title: Biochemical and pharmacological characterization of human c-Met neutralizing monoclonal antibody CE-355621.
abstract: The c-Met proto-oncogene is a multifunctional receptor tyrosine kinase that is stimulated by its ligand, hepatocyte growth factor (HGF), to induce cell growth, motility and morphogenesis. Dysregulation of c-Met function, through mutational activation or overexpression, has been observed in many types of cancer and is thought to contribute to tumor growth and metastasis by affecting mitogenesis, invasion, and angiogenesis. We identified human monoclonal antibodies that bind to the extracellular domain of c-Met and inhibit tumor growth by interfering with ligand-dependent c-Met activation. We identified antibodies representing four independent epitope classes that inhibited both ligand binding and ligand-dependent activation of c-Met in A549 cells. In cells, the antibodies antagonized c-Met function by blocking receptor activation and by subsequently inducing downregulation of the receptor, translating to phenotypic effects in soft agar growth and tubular morphogenesis assays. Further characterization of the antibodies in vivo revealed significant inhibition of c-Met activity (≥ 80% lasting for 72-96 h) in excised tumors corresponded to tumor growth inhibition in multiple xenograft tumor models. Several of the antibodies identified inhibited the growth of tumors engineered to overexpress human HGF and human c-Met (S114 NIH 3T3) when grown subcutaneously in athymic mice. Furthermore, lead candidate antibody CE-355621 inhibited the growth of U87MG human glioblastoma and GTL-16 gastric xenografts by up to 98%. The findings support published pre-clinical and clinical data indicating that targeting c-Met with human monoclonal antibodies is a promising therapeutic approach for the treatment of cancer.
authors.affiliation: Pfizer Global Research and Development, Groton, CT, USA. neil.michaud@astrazeneca.com
authors.forename: Neil R
authors.initials: NR
authors.lastname: Michaud
authors.forename: Jitesh P
authors.initials: JP
authors.lastname: Jani
authors.forename: Stephen
authors.initials: S
authors.lastname: Hillerman
authors.forename: Konstantinos E
authors.initials: KE
authors.lastname: Tsaparikos
authors.forename: Elsa G
authors.initials: EG
authors.lastname: Barbacci-Tobin
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Knauth
authors.forename: Henry
authors.initials: H
authors.lastname: Putz
authors.forename: Mary
authors.initials: M
authors.lastname: Campbell
authors.forename: George A
authors.initials: GA
authors.lastname: Karam
authors.forename: Boris
authors.initials: B
authors.lastname: Chrunyk
authors.forename: David F
authors.initials: DF
authors.lastname: Gebhard
authors.forename: Larry L
authors.initials: LL
authors.lastname: Green
authors.forename: Jinghai J
authors.initials: JJ
authors.lastname: Xu
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Dunn
authors.forename: Tim M
authors.initials: TM
authors.lastname: Coskran
authors.forename: Jean-Martin
authors.initials: JM
authors.lastname: Lapointe
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Cohen
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Coleman
authors.forename: Vahe
authors.initials: V
authors.lastname: Bedian
authors.forename: Patrick
authors.initials: P
authors.lastname: Vincent
authors.forename: Shama
authors.initials: S
authors.lastname: Kajiji
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Steyn
authors.forename: Gary V
authors.initials: GV
authors.lastname: Borzillo
authors.forename: Gerrit
authors.initials: G
authors.lastname: Los
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D063646:Carcinogenesis / Q000187:drug effects / Q000276:immunology; D048708:Cell Growth Processes / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D009024:Morphogenesis / Q000187:drug effects; D041681:NIH 3T3 Cells; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000276:immunology*; D019076:Transgenes / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D016056:Immunodominant Epitopes; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met