Multiscale Diffusion, Dynamic Cluster Formation, and Intermolecular Interactions in Pharmaceutically Relevant...

Area of Science:

• Biopharmaceutical formulation
• Protein aggregation dynamics
• Neutron scattering applications

Background:

• Monoclonal antibodies (mAbs) are key biopharmaceuticals, often given intravenously.
• Subcutaneous (SC) injection of mAbs offers patient convenience but requires highly concentrated formulations.
• High mAb concentrations can increase solution viscosity, challenging SC injectability and stability.

Purpose of the Study:

• Investigate the factors affecting viscosity in concentrated mAb solutions for SC injection.
• Determine the relationship between mAb concentration, temperature, and solution properties.
• Understand the protein dynamics and interactions influencing mAb formulation viscosity.

Main Methods:

• Employed complementary neutron scattering techniques: neutron spin-echo (NSE) and small-angle neutron scattering (SANS).
• Studied nine different IgG1/IgG4 subtype mAbs in aqueous solutions.
• Analyzed protein concentration and temperature effects on mAb diffusion, interactions, and dynamics.

Main Results:

• Confirmed that the formation of short-lived mAb clusters (more than two monomers) is a primary driver of high solution viscosity.
• Demonstrated the link between mAb clustering, phase separation, and solution opalescence.
• Bridged the time-scale gap between neutron backscattering (NBS) and viscometry for mAb solutions.

Conclusions:

• Short-lived mAb clustering is critical for understanding and controlling viscosity in subcutaneous injection formulations.
• Neutron scattering techniques (NSE and SANS) provide essential insights into mAb solution behavior.
• Findings aid in developing stable, injectable mAb formulations for improved patient self-administration.