Antiangiogenic therapy of established tumors in human skin/severe combined immunodeficiency mouse chimeras by anti-endoglin (CD105) monoclonal antibodies, and synergy between anti-endoglin antibody and cyclophosphamide.

摘要: Endoglin (EDG; CD105) is a proliferation-associated cell membrane antigen of endothelial cells and strongly expressed on the tumor-associated angiogenic vascular endothelium. Furthermore, EDG essential for angiogenesis component transforming growth factor (TGF)-β receptor complex. The present three anti-EDG monoclonal antibodies (mAbs), SN6f, SN6j, SN6k, react with proliferating human but cross-react very weakly murine cells. Analysis Scatchard plot direct binding these mAbs to umbilical vein showed equilibrium constants 8.3 × 10 9 , 3.1 1.0 liter/mol, respectively, SN6k. These did not MCF-7 breast cancer To facilitate antiangiogenic tumor therapy by in animal models, we used skin/severe combined immunodeficiency (SCID) mouse chimeras bearing tumors MCF-7. Blood vessels were analyzed immunostaining species (human or mouse)-specific anti-CD31 including an antihuman mAb termed SN6h. completely healed grafted skins consisted mixture (43.5%) (56.5%) vessels, whereas only detected adjacent s.c. tissues. Therefore, infiltrate into skin grafts from tissues, limited within boundary skins. Growth increased ratio human:murine vessels. Analyses before after transplantation that SN6h reacted tumor-induced blood nonangiogenic CD31 both results show capable distinguishing vasculature model. Antiangiogenic established was carried out i.v. administration mAb(s) via tail mice. SN6j SN6k effective suppressing tumors, suppression weaker SN6f. indicate absence correlation between antigen-binding avidity vivo antitumor efficacy suggest importance other factors ( e.g. epitopes) efficacy. No significant toxicity detected. Combination SN6f define mutually nonoverlapping epitopes additive effect. cyclophosphamide using schedule drug dosing synergistic combination induced lasting complete regression two eight treated chimeras. We examined large at end therapeutic experiment. test resulted weak Cyclophosphamide suppressive against also partial i.e. 35%) systemic naked can suppress markedly enhanced combining chemotherapeutic dosing. should stronger patients whose depend entirely