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Toward Biotherapeutics Formulation Composition Engineering using Site-Identification by Ligand Competitive Saturation

Sandeep Somani¹, Sunhwan Jo², Renuka Thirumangalathu³

¹Discovery Sciences, Janssen Research and Development (Janssen R&D), Spring House, PA 19477, USA.

Journal of Pharmaceutical Sciences

|November 2, 2020

Summary

A new computational method, SILCS-Biologics, models protein formulation interactions at an atomistic level. It predicts how excipients like arginine and lysine affect protein viscosity, aiding therapeutic development.

Area of Science:

Biochemistry
Computational Biology
Pharmaceutical Sciences

Background:

Protein formulation is crucial for therapeutic efficacy.
Physicochemical properties depend on molecular interactions.
Current methods lack atomistic detail for complex formulations.

Purpose of the Study:

Introduce SILCS-Biologics, a novel in silico approach for structure-based protein formulation modeling.
Model protein-protein and protein-excipient interactions at an atomistic level.
Investigate the mechanism behind excipient-induced viscosity changes in monoclonal antibody formulations.

Main Methods:

Utilized Site-Identification by Ligand Competitive Saturation (SILCS) technology.
Applied SILCS-Biologics to a monoclonal antibody Fab domain (mAbN).
Modeled interactions between mAbN Fab domains and arginine HCl, proline, and lysine HCl.

Main Results:

SILCS-Biologics successfully modeled atomistic interactions and protein flexibility.
Predicted hotspot regions for protein-protein and protein-excipient interactions.
Provided a structure-based hypothesis for viscosity modulation by arginine, lysine, and proline.

Conclusions:

SILCS-Biologics offers a powerful framework for understanding protein formulation behavior.
The computational approach can guide the selection of excipients to control viscosity.
Further validation and expansion to full antibodies and other biologics are underway.

Keywords:

Arginine Excipient Flexibility Formulation FragMaps High-concentration In silico modeling Interaction Lysine Molecular dynamics Proline Protein Screening Viscosity

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