Induction of lasting complete regression of preformed distinct solid tumors by targeting the tumor vasculature using two new anti-endoglin monoclonalantibodies

Endoglin (EDG, CD105) is a proliferation-associated antigen on endothelial cells. In this study, two new anti-EDG monoclonal antibodies (mAbs) Y4-2F1 (or termed SN6j) and P3-2G8 (SN6k) were generated and used for treating dis tinct preformed tumors, These mAbs, both IgG1-kappa antibodies, cross-react ed weakly with mouse endothelial cells but defined epitopes different from the epitope defined by a previously reported anti-EDG mAb K4-2C10 (B. K. Se on et al., Clin, Cancer Res., 3: 1031-1044, 1997), SN6j and SN6k reacted st rongly with human endothelial cells and vascular endothelium of malignant h uman tissues but showed no significant reactivity with tumor cells per se. The deglycosylated ricin A chain (dgRA) conjugates of the two mAbs showed a weak but specific cytotoxic activity against murine endothelial cells in v itro, In the therapeutic studies, severe combined immunodeficient mice were inocu lated s.c. with MCF-7 human breast cancer cells and left untreated until pa lpable tumors of distinct size (4-6 mm in diameter) appeared. Mice with the distinct tumors were treated by i.v. administration of individual anti-EDG conjugates, unconjugated mAbs, or a control conjugate, Long-lasting comple te regression of the tumors was induced in the majority of tumor-bearing mi ce (n = 8 for each conjugate) when 40 mu g of the individual conjugates wer e administered three times via the tail vein. It is remarkable that the tum ors remained regressed without further therapy for as long as the mice were followed (i.e., 100 days). Control conjugate did not induce regression of the tumors in any of the treated mice, although weak nonspecific effects we re observed in some of the mice (n = 8), The effects of unconjugated mAbs w ere small with the dose used, i.e,, 34 mu g three times. The anti-EDG conju gates showed antiangiogenic activity in the dorsal air sac assay in mice. T he results suggest good potential of these conjugates for the clinical appl ication.