Discovery of compounds with viscosity-reducing effects on biopharmaceutical formulations with monoclonal antibodies

Matic Proj; Mitja Zidar; Blaž Lebar; Nika Strašek; Goran Miličić; Aleš Žula; Stanislav Gobec

doi:10.1016/j.csbj.2022.09.035

Discovery of compounds with viscosity-reducing effects on biopharmaceutical formulations with monoclonal antibodies

Comput Struct Biotechnol J. 2022 Sep 26:20:5420-5429. doi: 10.1016/j.csbj.2022.09.035. eCollection 2022.

Authors

Matic Proj¹, Mitja Zidar², Blaž Lebar¹, Nika Strašek¹, Goran Miličić², Aleš Žula², Stanislav Gobec¹

Affiliations

¹ University of Ljubljana, Faculty of Pharmacy, Chair of Pharmaceutical Chemistry, Ljubljana, Slovenia.
² Biologics Drug Product, Technical Research and Development, Global Drug Development, Novartis, Lek d.d., Slovenia.

Abstract

For the development of concentrated monoclonal antibody formulations for subcutaneous administration, the main challenge is the high viscosity of the solutions. To compensate for this, viscosity reducing agents are commonly used as excipients. Here, we applied two computational chemistry approaches to discover new viscosity-reducing agents: fingerprint similarity searching, and physicochemical property filtering. In total, 94 compounds were selected and experimentally evaluated on two model monoclonal antibodies, which led to the discovery of 44 new viscosity-reducing agents. Analysis of the results showed that using a simple filter that selects only compounds with three or more charge groups is a good 'rule of thumb' for selecting potential viscosity-reducing agents for two model monoclonal antibody formulations.

Keywords: Biopharmaceuticals; Computational screening; GRAS, Generally Recognized as Safe; HIC, hydrophobic interaction chromatography; MW, molecular weight; PSA, polar surface area; Protein formulations; SASA, solvent accessible surface area; SlogP, partition coefficient; VRAs, viscosity-reducing agents; Viscosity; Viscosity-reducing agents; mAbs, monoclonal antibodies.