Exploring Chemical Space for New Substances to Stabilize a Therapeutic Monoclonal Antibody

The physical stability of therapeutic proteins is a major concern in the development of liquid protein formulations. The number of degrees of freedom to control a given protein's stability is limited to pH, ionic strength, and type and concentration of excipient. There are only very few, mostly similar excipients currently in use, restricted to the list of substances generally recognized as safe for human use by the U.S. Food and Drug Administration. Opposed to this limited number of available excipients, there is the vast chemical space, which is hypothesized to consist of 1060 compounds. Its potential to stabilize proteins has never been explored systematically in the context of the formulation of therapeutic proteins. Here we present a screening strategy to discover new excipients to further improve an already stable formulation of a therapeutic antibody. The data are used to build a predictive model that evaluates the stabilizing potential of small molecules. We argue that before worrying about the hurdles of toxicity and approval of novel excipient candidates, it is mandatory to assess the actual potential hidden in the chemical space. (C) 2020 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.