to a subject in need thereof a therapeutically effective amount of a netrin-1 binding antibody or antigen-binding fragment thereof, which netrin-1 binding antibody or antigen-binding fragment thereof specifically binds to a polypeptide having the amino acid sequence SEQ ID NO: 3 or 35 or a variant polypeptide having at least 85% identity to SEQ ID NO: 3 or 35.

### Claim 2 (depends on 1)

The method of claim 1, wherein the antibody is a monoclonal antibody.

### Claim 3

A method of treatment of cancer comprising administering to a subject in need thereof a therapeutically effective amount of a netrin-1 binding antibody or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment thereof comprises:
(i) a Variable Heavy (VH) chain comprising a CDR1-H polypeptide comprising SEQ ID NO: 28, a CDR2-H polypeptide comprising SEQ ID NO: 29 and a CDR3-H polypeptide comprising SEQ ID NO: 30; and
(ii) a Variable Light (VL) chain comprising a CDR1-L comprising SEQ ID NO: 31, a CDR2-L polypeptide comprising SEQ ID NO: 32 and a CDR3-L polypeptide comprising SEQ ID NO: 9.

### Claim 4 (depends on 3)

The method of claim 3, wherein the antibody is a monoclonal antibody.

### Claim 5 (depends on 4)

The method of claim 4, wherein the monoclonal antibody or antigen-binding fragment thereof comprises an amino acid sequence selected from the group consisting of SEQ ID NO:
10, SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13.

### Claim 6 (depends on 4)

The method of claim 4, wherein the monoclonal antibody or antigen-binding fragment thereof comprises both SEQ ID NO: 10 and SEQ ID NO: 11.

### Claim 7 (depends on 4)

The method of claim 4, wherein the monoclonal antibody comprises both SEQ ID NO: 12 and SEQ ID NO: 13.

### Claim 8 (depends on 4)

The method of claim 4, wherein the monoclonal antibody or antigen-binding fragment thereof comprises an amino acid sequence selected from the group consisting of from SEQ ID NO:14 to SEQ ID NO: 27.

### Claim 9 (depends on 4)

The method of claim 4, wherein the monoclonal antibody or antigen-binding fragment thereof comprises an amino acid sequence selected from the group consisting of from SEQ ID NO: 14 to SEQ ID NO: 19 and an amino acid sequence selected from the group consisting of from SEQ ID NO: 20 to SEQ ID NO: 27.

### Claim 10 (depends on 4)

The method of claim 4, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a pair of amino acid sequences selected from the group consisting of pairs: SEQ ID NOS: 14 and 20; SEQ ID NOS: 15 and 21; SEQ ID NOS: 16 and 22; SEQ ID NOS: 17 and 23; SEQ ID NOS: 17 and 24; SEQ ID NOS: 16 and 25; SEQ ID NOS: 17 and 26; SEQ ID NOS: 17 and 22; SEQ ID NOS: 18 and 25; and SEQ ID NOS: 16 and 21.

### Claim 11 (depends on 2)

The method of claim 2, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a VL polypeptide comprising sequence SEQ ID NO:16 and a VH polypeptide comprising sequence SEQ ID NO:22.

### Claim 12 (depends on 2)

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

### Claim 13 (depends on 4)

The method of claim 4, wherein the monoclonal antibody or antigen-binding fragment thereof is humanized.

### Claim 14 (depends on 4)

The method of claim 4, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a VL polypeptide comprising SEQ ID NO: 16 and a VH polypeptide comprising SEQ ID NO: 22.

### Claim 15 (depends on 2)

The method of claim 2, wherein the monoclonal antibody has a light chain and a heavy chain and further comprises a human kappa constant domain in the light chain, and a human IgG1 constant domain in the heavy chain.

### Claim 16 (depends on 4)

The method of claim 4, wherein the monoclonal antibody has a light chain and a heavy chain and further comprising a human kappa constant domain in the light chain, and a human IgG1 constant domain in the heavy chain.

### Claim 17 (depends on 4)

The method of claim 4, wherein the monoclonal antibody or antigen-binding fragment thereof comprises:
(i) a Variable Heavy (VH) chain comprising a CDR1-H polypeptide comprising SEQ ID NO: 28, a CDR2-H polypeptide comprising SEQ ID NO: 29 and a CDR3-H polypeptide comprising SEQ ID NO: 30; and
(ii) a Variable Light (VL) chain comprising a CDR1-L comprising SEQ ID NO: 31, a CDR2-L polypeptide comprising SEQ ID NO: 32 and a CDR3-L polypeptide comprising SEQ ID NO: 9;
wherein said monoclonal antibody or antigen-binding fragment thereof comprises VH and VL polypeptides which each are at least 85% identical respectively to the VH polypeptide of SEQ ID NO: 27 and the VL polypeptide of SEQ ID NO: 19; to the VH polypeptide of SEQ ID NO: 20 and the VL polypeptide of SEQ ID NO: 14; to the VH polypeptide of SEQ ID NO: 21 and the VL polypeptide of SEQ ID NO: 15; to the VH polypeptide of SEQ ID NO: 22 and the VL polypeptide of SEQ ID NO: 16; to the VH polypeptide of SEQ ID NO: 23 and the VL polypeptide of SEQ ID NO: 17; to the VH polypeptide of SEQ ID NO: 24 and the VL polypeptide of SEQ ID NO: 17; to the VH polypeptide of SEQ ID NO: 25 and the VL polypeptide of SEQ ID NO: 16; to the VH polypeptide of SEQ ID NO: 26 and the VL polypeptide of SEQ ID NO: 17; to the VH polypeptide of SEQ ID NO: 22 and the VL polypeptide of SEQ ID NO: 17; to the VH polypeptide of SEQ ID NO: 25 and the VL polypeptide of SEQ ID NO: 18; or to the VH polypeptide of SEQ ID NO: 21 and the VL polypeptide of SEQ ID NO: 16.

### Claim 18 (depends on 4)

The method of claim 4, wherein the monoclonal antibody or antigen-binding fragment thereof comprises:
(i) a Variable Heavy (VH) chain comprising a CDR1-H polypeptide comprising SEQ ID NO: 28, a CDR2-H polypeptide comprising SEQ ID NO: 29 and a CDR3-H polypeptide comprising SEQ ID NO: 30; and
(ii) a Variable Light (VL) chain comprising a CDR1-L comprising SEQ ID NO: 31, a CDR2-L polypeptide comprising SEQ ID NO: 32 and a CDR3-L polypeptide comprising SEQ ID NO: 9;
wherein said antibody or antigen-binding fragment thereof comprises VH and VL polypeptides which each are at least 85% identical respectively to the VH polypeptide of SEQ ID NO: 22 and the VL polypeptide of SEQ ID NO: 16.

### Claim 19 (depends on 1)

The method of claim 1, wherein the cancer is one expressing a netrin-1 receptor and expressing netrin-1.

### Claim 20 (depends on 3)

The method of claim 3, wherein the cancer is one expressing a netrin-1 receptor and expressing netrin-1.