# US 9,518,124 B2 · Anti-Notch3 agonist antibodies and their use in the treatment of Notch3-related diseases

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- Number: US 9,518,124 B2
- Document ID: US9518124B2
- Status: Granted
- Kind: B2
- Application number: 13/972,443
- Filed: 2013-08-21
- Published: 2014-04-03
- Granted: 2016-12-13
- Earliest claimed: 2006-10-19
- Assignees: Genentech, Inc.
- Applicants: Genentech, Inc.
- Inventors: Kang Li; Bin-Bing Stephen Zhou; Wenjuan Wu; Sek Chung Fung; Sanjaya Singh
- Web page: https://patentgrep.com/patent/US9518124B2

## CPC

- C07K 16/30: from tumour cells
- 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)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/06: Antimigraine agents
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/00: Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- G01N 33/5759: {involving compounds localised on the membrane of tumour or cancer cells}
- G01N 33/6893: {related to diseases not provided for elsewhere}
- A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53)
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/5152: {Tumor cells}
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/567: Framework region [FR]
- C07K 2317/75: Agonist effect on antigen
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- 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
- 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)
- 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 present invention relates to agonist antibodies that specifically bind to Notch 3 and activate signaling. The present invention includes antibodies binding to an epitope comprising the first Lin12 domain. The present invention also includes uses of these antibodies to treat or prevent Notch 3 related diseases or disorders.

## Claims

### Claim 1

A method of activating Notch3 signaling in a cell comprising the step of contacting the cell with a monoclonal antibody that specifically binds to Notch 3 receptor, wherein the antibody specifically binds to an epitope in SEQ ID NO:10, and wherein the antibody activates Notch 3 receptor-mediated signaling through the Notch 3 receptor independent of ligand binding to the Notch 3 receptor.

### Claim 2 (depends on 1)

The method of claim 1, wherein the antibody is an antigen-binding antibody fragment.

### Claim 3 (depends on 1)

The method of claim 1, wherein the antibody is a single chain Fv.

### Claim 4 (depends on 1)

The method of claim 1, wherein the antibody is a human, humanized, or chimeric antibody.

### Claim 5 (depends on 1)

The method of claim 1, wherein the antibody comprises a variable heavy (VH) chain region comprising CDR-H1 of SEQ ID NO:4, CDR-H2 of SEQ ID NO:5, and CDR-H3 of SEQ ID NO:6, and a variable light (VL) chain region comprising CDR-L1 of SEQ ID NO:7, CDR-L2 of SEQ ID NO:8, and CDR-L3 of SEQ ID NO:9.

### Claim 6 (depends on 5)

The method of claim 5, wherein the VH chain region comprises SEQ ID NO:2, and the VL chain region comprises SEQ ID NO:3.

### Claim 7 (depends on 1)

The method of claim 1, wherein Notch 3 receptor-mediated signaling in the cell is increased by at least about 4-fold after activation with the antibody.

### Claim 8 (depends on 1)

The method of claim 1, wherein Notch 3 receptor-mediated signaling in the cell is measured using a reporter assay.

### Claim 9 (depends on 1)

The method of claim 1, wherein Notch 3 receptor-mediated signaling in the cell is measured by detecting Notch3 proteolytic cleavage.

### Claim 10 (depends on 9)

The method of claim 9, wherein Notch3 proteolytic cleavage is detected using Immunohistochemistry or an enzyme-linked immunoabsorbent assay (ELISA).

### Claim 11

A method of activating Notch3 signaling in a cell comprising the step of contacting the cell with a monoclonal antibody that specifically binds to Notch 3 receptor, wherein the antibody specifically binds to an epitope in SEQ ID NO:11, and wherein the antibody activates Notch 3 receptor-mediated signaling through the Notch 3 receptor independent of ligand binding to the Notch 3 receptor.

### Claim 12 (depends on 11)

The method of claim 11, wherein the antibody is an antigen-binding antibody fragment.

### Claim 13 (depends on 11)

The method of claim 11, wherein the antibody is a single chain Fv.

### Claim 14 (depends on 11)

The method of claim 11, wherein the antibody is a human, humanized, or chimeric antibody.

### Claim 15 (depends on 11)

The method of claim 11, wherein the antibody comprises a variable heavy (VH) chain region comprising CDR-H1 of SEQ ID NO:4, CDR-H2 of SEQ ID NO:5, and CDR-H3 of SEQ ID NO:6, and a variable light (VL) chain region comprising CDR-L1 of SEQ ID NO:7, CDR-L2 of SEQ ID NO:8, and CDR-L3 of SEQ ID NO:9.

### Claim 16 (depends on 15)

The method of claim 15, wherein the VH chain region comprises SEQ ID NO:2, and the VL chain region comprises SEQ ID NO:3.

### Claim 17 (depends on 11)

The method of claim 11, wherein Notch 3 receptor-mediated signaling in the cell is increased by at least about 4-fold after activation with the antibody.

### Claim 18 (depends on 11)

The method of claim 11, wherein Notch 3 receptor-mediated signaling in the cell is measured using a reporter assay.

### Claim 19 (depends on 11)

The method of claim 11, wherein Notch 3 receptor-mediated signaling in the cell is measured by detecting Notch3 proteolytic cleavage.

### Claim 20 (depends on 19)

The method of claim 19, wherein Notch3 proteolytic cleavage is detected using Immunohistochemistry or an enzyme-linked immunoabsorbent assay (ELISA).