Anti-PlGF inhibits growth of VEGF(R)-inhibitor–resistant tumors without affecting healthy vessels

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