Pharmacokinetics of the BsAbs in cynomolgus monkeys
The in vivo pharmacokinetic properties of BsAb-1 and BsAb-2 were examined in cynomolgus monkeys following a single IV dose of 5 mg/kg each as it was well established that there were insignificant peripheral levels of antigen for the Fab and scFv components of BsAb to bind in normal cynomolgus monkeys. As a result, the influence of target binding on the clearance is negligible and cynomolgus monkeys served as an acceptable in vivo model to evaluation the inherent pharmacokinetics of the BsAbs.
Following administration to cynomolgus monkeys, BsAb-1 and BsAb-2 showed a clearance of ~2.0 (+ 0.34) mL/h/kg and ~0.23 (+ 0.01) mL/h/kg, respectively, and a half-life of ~40 hours and ~248 hours, respectively (Figure 1B and Table 3). BsAb-1 was characterized by ~10-fold faster elimination relative to BsAb-2 (Table 3). Anti-drug antibodies (ADA) were observed for both BsAb-1 and BsAb-2 later in the concentration versus time profile (>240 hours post dose) (ADA titer data not shown). Since the ADA was evident at >240 hours after administration, there was enough concentration versus time data to assess the clearance of the molecules and thus, the ADA did not influence the interpretation of the kinetic data. Given the ligand binding properties for the two BsAbs are the same, the kinetic observations suggest that non-ligand mediated clearance factor(s) specifically related to the BsAb orientation are likely responsible for the in vivo pharmacokinetics.