419745 Therapeutic Protein Aggregation: A Colloid Science Perspective

Thursday, November 12, 2015: 1:30 PM
Canyon B (Hilton Salt Lake City Center)
Lucrèce Nicoud1, Marco Lattuada2, Paolo Arosio3, Stefano Lazzari4 and Massimo Morbidelli1, (1)Institute for Chemical and Bioengineering, ETH Zurich, Zurich, Switzerland, (2)Aolphe Merkle Institute, University of Fribourg, 1700 Fribourg, Switzerland, (3)Chemistry and Applied Biosciences, ETH Zürich, Zurich, Switzerland, (4)Department of Chemical Engineering, MIT, Cambridge, MA

Protein-based drugs such as monoclonal antibodies (mAb) have been increasingly developed since the 1980s, and are nowadays widely used in the treatment of several human diseases including rheumatoid arthritis and cancer. However, the formation of protein aggregates in biopharmaceuticals is a major concern, as it may compromise drug efficacy, or trigger unwanted immunogenicity. Protein aggregation is a complex multistep phenomenon that involves time and length scales spanning several orders of magnitude, and strategies seeking to enhance therapeutic protein stability are currently still largely empirical in practice.

Concepts from polymer and colloid science are emerging as powerful tools in the analysis of protein aggregation. Although proteins in aqueous media are molecular mixtures, and thus represent true solutions, they can be treated in many respects as colloidal dispersions. In this work, we discuss how key concepts borrowed from colloid science can be applied to gain knowledge on the kinetics of therapeutic protein aggregation across different length scales. In particular, we discuss the use of coarse-grained molecular interaction potentials to quantify protein colloidal stability. Moreover, we show how population balance equations simulations combined with detailed experimental characterization can provide insights into the mechanisms of aggregate formation at the mesoscale. We start our studies under dilute conditions and move progressively towards high protein concentrations, which are relevant for drug formulation. At high protein concentration, we are especially interested in gaining knowledge on the interplay between aggregate formation and viscosity increase. In this frame, we make use of the concept of occupied volume fraction, and we quantify irregular aggregate morphologies within the fractal geometry. Understanding aggregation mechanisms at high concentrations remains an open challenge, both for drug formulation, as well as for colloid science.

[1] L. Nicoud, M. Owczarz, P. Arosio, and M. Morbidelli. Biotechnol. J. (2015) A multiscale view of therapeutic protein aggregation: A colloid science perspective.

[2] L. Nicoud, N. Cohrs, P. Arosio, E. Norrant, and M. Morbidelli. Biophys. Chem. (2015) Effect of polyol sugars on the stabilization of monoclonal antibodies.

[3] L. Nicoud, M. Sozo, P. Arosio, A. Yates, E. Norrant, and M. Morbidelli. J. Phys. Chem. B (2014) Role of cosolutes in the aggregation kinetics of monoclonal antibodies.

[4] L. Nicoud, P. Arosio, M. Sozo, A. Yates, E. Norrant, and M. Morbidelli. J. Phys. Chem. B (2014) Kinetic analysis of the multistep aggregation mechanism of monoclonal antibodies.

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See more of this Session: Colloidal Dispersions II
See more of this Group/Topical: Engineering Sciences and Fundamentals