TY - JOUR

T1 - Using Cluster Theory to Calculate the Experimental Structure Factors of Antibody Solutions

AU - Skar-Gislinge, Nicholas

AU - Camerin, Fabrizio

AU - Stradner, Anna

AU - Zaccarelli, Emanuela

AU - Schurtenberger, Peter

N1 - Publisher Copyright: © 2023 The Authors. Published by American Chemical Society.

PY - 2023/5/1

Y1 - 2023/5/1

N2 - 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.

AB - 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.

KW - antibodies

KW - cluster theory

KW - colloids

KW - Monte Carlo simulations

KW - patchy models

KW - small-angle X-ray scattering

UR - http://www.scopus.com/inward/record.url?scp=85154069525&partnerID=8YFLogxK

U2 - 10.1021/acs.molpharmaceut.3c00191

DO - 10.1021/acs.molpharmaceut.3c00191

M3 - Journal article

C2 - 37067466

AN - SCOPUS:85154069525

VL - 20

SP - 2738

EP - 2753

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

SN - 1543-8384

IS - 5

ER -