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Angiostatin-Like Activity of a Monoclonal Antibody to the Catalytic Subunit of F₁F₀ ATP Synthase

Departments of ¹ Pathology and ² Radiation Oncology, Duke University Medical Center; ³ Program in Neuroscience, JL Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina; ⁴ Mitosciences LLC; and ⁵ Institute of Molecular Biology, University of Oregon, Eugene, Oregon

Requests for reprints: Salvatore V. Pizzo, Duke University Medical Center, Box 3712, Durham, NC 27710. Phone: 919-684-3529; Fax: 919-684-8689; E-mail: pizzo001{at}mc.duke.edu.

The antiangiogenic protein angiostatin inhibits ATP synthase on the endothelial cell surface, blocking cellular proliferation. To examine the specificity of this interaction, we generated monoclonal antibodies (mAb) directed against ATP synthase. mAb directed against the ß-catalytic subunit of ATP synthase (MAb3D5AB1) inhibits the activity of the F₁ domain of ATP synthase and recognizes the catalytic ß-subunit of ATP synthase. We located the antibody recognition site of MAb3D5AB1 in domains containing the active site of the ß-subunit. MAb3D5AB1 also binds to purified Escherichia coli F₁ with an affinity 25-fold higher than the affinity of angiostatin for this protein. MAb3D5AB1 inhibits the hydrolytic activity of F₁ ATP synthase at lower concentrations than angiostatin. Like angiostatin, MAb3D5AB1 inhibits ATP generation by ATP synthase on the endothelial cell surface in acidic conditions, the typical tumor microenvironment where cell surface ATP synthase exhibits greater activity. MAb3D5AB1 disrupts tube formation and decreases intracellular pH in endothelial cells exposed to low extracellular pH. Neither angiostatin nor MAb3D5AB1 showed an antiangiogenic effect in the corneal neovascularization assay; however, both were effective in the low-pH environment of the chicken chorioallantoic membrane assay. Thus, MAb3D5AB1 shows angiostatin-like properties superior to angiostatin and may be exploited in cancer chemotherapy. [Cancer Res 2007;67(10):4716–24]

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