# US 2023/0303676 A1 · Anti-netrin-1 antibody to treat liver inflammation

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- Number: US 2023/0303676 A1
- Document ID: US20230303676A1
- Status: Published application
- Kind: A1
- Application number: 18/122,273
- Filed: 2023-03-16
- Published: 2023-09-28
- Earliest claimed: 2022-03-18
- Assignees: Netris Pharma
- Applicants: Netris Pharma
- Inventors: ROMAIN BARNAULT; CLAIRE VERZEROLI; CAROLE FOURNIER; PATRICK MEHLEN; BENJAMIN GIBERT; FABIEN ZOULIM; ROMAIN PARENT
- Web page: https://patentgrep.com/patent/US20230303676A1

## CPC

- C07K 16/22: against growth factors {; against growth regulators}
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- 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
- 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 netrin-1 protein displays anti-inflammatory activity in the liver and is an unexpected proinflammatory factor in CLD. The present invention provides for blocking or capturing netrin-1 in the liver for treating liver inflammation, and thus methods for treating liver inflammation. To perform this, the invention makes use of a polyclonal or monoclonal antibody specifically binding to netrin-1, including a series of humanized monoclonal antibodies.

## Claims

### Claim 1

A method for treating liver inflammation in a patient in need thereof, comprising administering said patient with an efficient amount of an anti-netrin-1 monoclonal antibody or an anti-netrin-1-binding fragment thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the anti-netrin-1 monoclonal antibody and the anti-netrin-1-binding fragment thereof specifically binds to a polypeptide of sequence SEQ ID NO: 33.

### Claim 3 (depends on 1)

The method of claim 1, wherein the anti-netrin-1 monoclonal antibody and the anti-netrin-1-binding fragment thereof comprises
a variable domain VH comprising:
a H-CDR1 having a sequence set forth as SEQ ID NO: 28;
a H-CDR2 having a sequence set forth as SEQ ID NO: 29;
a H-CDR3 having a sequence set forth as SEQ ID NO: 30;
a variable domain VL comprising:
a L-CDR1 having a sequence set forth as SEQ ID NO: 31;
a L-CDR2 having a sequence set forth as SEQ ID NO: 32;
a L-CDR3 having a sequence set forth as SEQ ID NO: 9.

### Claim 4 (depends on 1)

The method of claim 1, wherein the anti-netrin-1 monoclonal antibody and the anti-netrin-1-binding fragment thereof comprises a pair of VH and VL sequences selected from the following pairs: SEQ ID NO: 27 and 19, SEQ ID NO: 20 and 14, SEQ ID NO: 21 and 15, SEQ ID NO: 22 and 16, SEQ ID NO: 23 and 17, SEQ ID NO: 24 and 17, SEQ ID NO: 25 and 16, SEQ ID NO: 26 and 17, SEQ ID NO: 22 and 17, SEQ ID NO: 25 and 18, SEQ ID NO: 21 and 16.

### Claim 5 (depends on 4)

The method of claim 4, wherein the anti-netrin-1 monoclonal antibody comprises a Human IgG1 Constant heavy chain (CH) and/or a Human IgG1 Constant light chain (CL).

### Claim 6 (depends on 5)

The method of claim 5, wherein said CL is a human kappa constant domain.

### Claim 7 (depends on 1)

The method of claim 1, wherein the anti-netrin-1 monoclonal antibody and the anti-netrin-1-binding fragment thereof comprises a VH of sequence of SEQ ID NO: 22 and a VL of sequence SEQ ID NO: 16.

### Claim 8 (depends on 7)

The method of claim 7, wherein the anti-netrin-1 monoclonal antibody comprises a Human IgG1 Constant heavy chain (CH) and/or a Human IgG1 Constant light chain (CL).

### Claim 9 (depends on 7)

The method of claim 7, wherein the anti-netrin-1 monoclonal antibody comprises a human IgG1 CH Genbank AEL33691.1 modified R97K, and a human IgG1 CL Kappa Genbank CAC20459.1.

### Claim 10

A method for treating liver inflammation in a patient having liver inflammation wherein netrin-1 is present and has a proinflammatory action in the liver, comprising administering said patient with an efficient amount of an anti-netrin-1 monoclonal antibody or an anti-netrin-1-binding fragment thereof.

### Claim 11 (depends on 10)

The method of claim 10, wherein the anti-netrin-1 monoclonal antibody and the anti-netrin-1-binding fragment thereof comprises
a variable domain VH comprising:
a H-CDR1 having a sequence set forth as SEQ ID NO: 28;
a H-CDR2 having a sequence set forth as SEQ ID NO: 29;
a H-CDR3 having a sequence set forth as SEQ ID NO: 30;
a variable domain VL comprising:
a L-CDR1 having a sequence set forth as SEQ ID NO: 31;
a L-CDR2 having a sequence set forth as SEQ ID NO: 32;
a L-CDR3 having a sequence set forth as SEQ ID NO: 9.

### Claim 12 (depends on 10)

The method of claim 10, wherein the anti-netrin-1 monoclonal antibody and the anti-netrin-1-binding fragment thereof comprises a VH of sequence of SEQ ID NO: 22 and a VL of sequence SEQ ID NO: 16.

### Claim 13 (depends on 10)

The method of claim 10, further comprising inhibiting the proinflammatory impact of netrin-1 on chemokines and Ly6C+ macrophages.

### Claim 14 (depends on 10)

The method of claim 10, further comprising reversing the induction of at least one chemokine selected from the group consisting of Ccl2, Ccl3, Ccl5, and Ccl8.

### Claim 15 (depends on 10)

The method of claim 10, further comprising reversing the induction of at least one selected from the group consisting of Stat1, Oas1a, Oasl1, Ifi44, Ptgs2 and prostaglandin I2 (Ptgir).

### Claim 16 (depends on 10)

The method of claim 10, further comprising reversing at least one of the transcripts encoding the chemoattractant Cxcl10, Ccl2 or Ccl5, the canonical inflammatory cytokine IL1B, the macrophage inflammatory protein Mip2, the Stat1 transducer and the Gnb1 transducer.