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Speaker: Peter Schurtenberger

The Antibodies in Solution: a LINXS – NIST Webinar Series provides background information related to the currently ongoing LINXS antibody research program. This is a concerted experimental and theoretical effort that aims to investigate the properties of monoclonal antibodies in solution, which comprise a major platform for potential drug candidates and are of high academic and pharmaceutical interest. An international consortium of researchers at academic institutions, research centers, NIST and Novartis has teamed up for this. Didactical lectures given by members of the consortium on different experimental and theoretical topics that are highly relevant for state-of-the-art antibody research as well as insights from pharmaceutical industry will be broadcasted. A central aspect of the webinar series will be to illustrate the full power of neutron and X-ray scattering science that can be achieved in combination with complementary experimental methods and different unifying simulation techniques.

Abstract:

Monoclonal antibodies (mAbs) have moved into the focus of pharmaceutical industry as a major platform for potential drug candidates. However, successful mAb applications that allow for facile home administration require stable and low viscosity high concentration formulations, which are often difficult to achieve. mAbs are prone to exhibit reversible self-association at high concentrations that result in enhanced viscosity. This creates the need for an advanced predictive understanding of the stability and viscosity of concentrated protein solutions. Here we investigate the link between self-assembly and viscosity in concentrated solutions of monoclonal antibodies using a soft condensed matter approach that combines different experimental techniques (primarily static and dynamic light scattering, small-angle X-ray scattering and microrheology), with theory and simulations based on colloid models. We in particular focus on the importance of electrostatic interactions in controlling self-assembly, and provide a theoretical and experimental framework for a quantitative assessment of antibody charge,  interactions, self-assembly and flow properties.

The complexity of the system, formed by anisotropic and flexible large molecules that interact through a number of different intermolecular forces, makes a theoretical treatment capable of providing a quantitative link between the molecular structure and the various structural and dynamic quantities obtained in experiments a real challenge. Experimental data obtained from scattering and rheology experiments are commonly interpreted using simple colloid models. However, it has also been recognized that proteins such as mAbs are much more complex than the typical hard sphere-like synthetic model colloids. Proteins are not perfect spheres, and their interaction potentials are in general not isotropic, and using theories developed for such particles are thus clearly inadequate in many cases. Here we will make an attempt to critically discuss the somewhat controversial exploitation of colloid science concepts to better understand protein solutions.

We will look at different coarse graining strategies that allow us to incorporate crucial molecular information into colloid-like models that are then amenable to computer simulations as well as numerical and analytical calculations. We present comparisons between experimental data and theoretical predictions for different antibodies that form either stable low viscosity concentrated solutions or are prone to self-assemble into transient clusters that result in strongly increased viscosity values. Finally, we will look at current limits of such colloid-inspired approaches, and outline possible strategies for further improvements.