Abstract
Monoclonal antibody solutions are set to become a major therapeutic tool in the years to come, capable of targeting various diseases by clever design of their antigen binding site. However, the formulation of stable solutions suitable for patient self-administration typically presents challenges, as a result of the increase in viscosity that often occurs at high concentrations. Here, we establish a link between the microscopic molecular details and the resulting properties of an antibody solution through the characterization of clusters, which arise in the presence of self-associating antibodies. In particular, we find that experimental small-angle X-ray scattering data can be interpreted by means of analytical models previously exploited for the study of polymeric and colloidal objects, based on the presence of such clusters. The latter are determined by theoretical calculations and supported by computer simulations of a coarse-grained minimal model, in which antibodies are treated as Y-shaped colloidal molecules and attractive domains are designed as patches. Using the theoretically predicted cluster size distributions, we are able to describe the experimental structure factors over a wide range of concentration and salt conditions. We thus provide microscopic evidence for the well-established fact that the concentration-dependent increase in viscosity is originated by the presence of clusters. Our findings bring new insights on the self-assembly of monoclonal antibodies, which can be exploited for guiding the formulation of stable and effective antibody solutions.
Originalsprog | Engelsk |
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Tidsskrift | Molecular Pharmaceutics |
Vol/bind | 20 |
Udgave nummer | 5 |
Sider (fra-til) | 2738-2753 |
Antal sider | 16 |
ISSN | 1543-8384 |
DOI | |
Status | Udgivet - 1 maj 2023 |
Bibliografisk note
Funding Information:We thank T. Garting for help with the microrheology measurements and C. Rieschel for helpful discussions. This work was financed by the Swedish Research Council (VR; grant nos. 2016-03301, 2018-04627 and 2022-03142), the Faculty of Science at Lund University, the Knut and Alice Wallenberg Foundation (project grant KAW 2014.0052), the European Research Council (ERC-339678-COMPASS) and Novo Nordisk. The SAXS measurements at low concentrations were performed at the SWING beamline of the synchrotron SOLEIL, and we gratefully acknowledge the help of the local contact J. Perez and the support from S. R. Midtgaard and A. Haahr Larsen.
Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.