Abstract
Therapeutic strategies utilizing multi-functional and bispecific
antibodies (BsAb) that engage multiple pathways are a promising way to
improve and prolong efficacy of biologics in complex disease indications.
In the early stages of discovery, BsAbs often exhibit a broad range of
pharmacokinetic (PK) behavior. Optimization of the neonatal Fc receptor
(FcRn) interactions and removal of undesirable physiochemical properties
have been used to improve the ‘pharmacokinetic developability’ for
various monoclonal antibody (mAb) therapeutics, yet there is a sparsity
of such information for BsAbs. The present work evaluated the influence
of FcRn interactions and inherent physiochemical properties on the
pharmacokinetics of two related single chain variable fragment (scFv)
based BsAbs. Despite their close relation, the two BsAbs exhibited
disparate PK in cynomolgus monkeys with BsAb-1 having aberrant clearance
of ~2 mL/hr/kg and BsAb-2 displaying a typical PK with a
clearance of ~0.2 mL/hr/kg. Evaluation of the
biophysical characteristics of the molecules, such as charge,
non-specific binding, thermal stability, and hydrophobic properties, as
well as FcRn interaction characterization showed some differences.
In-depth drug disposition results revealed that poor physical stability
and incomplete release from FcRn are the primary factors these
contributed to the rapid clearance of the BsAb with aberrant PK.