The interplay of non-specific binding, target-mediated clearance and FcRn interactions on the pharmacokinetics of humanized antibodies

MAbs
Amita Datta-MannanVictor J Wroblewski

Abstract

The application of protein engineering technologies toward successfully improving antibody pharmacokinetics has been challenging due to the multiplicity of biochemical factors that influence monoclonal antibody (mAb) disposition in vivo. Physiological factors including interactions with the neonatal Fc receptor (FcRn) and specific antigen binding properties of mAbs, along with biophysical properties of the mAbs themselves play a critical role. It has become evident that applying an integrated approach to understand the relative contribution of these factors is critical to rationally guide and apply engineering strategies to optimize mAb pharmacokinetics. The study presented here evaluated the influence of unintended non-specific interactions on the disposition of mAbs whose clearance rates are governed predominantly by either non-specific (FcRn) or target-mediated processes. The pharmacokinetics of 8 mAbs representing a diverse range of these properties was evaluated in cynomolgus monkeys. Results revealed complementarity-determining region (CDR) charge patch engineering to decrease charge-related non-specific binding can have a significant impact on improving the clearance. In contrast, the influence of enhanced in vitro FcRn ...Continue Reading

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Citations

Mar 27, 2016·Pharmacology & Therapeutics·João Pedro MartinsBruno Sarmento
Jan 18, 2017·Proceedings of the National Academy of Sciences of the United States of America·Tushar JainK Dane Wittrup
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Sep 11, 2021·Proceedings of the National Academy of Sciences of the United States of America·Lucky AhmedSandeep Kumar

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Methods Mentioned

BETA
surface plasmon resonance
differential scanning calorimetry
size exclusion chromatography
chip
electrophoresis
ELISAs

Software Mentioned

WinNonlin Professional
Karat

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