A monoclonal antibody against murine PlGF blocks primary tumor growth in syngeneic mouse tumor models

Gene targeting studies in mice have elucidated a functional role of placental growth factor PlGF, a homologue of VEGF, in pathological angiogenesis. Loss of PlGF, while not causing any vascular defects during embryonic development, reproduction or normal adult life, impaired angiogenesis in pathological conditions, such as cancer. We generated a neutralizing anti- mPlGF monoclonal antibody which inhibits PlGF binding to its receptor Flt1. Here we report the effect of this anti-mPlGF mAb on tumor angiogenesis and growth in syngeneic, subcutaneous B16 melanoma, CT26 colon and orthotopic Panc02 pancreatic tumor models. Treatment was initiated when tumors reached a size of 60mm³ or at 3 days after orthotopic tumor cell inoculation. Compared to a control antibody, intraperitoneal administration of anti-mPlGF mAb every other day significantly suppressed the growth of primary B16 melanoma tumors (end-stage tumor volume: 1,470±81mm³ after anti-PlGF vs. 2,660±81mm³ after control; p=0.001), colon CT26 tumors (729±73mm³ vs. 1,533±113mm³; p=0.001) and pancreatic Panc02 tumors (1,230±220mm³ vs. 2,313±290mm³; p=0.007). Histological examination on CD31-stained tumor sections revealed that the vessel density in anti-mPlGF mAb treated tumors was reduced. Moreover, unlike VEGF inhibitors, the anti- mPlGF mAb failed to affect pregnancy or skin wound healing, did not induce hypertension or pruning of quiescent vessels in the trachea and thyroid gland, and failed to elevate plasma levels of PAI–1, a marker of thrombotic risk. These findings may offer novel therapeutic opportunities for the treatment of cancer.

Keywords: B16 melanoma, CT26 colon tumor, PlGF, angiogenesis, monoclonal antibody, orthotopic pancreatic tumor