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.