23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity.

Abstract

Dysregulation of Notch signaling has been implicated in the development of many different types of cancer. Notch inhibitors are being tested in the clinic, but in most cases gastrointestinal and other toxicities have limited the dosage and, therefore, the effectiveness of these therapies. Herein, we describe the generation of a monoclonal antibody against the ligand-binding domain of the Notch1 receptor that specifically blocks ligand-induced activation. This antibody, 23814, recognizes both human and murine Notch1 with similar affinity, enabling examination of the effects on both tumor and host tissue in preclinical models. 23814 blocked Notch1 function in vivo, inhibited functional angiogenesis, and inhibited tumor growth without causing gastrointestinal toxicity. The lack of toxicity allowed for combination of 23814 and the VEGFR inhibitor tivozanib, resulting in significant growth inhibition of several VEGFR inhibitor-resistant tumor models. Analysis of the gene expression profiles of an extensive collection of murine breast tumors enabled the successful prediction of which tumors were most likely to respond to the combination of 23814 and tivozanib. Therefore, the use of a specific Notch1 antibody that does not induce significant toxicity may allow combination treatment with angiogenesis inhibitors or other targeted agents to achieve enhanced therapeutic benefit.

• Authors: Theresa Proia, Feng Jiang, Alisa Bell, Richard Nicoletti, Lingxin Kong, Kelly Kreuter, Laura Poling, William M Winston, Meghan Flaherty, Solly Weiler, Samantha Perino, Ronan O'Hagan, Jie Lin, Jeno Gyuris, Heidi Okamura
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 14 Issue 8 Pg. 1858-67 (Aug 2015) ISSN: 1538-8514 [Electronic] United States
• PMID: 25995436 (Publication Type: Journal Article)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Angiogenesis Inhibitors
• Antibodies, Blocking
• Antibodies, Monoclonal
• Ligands
• Phenylurea Compounds
• Quinolines
• Receptor, Notch1
• tivozanib
• Receptors, Vascular Endothelial Growth Factor

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antibodies, Blocking (pharmacology, toxicity)
• Antibodies, Monoclonal (pharmacology, toxicity)
• Cell Line, Tumor
• Disease Models, Animal
• Drug Synergism
• Female
• Humans
• Ligands
• Mice
• Neovascularization, Pathologic (metabolism)
• Phenylurea Compounds (pharmacology)
• Quinolines (pharmacology)
• Receptor, Notch1 (agonists)
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays