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Pharmacokinetic Developability And Disposition Profiles Of Bispecific Antibodies
  • +2
  • Amita Datta-Mannan,
  • Robin Brown,
  • Stephanie Key,
  • Paul Cain,
  • Yiqing Feng
Amita Datta-Mannan
Eli Lilly and Company

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Robin Brown
Eli Lilly and Company
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Stephanie Key
Eli Lilly and Company
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Paul Cain
Eli Lilly and Company
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Yiqing Feng
Eli Lilly and Company
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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.