Novel antiangiogenic strategies with complementary mechanisms are needed to maximize
efficacy and minimize resistance to current angiogenesis inhibitors. We explored the
therapeutic potential and mechanisms of alphaPlGF, an antibody against placental growth
factor (PlGF), a VEGF homolog, which regulates the angiogenic switch in disease, but
not in health. alphaPlGF inhibited growth and metastasis of various tumors, including
those resistant to VEGF(R) inhibitors (VEGF(R)Is), and enhanced the efficacy of chemotherapy
and VEGF(R)Is. alphaPlGF inhibited angiogenesis, lymphangiogenesis, and tumor cell
motility. Distinct from VEGF(R)Is, alphaPlGF prevented infiltration of angiogenic
macrophages and severe tumor hypoxia, and thus, did not switch on the angiogenic rescue
program responsible for resistance to VEGF(R)Is. Moreover, it did not cause or enhance
VEGF(R)I-related side effects. The efficacy and safety of alphaPlGF, its pleiotropic
and complementary mechanism to VEGF(R)Is, and the negligible induction of an angiogenic
rescue program suggest that alphaPlGF may constitute a novel approach for cancer treatment.