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.
Highlights
Integrin a5b1 is a classic fibronectin (Fn) receptor that plays important roles in vascular biology including embryonic vasculogenesis, vascular remodeling, pathologic angiogenesis, and inflammation [1,2,3]
We showed that PF-5412, a fully human dual functional monoclonal antibody (mAb) against integrin a5b1, potently and dose dependently blocked endothelial cell (EC) adhesion, migration, tubule formation, and survival (Fig. 1)
The mAb inhibited angiogenesis mediated by human endothelial cells/vessels in in vivo models developed to harbor the human angiogenesis components (Fig. 3A and B)
Summary
Integrin a5b1 is a classic fibronectin (Fn) receptor that plays important roles in vascular biology including embryonic vasculogenesis, vascular remodeling, pathologic angiogenesis, and inflammation [1,2,3]. Its involvement in the function of tumor-associated endothelium and stroma cells has been reported [4]. Promotes endothelial cell (EC) adhesion, migration, proliferation, survival, and differentiation [5, 6]. A5b1 is frequently overexpressed in tumor cells and has been associated with hypoxia, survival, epithelial-mesenchymal transition, invasion, and metastasis [7,8,9]. The overall survival in patients with lung cancers and breast cancers was found to be inversely correlated with the degree of tumor a5 expression [8, 14], providing a basis for targeting a5b1 for cancer therapy. M200 generated disease stabilization and a number of partial responses in previously heavily treated metastatic renal cell carcinoma patients [16]
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