Efficacy and concentration-response of murine anti-VEGF monoclonal antibody in tumor-bearing mice and extrapolation to humans

The development of a neovascular supply (angiogenesis) is a major aspect of tumorigenesis. Recent work has indicated that vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis. In vitro and in vivo st udies have demonstrated that an anti-VEGF antibody is capable of suppressin g the growth of human tumor cell lines. The following study was conducted i n tumor-bearing nude mice to evaluate the concentration-response relationsh ip of murine anti-VEGF monoclonal antibody (muMAb VEGF) so that an efficaci ous plasma concentration of the recombinant humanized form (rhuMAb VEGF) in cancer patients could be estimated. (This study was included in our Invest igational New Drug application to support the clinical dosing regimen and p rojected human safety factors for the toxicology program.) Additionally, th e growth dynamics of the tumors were evaluated as a function of dose to exp lore whether a mechanismic interpretation of tumor growth inhibition by muM Ab VEGF is possible. On day 1, A673 human rhabdomyosarcoma cells (2 x 10(6) cells/mouse) were injected subcutaneously in 188 beige nude mice (16-24 g) . Treatment with muMAb VEGF (0.05-5.0 mg/kg; n = 24/group), phosphate-buffe red saline (n = 10), or anti-gp120 isotype-matched control antibody (5.0 mg /kg; n = 10) began 24 hr later. Each animal received intraperitoneal inject ions of test material twice weekly for 4 wk. Immediately prior to each dose , 2 mice from each muMAb VEGF group were selected randomly, and plasma was collected for pharmacokinetic evaluation; at the end of the study, samples were collected from all animals for pharmacokinetic evaluation. Tumor dimen sions were recorded weekly, and at the end of the study, tumor weight and d imensions were recorded. Satisfactory tumor suppression in nude mice was ac hieved at muMAb VEGF doses of greater than or equal to 2.5 mg/kg, where the average trough muMAb VEGF plasma concentration was 30 mu g/ml (concentrati ons in individual animals >10 mu g/ml). Assuming the pharmacokinetics of rh uMAb VEGF in patients will resemble the pharmacokinetics of a similar human ized anticancer monoclonal antibodies, a clinical dosing regimen was design ed to maintain the rhuMAb VEGF plasma concentration in this efficacious ran ge. This study shows an approach that can be used to estimate a human dosin g regimen from preclinical pharmacokinetic/pharmacodynamic data. Because we have just initiated clinical trials with rhuMAb VEGF, we cannot judge clin ical outcome in relation to these preclinical predictions; nonetheless, it is hoped that by sharing our approach and thought processes with other inve stigators we can assist the discovery and development of anticancer therape utics.