Pharmacokinetic Developability and Disposition Profiles of Bispecific Antibodies: A Case Study with Two Molecules

Datta-Mannan, Amita; Brown, Robin; Key, Stephanie; Cain, Paul; Feng, Yiqing

doi:10.3390/antib11010002

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Pharmacokinetic Developability and Disposition Profiles of Bispecific Antibodies: A Case Study with Two Molecules

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Department of Exploratory Medicine and Pharmacology, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46225, USA

Department of Drug Disposition, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46225, USA

Lilly Research Laboratories, Lilly Technology Center North, Biotechnology Discovery Research, Indianapolis, IN 46221, USA

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Academic Editor: John De Kruif

Antibodies 2022, 11(1), 2; https://doi.org/10.3390/antib11010002

Received: 10 September 2021 / Revised: 25 October 2021 / Accepted: 21 December 2021 / Published: 28 December 2021

(This article belongs to the Special Issue Monoclonal Antibody-Directed Therapy Series II)

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Abstract

Bispecific antibodies (BsAb) that engage multiple pathways are a promising therapeutic strategy to improve and prolong the efficacy of biologics in complex diseases. 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 PK of two related single chain variable fragment (scFv)-based BsAbs. Despite their close relation, the two BsAbs exhibit disparate PK in cynomolgus monkeys with BsAb-1 having an aberrant clearance of ~2 mL/h/kg and BsAb-2 displaying a an ~10-fold slower clearance (~0.2 mL/h/kg). Evaluation of the physiochemical characteristics of the molecules, including charge, non-specific binding, thermal stability, and hydrophobic properties, as well as FcRn interactions showed some differences. In-depth drug disposition results revealed that a substantial disparity in the complete release from FcRn at a neutral pH is a primary factor contributing to the rapid clearance of the BsAb-1 while other biophysical characteristics were largely comparable between molecules. View Full-Text

Keywords: bispecific antibody; monoclonal antibody; scFv; single-chain variable fragment; pharmacokinetic; FcRn neonatal Fc receptor; physiochemical properties

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MDPI and ACS Style

Datta-Mannan, A.; Brown, R.; Key, S.; Cain, P.; Feng, Y. Pharmacokinetic Developability and Disposition Profiles of Bispecific Antibodies: A Case Study with Two Molecules. Antibodies 2022, 11, 2. https://doi.org/10.3390/antib11010002

AMA Style

Datta-Mannan A, Brown R, Key S, Cain P, Feng Y. Pharmacokinetic Developability and Disposition Profiles of Bispecific Antibodies: A Case Study with Two Molecules. Antibodies. 2022; 11(1):2. https://doi.org/10.3390/antib11010002

Chicago/Turabian Style

Datta-Mannan, Amita, Robin Brown, Stephanie Key, Paul Cain, and Yiqing Feng. 2022. "Pharmacokinetic Developability and Disposition Profiles of Bispecific Antibodies: A Case Study with Two Molecules" Antibodies 11, no. 1: 2. https://doi.org/10.3390/antib11010002

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Pharmacokinetic Developability and Disposition Profiles of Bispecific Antibodies: A Case Study with Two Molecules

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