# US 11,028,178 B2 · Method of treating nonalcoholic steatohepatitis by administering an antagonist human tumor necrosis factor receptor 1 (HUTNFR1) antibody

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- Number: US 11,028,178 B2
- Document ID: US11028178B2
- Status: Granted
- Kind: B2
- Application number: 16/766,841
- Filed: 2018-11-27
- Published: 2020-09-24
- Granted: 2021-06-08
- Earliest claimed: 2017-11-27
- Assignees: Baliopharma AG
- Applicants: Baliopharm AG
- Inventors: Heike Bantel; Klaus Pfizenmaier; Andreas Herrmann
- Web page: https://patentgrep.com/patent/US11028178B2

## CPC

- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 2039/505: {comprising antibodies}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- 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)
- 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

## Abstract

An antibody specifically recognizing human tumor necrosis factor 1 (hu TNFR1), for use in treating nonalcoholic steatohepatitis (NASH) and disease conditions associated thereto.

## Claims

### Claim 1

A method of treating nonalcoholic steatohepatitis (NASH) and disease conditions associated thereto in a subject in need thereof, comprising administering to the subject an effective amount of an antagonist antibody specifically recognizing human tumor necrosis factor receptor 1 (huTNFR1).

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

The method of claim 1, wherein the antibody is a monospecific, bivalent, full-length antibody.

### Claim 4 (depends on 3)

The method of claim 3, wherein the antibody comprises an IgG1 Fc domain which is deficient in mediating effector function.

### Claim 5 (depends on 1)

The method of claim 1, wherein the antibody monovalently recognizes the huTNFR1.

### Claim 6 (depends on 1)

The method of claim 1, wherein the antibody comprises
a) a heavy chain variable domain (VH) comprising the complementarity-determining regions (CDRs): VH-CDR1, VH-CDR2, and VH-CDR3; and
b) a light chain variable domain (VL) comprising the CDRs: VL-CDR1, VL-CDR2, and VL-CDR3,
wherein
i)
VH-CDR1 comprises or consists of SEQ ID NO:1;
VH-CDR2 comprises or consists of SEQ ID NO:2
VH-CDR3 comprises or consists of SEQ ID NO:3
VL-CDR1 comprises or consists of SEQ ID NO:4
VL-CDR2 comprises or consists of SEQ ID NO:5
VL-CDR3 comprises or consists of SEQ ID NO:6;
or
ii)
VH-CDR1 comprises or consists of SEQ ID NO:23;
VH-CDR2 comprises or consists of SEQ ID NO:24
VH-CDR3 comprises or consists of SEQ ID NO:25
VL-CDR1 comprises or consists of SEQ ID NO:26
VL-CDR2 comprises or consists of SEQ ID NO:27
VL-CDR3 comprises or consists of SEQ ID NO:28;
wherein numbering is according to the Kabat EU index;
or a functionally active variant of any of i) or ii) above, which comprises up to 1 or 2 point mutations point mutations in each of the CDR sequences, and which specifically recognizes the huTNFR1.

### Claim 7 (depends on 1)

The method of claim 1, wherein the antibody comprises a VH sequence comprising or consisting of SEQ ID NO:7 or 9; and a VL sequence comprising or consisting of SEQ ID NO:8 or 10, or a functionally active variant thereof comprising up to 1 point mutation in each of the CDR sequences, and at least 60% sequence identity in the framework (FR) sequences FR1-4 of VH and VL.

### Claim 8 (depends on 1)

The method of claim 1, wherein the disease conditions are any of hepatic steatosis, inflamed liver, liver fibrosis and hepatocellular carcinoma.

### Claim 9 (depends on 1)

The method of claim 1, wherein an effective amount of the antibody is administered to the subject to antagonize TNFa/huTNFR1 signaling.

### Claim 10 (depends on 1)

The method of claim 1, wherein an effective amount of the antibody is administered to the subject to reduce any one or more of
a) steatosis, triglyceride content, inflammation, and/or apoptosis in liver tissue;
b) the serum aminotransferase level;
c) insulin-resistance and optionally to improve glucose-tolerance; and/or
d) the NAFLD activity score.

### Claim 11 (depends on 1)

The method of claim 1, wherein the antibody is administered to the subject at a dose ranging from 0.05 mg/kg to 20 mg/kg.

### Claim 12 (depends on 1)

The method of claim 1, wherein the antibody is administered to the subject in combination with a treatment with anti-inflammatory drugs, or therapies using a farnesoid X receptor (FXR) agonist, a glucagon-like peptide-1 receptor (GLP1R) agonist, or a peroxisome proliferator-activated receptor (PPAR) agonist.

### Claim 13 (depends on 1)

The method of claim 1, wherein the subject is also suffering from type II diabetes mellitus, type I diabetes mellitus, pre-diabetes, insulin resistance, or obesity, wherein obesity is defined as the patient having a body mass index of at least 30.

### Claim 14 (depends on 1)

The method of claim 1, wherein the antibody recognizes an epitope represented by amino acids 1 to 115 in the N-terminal region of huTNFR1.

### Claim 15 (depends on 4)

The method of claim 4, wherein the antibody comprises at least one mutation selected from the group consisting of E233P, L234V, L235A, ΔG236, A327G, A330S and P331S, wherein numbering is according to the Kabat EU index.

### Claim 16 (depends on 15)

The method of claim 15, wherein the antibody comprises A327G/A330S/P331S.