title: A human antibody-drug conjugate targeting EphA2 inhibits tumor growth in vivo.
abstract: The EphA2 receptor tyrosine kinase is selectively expressed on the surface of many different human tumors. We have previously shown that tumor cells can be targeted by EphA2 monoclonal antibodies and that these antibodies function, in part, by inducing EphA2 internalization and degradation. In this report, we describe the isolation and characterization of a fully human monoclonal antibody (1C1) that selectively binds both the human and rodent EphA2 receptor. After cell binding, the antibody induces rapid tyrosine phosphorylation, internalization, and degradation of the EphA2 receptor. Because monoclonal antibodies that selectively bind tumor cells and internalize provide a vehicle for targeted delivery of cytotoxics, 1C1 was conjugated to the microtubule inhibitor monomethylauristatin phenylalanine using a stable maleimidocaproyl linker. The anti-EphA2 antibody-drug conjugate [1C1-maleimidocaproyl-MMAF (mcMMAF)] stimulated the activation of caspase-3/caspase-7 and the death of EphA2-expressing cells with IC(50) values as low as 3 ng/mL. Similarly, the conjugate induced degradation of the EphA2 receptor and inhibited tumor growth in vivo. Administration of 1C1-mcMMAF at doses as low as 1 mg/kg once weekly resulted in significant growth inhibition of EphA2-expressing tumors without any observable adverse effects in mouse xenograft and rat syngeneic tumor models. Our data support the use of an antibody-drug conjugate approach to selectively target and inhibit the growth of EphA2-expressing tumors.
authors.affiliation: MedImmune, Gaithersburg, MD 20878, USA. jacksond@medimmune.com
authors.forename: Dowdy
authors.initials: D
authors.lastname: Jackson
authors.forename: John
authors.initials: J
authors.lastname: Gooya
authors.forename: Shenlan
authors.initials: S
authors.lastname: Mao
authors.forename: Krista
authors.initials: K
authors.lastname: Kinneer
authors.forename: Linda
authors.initials: L
authors.lastname: Xu
authors.forename: Margarita
authors.initials: M
authors.lastname: Camara
authors.forename: Christine
authors.initials: C
authors.lastname: Fazenbaker
authors.forename: Ryan
authors.initials: R
authors.lastname: Fleming
authors.forename: Sudha
authors.initials: S
authors.lastname: Swamynathan
authors.forename: Damon
authors.initials: D
authors.lastname: Meyer
authors.forename: Peter D
authors.initials: PD
authors.lastname: Senter
authors.forename: Changshou
authors.initials: C
authors.lastname: Gao
authors.forename: Herren
authors.initials: H
authors.lastname: Wu
authors.forename: Michael
authors.initials: M
authors.lastname: Kinch
authors.forename: Steven
authors.initials: S
authors.lastname: Coats
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kiener
authors.forename: David A
authors.initials: DA
authors.lastname: Tice
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009842:Oligopeptides / Q000627:therapeutic use; D051381:Rats; D011916:Rats, Inbred F344; D036104:Receptor, EphA2 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D009842:Oligopeptides; C513576:monomethylauristatin F; D036104:Receptor, EphA2