A single molecular descriptor to predict solution behavior of therapeutic antibodies.

Autor: Kingsbury JS; Biologics Development, Sanofi, Framingham, MA, USA., Saini A; Biologics Development, Sanofi, Framingham, MA, USA., Auclair SM; Biologics Development, Sanofi, Framingham, MA, USA., Fu L; Biologics Development, Sanofi, Framingham, MA, USA., Lantz MM; Biologics Development, Sanofi, Framingham, MA, USA., Halloran KT; Biologics Development, Sanofi, Framingham, MA, USA., Calero-Rubio C; Biologics Development, Sanofi, Framingham, MA, USA., Schwenger W; Biologics Development, Sanofi, Framingham, MA, USA., Airiau CY; Biologics Development, Sanofi, Framingham, MA, USA., Zhang J; Biologics Development, Sanofi, Framingham, MA, USA., Gokarn YR; Biologics Development, Sanofi, Framingham, MA, USA.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2020 Aug 05; Vol. 6 (32), pp. eabb0372. Date of Electronic Publication: 2020 Aug 05 (Print Publication: 2020).
DOI: 10.1126/sciadv.abb0372
Abstrakt: Despite the therapeutic success of monoclonal antibodies (mAbs), early identification of developable mAb drug candidates with optimal manufacturability, stability, and delivery attributes remains elusive. Poor solution behavior, which manifests as high solution viscosity or opalescence, profoundly affects the developability of mAb drugs. Using a diverse dataset of 59 mAbs, including 43 approved products, and an array of molecular descriptors spanning colloidal, conformational, charge-based, hydrodynamic, and hydrophobic properties, we show that poor solution behavior is prevalent (>30%) in mAbs and is singularly predicted (>90%) by the diffusion interaction parameter ( k D ), a dilute-solution measure of colloidal self-interaction. No other descriptor, individually or in combination, was found to be as effective as k D . We also show that well-behaved mAbs, a substantial subset of which bear high positive charge and pI, present no disadvantages with respect to pharmacokinetics in humans. Here, we provide a systematic framework with quantitative thresholds for selecting well-behaved therapeutic mAbs during drug discovery.
(Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
Databáze: MEDLINE
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