title: Preclinical evaluation of an anti-alpha5beta1 integrin antibody as a novel anti-angiogenic agent.
abstract: Integrin alpha5beta1, the principal fibronectin receptor, is an important survival factor, playing a key role in angiogenesis. Angiogenesis is critical for tumor growth, and anti-angiogenic therapies have met clinical success. To validate the therapeutic potential of an anti-alpha5beta1 strategy, we generated volociximab (M200) a chimeric human IgG4 version of the alpha5beta1 function-blocking murine antibody IIA1; and F200, the Fab derivative. Volociximab, F200 and IIA1 showed similar activity by ELISA (EC50= 0.2nM), Biacore (Kd= 0.1-0.4nM) and inhibition of fibronectin binding (IC50= 2-3nM). The inhibitory potential of alpha5beta1 antibodies was compared to HuMV833, an anti-VEGF antibody. Both volociximab and HuMV833 inhibited HUVEC proliferation (IC50 of volociximab = 0.2-0.5nM; IC50 of HuMV833 = 45nM). However, IIA1, volociximab and F200 were also potent inhibitors of an in vitro model of angiogenesis (HUVEC tube formation assay), unlike HuMV833. Additionally, volociximab inhibited in vitro tube formation induced by VEGF and/or bFGF, suggesting a mechanism of action independent of growth factor stimulus. In fact, inhibition of alpha5beta1 function by volociximab induced apoptosis of actively proliferating, but not resting, endothelial cells. Volociximab does not cross-react with rodent alpha5beta1, therefore in vivo validation of an anti-alpha5beta1 approach was conducted in a cynomolgus model of choroidal revascularization. Volociximab and F200 were potent inhibitors of neovessel formation in this model. These data demonstrate that volociximab has therapeutic potential in diseases in which new vessel formation is a component of the pathology.
authors.affiliation: PDL Biopharma Inc, Fremont CA 94555, USA. vanitha@pdl.com
authors.forename: Vanitha
authors.initials: V
authors.lastname: Ramakrishnan
authors.forename: Vinay
authors.initials: V
authors.lastname: Bhaskar
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Law
authors.forename: Melanie H L
authors.initials: MH
authors.lastname: Wong
authors.forename: Robert B
authors.initials: RB
authors.lastname: DuBridge
authors.forename: Danna
authors.initials: D
authors.lastname: Breinberg
authors.forename: Christopher
authors.initials: C
authors.lastname: O'Hara
authors.forename: David B
authors.initials: DB
authors.lastname: Powers
authors.forename: Gao
authors.initials: G
authors.lastname: Liu
authors.forename: Jennifer
authors.initials: J
authors.lastname: Grove
authors.forename: Peter
authors.initials: P
authors.lastname: Hevezi
authors.forename: Kellie M
authors.initials: KM
authors.lastname: Cass
authors.forename: Susan
authors.initials: S
authors.lastname: Watson
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Evangelista
authors.forename: Rick A
authors.initials: RA
authors.lastname: Powers
authors.forename: Barbara
authors.initials: B
authors.lastname: Finck
authors.forename: Margaret
authors.initials: M
authors.lastname: Wills
authors.forename: Ingrid
authors.initials: I
authors.lastname: Caras
authors.forename: Yuni
authors.initials: Y
authors.lastname: Fang
authors.forename: Donald
authors.initials: D
authors.lastname: McDonald
authors.forename: Dale
authors.initials: D
authors.lastname: Johnson
authors.forename: Richard
authors.initials: R
authors.lastname: Murray
authors.forename: Ursula
authors.initials: U
authors.lastname: Jeffry
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D019556:COS Cells; D002522:Chlorocebus aethiops; D004353:Drug Evaluation, Preclinical; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D039081:Integrin alpha5beta1 / Q000737:chemistry / Q000276:immunology*; D007700:Kinetics; D008252:Macaca fascicularis; D008268:Macular Degeneration / Q000188:drug therapy; D009389:Neovascularization, Pathologic; D000069283:Rituximab
chemical_list: D020533:Angiogenesis Inhibitors; D000906:Antibodies; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D039081:Integrin alpha5beta1; C516631:volociximab; D000069283:Rituximab