title: Dual functional monoclonal antibody PF-04605412 targets integrin alpha5beta1 and elicits potent antibody-dependent cellular cytotoxicity.
abstract: Integrin α5β1 is overexpressed in tumor-associated stroma and cancer cells, and has been implicated in angiogenesis, tumor survival, and metastasis. Antibody-dependent cellular cytotoxicity (ADCC) by immune effector cells has been shown to contribute to clinical efficacy for several IgG1 monoclonal antibody (mAb) therapeutics. Taking advantage of these two mechanisms, we generated a fully human, fragment crystalizable (Fc)-engineered IgG1 mAb, PF-04605412 (PF-5412), which specifically neutralizes α5 and binds the Fcγ receptors (FcγR) with enhanced affinity. In vitro, PF-5412 potently inhibited α5β1-mediated intracellular signaling, cell adhesion, migration, and endothelial cell (EC) tubulogenesis. PF-5412 induced significantly greater ADCC in α5-expressing tumor cells and ECs compared with a wild-type IgG1 (IgG1/wt) or IgG2 of identical antigen specificity. The degree of ADCC correlated with the abundance of natural killer (NK) cells in the peripheral blood mononuclear cells but was independent of donor FcγRIIIa polymorphism. In animal studies, PF-5412 displayed robust and dose-dependent antitumor efficacy superior to that observed with IgG1/wt, IgG2, or IgG4 of identical antigen specificity. The degree of efficacy correlated with α5 expression, macrophage and NK cell infiltration, and NK activity in the tumor. Depletion of host macrophages abrogated antitumor activity, suggesting a critical contribution of macrophage-mediated antitumor activity of PF-5412. Combination of PF-5412 with sunitinib significantly improved antitumor efficacy compared with either agent alone. The dual mechanism of action and robust antitumor efficacy of PF-5412 support its clinical development for the treatment of a broad spectrum of human malignancies.
authors.affiliation: Oncology Research Unit, Pfizer Inc., San Diego, CA 92121, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.forename: Lianglin
authors.initials: L
authors.lastname: Zhang
authors.forename: Enhong
authors.initials: E
authors.lastname: Chen
authors.forename: Jianying
authors.initials: J
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Jiang
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Chen
authors.forename: Grant
authors.initials: G
authors.lastname: Wickman
authors.forename: Karin
authors.initials: K
authors.lastname: Amundson
authors.forename: Simon
authors.initials: S
authors.lastname: Bergqvist
authors.forename: James
authors.initials: J
authors.lastname: Zobel
authors.forename: Dana
authors.initials: D
authors.lastname: Buckman
authors.forename: Sangita M
authors.initials: SM
authors.lastname: Baxi
authors.forename: Steven L
authors.initials: SL
authors.lastname: Bender
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Casperson
authors.forename: Dana D
authors.initials: DD
authors.lastname: Hu-Lowe
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity; D000068258:Bevacizumab; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D057809:HEK293 Cells; D000882:Haplorhini; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007211:Indoles / Q000494:pharmacology; D039081:Integrin alpha5beta1 / Q000096:biosynthesis / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D010587:Phagocytosis / Q000276:immunology; D011758:Pyrroles / Q000494:pharmacology; D017452:Receptors, IgG / Q000276:immunology; D000077210:Sunitinib
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D007211:Indoles; D039081:Integrin alpha5beta1; D011758:Pyrroles; D017452:Receptors, IgG; D000068258:Bevacizumab; D000077210:Sunitinib