A First Insight into the Developability of an Immunoglobulin G3: A Combined Computational and Experimental Approach

Area of Science:

• Biopharmaceutical development
• Protein engineering
• Immunology

Background:

• Monoclonal antibodies (mAbs) are crucial therapeutic scaffolds.
• Immunoglobulin G 3 (IgG3) mAbs offer therapeutic potential but lack characterization.
• High-concentration mAb formulations face challenges with viscosity, stability, and injectability due to protein-protein interactions.

Purpose of the Study:

• To characterize the molecular descriptors and biophysical properties of IgG3 mAbs.
• To assess the developability and manufacturability of IgG3 for high-concentration formulations.
• To understand the molecular basis of IgG3 physicochemical properties.

Main Methods:

• Comparative analysis of a model anti-IL-8 IgG1 and its IgG3 ortholog.
• Application of a combined computational and experimental framework.
• Measurement of molecular descriptors influencing mAb developability.

Main Results:

• IgG3 mAbs exhibited poorer conformational and colloidal stability compared to IgG1.
• Elevated solution viscosity was observed for IgG3 formulations.
• Key molecular descriptors impacting IgG3 developability were identified.

Conclusions:

• IgG3 mAbs present unique biophysical characteristics that require careful consideration for therapeutic development.
• The study provides foundational insights into IgG3 manufacturability for high-concentration formulations.
• Sequence engineering to control surface potential offers a strategy to enhance IgG3 developability.