Understanding pharmacokinetics and pharmacodynamics relationship of anti-IGF1R antibody in vivo

Abstract

3017

rhuMAb IGFR is a recombinant humanized monoclonal antibody against IGF1 receptor (IGF1R) which is being developed as a potential therapeutic for the treatment of cancer. rhuMAb IGFR blocks the interaction of ligands with IGF1R as well as, induces IGF1R down-regulation through receptor internalization and degradation. Treatment with rhuMAb IGFR inhibited tumor growth in the SK-N-AS xenograft model as a single agent and induced dose- and time-dependent down-regulation of IGF1R, as well as, phospho-Akt the downstream signaling molecule in tumors. A single dose study performed at multiple dose levels in cynomolgus monkeys allowed us to establish the relationship between the pharmacokinetics (PK) and pharmacodynamics (PD) of rhuMAb IGFR. Animals received a single intravenous (IV) bolus dose of rhuMAb IGFR at 0, 0.5, 1.5, 5, and 25 mg/kg with n=3 per sex per group. Serum rhuMAb IGFR concentrations were measured by ELISA and IGF1R expression on granulocytes was measured by FACS. Nonlinear clearance was observed for rhuMAb IGFR over the dose range tested likely due to a saturable receptor mediated clearance mechanism. At doses greater than or equal to 1.5 mg/kg, overall rhuMAb IGF1R exposure was proportional to dose. There was a direct relationship between serum rhuMAb IGFR concentrations and IGF1R down-regulation on granulocytes. The percentage of IGF1R positive granulocytes decreased after treatment, with greater than 80 to 90% surface down regulation observed at rhuMAb IGFR serum concentrations in the range of 1 to 50 mcg/mL. The duration of IGF1R down-regulation appeared dose-proportional, and correlated with serum rhuMAb IGFR concentration data. The ability of rhuMAb IGFR to induce IGF1R down-regulation on peripheral blood granulocytes has the potential to provide a convenient readout for monitoring its pharmacodanamic activity in the clinic.