title: 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.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Theresa
authors.initials: T
authors.lastname: Proia
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Feng
authors.initials: F
authors.lastname: Jiang
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Alisa
authors.initials: A
authors.lastname: Bell
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Richard
authors.initials: R
authors.lastname: Nicoletti
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Lingxin
authors.initials: L
authors.lastname: Kong
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Kelly
authors.initials: K
authors.lastname: Kreuter
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Laura
authors.initials: L
authors.lastname: Poling
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: William M
authors.initials: WM
authors.lastname: Winston
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Meghan
authors.initials: M
authors.lastname: Flaherty
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Solly
authors.initials: S
authors.lastname: Weiler
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Samantha
authors.initials: S
authors.lastname: Perino
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Ronan
authors.initials: R
authors.lastname: O'Hagan
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Jie
authors.initials: J
authors.lastname: Lin
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Jeno
authors.initials: J
authors.lastname: Gyuris
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts. heidi.okamura@agios.com.
authors.forename: Heidi
authors.initials: H
authors.lastname: Okamura
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology / Q000633:toxicity; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008024:Ligands; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000819:agonists*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D008024:Ligands; D010671:Phenylurea Compounds; D011804:Quinolines; D051881:Receptor, Notch1; C553176:tivozanib; D040262:Receptors, Vascular Endothelial Growth Factor