# US 10,494,427 B2 · Anti-netrin-1 antibody

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- Number: US 10,494,427 B2
- Document ID: US10494427B2
- Status: Granted
- Kind: B2
- Application number: 15/110,612
- Filed: 2015-01-09
- Published: 2018-03-15
- Granted: 2019-12-03
- Earliest claimed: 2014-01-10
- Assignees: Netris Pharma
- Applicants: Netris Pharma
- Inventors: Jean-Guy Delcros; Yann Dean
- Web page: https://patentgrep.com/patent/US10494427B2

## 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 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 the Applicant to produce 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 discloses a murine monoclonal antibody directed against this epitope and various humanized forms thereof.

## Claims

### Claim 1

A netrin-1 binding monoclonal antibody or antigen-binding fragment thereof, wherein said antibody and said antigen-binding fragment thereof comprise:
(i) a variable heavy chain (VH) region 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 chain (VL) region comprising a CDR1-L polypeptide 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 2 (depends on 1)

A pharmaceutical composition comprising the monoclonal antibody or antigen-binding fragment thereof according to claim 1, and a pharmaceutically acceptable vehicle, carrier or diluent.

### Claim 3 (depends on 1)

The netrin-1 binding monoclonal antibody or antigen-binding fragment thereof according to claim 1, which 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 4 (depends on 1)

The netrin-1 binding monoclonal antibody or antigen-binding fragment thereof according to claim 1, which comprises both sequences SEQ ID NO: 10 and 11.

### Claim 5 (depends on 1)

The netrin-1 binding monoclonal antibody or antigen-binding fragment thereof according to claim 1, which comprises both sequences SEQ ID NO: 12 and 13.

### Claim 6 (depends on 1)

The netrin-1 binding monoclonal antibody or antigen-binding fragment thereof according to claim 1, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO:14-18 and 20-26.

### Claim 7 (depends on 1)

The netrin-1 binding monoclonal antibody or antigen-binding fragment thereof according to claim 1, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 14 to 18 and an amino acid sequence selected from the group consisting of SEQ ID NO: 20 to 26.

### Claim 8 (depends on 1)

The netrin-1 binding monoclonal antibody or antigen-binding fragment thereof according to claim 1, which comprises a pair of amino acid sequences selected from the group consisting of pairs: SEQ ID NO: 14 and 20; 15 and 21; 16 and 22; 17 and 23; 17 and 24; 16 and 25; 17 and 26; 17 and 22; 18 and 25; and 16 and 21.

### Claim 9 (depends on 1)

The netrin-1 binding monoclonal antibody or antigen-binding fragment thereof according to claim 1, which comprises a VL region comprising SEQ ID NO:16 and a VH region comprising SEQ ID NO:22.

### Claim 10 (depends on 2)

The pharmaceutical composition of claim 2, wherein the monoclonal antibody or antigen-binding fragment thereof comprises the two amino acid sequences SEQ ID NO:16 and 22.

### Claim 11 (depends on 1)

The netrin-1 binding monoclonal antibody or antigen-binding fragment thereof according to claim 1, which monoclonal antibody or antigen-binding fragment is humanized.

### Claim 12 (depends on 1)

The netrin-1 binding monoclonal antibody according to claim 1, which comprises a VL region comprising SEQ ID NO: 16 and a VH region comprising SEQ ID NO: 22.

### Claim 13 (depends on 1)

The netrin-1 binding monoclonal antibody of claim 1, having 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 14 (depends on 12)

The netrin-1 binding monoclonal antibody of claim 12, having 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.