title: Dll4 Blockade in Stromal Cells Mediates Antitumor Effects in Preclinical Models of Ovarian Cancer.
abstract: The Notch ligand delta-like 4 (Dll4) has been identified as a promising target in tumor angiogenesis in preclinical studies, and Dll4 inhibitors have recently entered clinical trials for solid tumors, including ovarian cancers. In this study, we report the development of REGN421 (enoticumab), a fully human IgG1 monoclonal antibody that binds human Dll4 with sub-nanomolar affinity and inhibits Notch signaling. Administering REGN421 to immunodeficient mice engineered to express human Dll4 inhibited the growth of several human tumor xenografts in association with the formation of nonfunctional tumor blood vessels. In ovarian tumor xenograft models, Dll4 was expressed specifically by the tumor endothelium, and Dll4 blockade by human-specific or mouse-specific Dll4 antibodies exerted potent antitumor activity, which relied entirely on targeting Dll4 expressed by tumor stromal cells but not by the tumor cells themselves. However, Dll4 blockade reduced Notch signaling in both blood vessels and tumor cells surrounding the blood vessels, suggesting that endothelial-expressed Dll4 might induce Notch signaling in adjacent ovarian tumor cells. The antitumor effects of targeting Dll4 were augmented significantly by simultaneous inhibition of VEGF signaling, whereas this combined blockade reversed normal organ vascular changes induced by Dll4 blockade alone. Overall, our findings deepen the rationale for antibody-based strategies to target Dll4 in ovarian cancers, especially in combination with VEGF blockade.
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York. frank.kuhnert@regeneron.com.
authors.forename: Frank
authors.initials: F
authors.lastname: Kuhnert
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Guoying
authors.initials: G
authors.lastname: Chen
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Sandra
authors.initials: S
authors.lastname: Coetzee
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Nithya
authors.initials: N
authors.lastname: Thambi
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Carlos
authors.initials: C
authors.lastname: Hickey
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Jing
authors.initials: J
authors.lastname: Shan
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Pavel
authors.initials: P
authors.lastname: Kovalenko
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Irene
authors.initials: I
authors.lastname: Noguera-Troise
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Eric
authors.initials: E
authors.lastname: Smith
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Fairhurst
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Julian
authors.initials: J
authors.lastname: Andreev
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Kirshner
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Papadopoulos
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Gavin
authors.initials: G
authors.lastname: Thurston
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002135:Calcium-Binding Proteins; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D051880:Receptors, Notch / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; C519665:DLL4 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D051880:Receptors, Notch; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C000600154:enoticumab