Physical Chemistry, Department of Chemistry, Lund University, SE-221 00 Lund, Sweden.
Soft Condensed Matter, Debye Institute for Nanomaterials Science, Utrecht University, Princetonplein 5, 3584 CC Utrecht, The Netherlands.
Mol Pharm. 2023 May 1;20(5):2738-2753. doi: 10.1021/acs.molpharmaceut.3c00191. Epub 2023 Apr 17.
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.
单克隆抗体溶液有望成为未来几年的主要治疗工具，通过巧妙设计其抗原结合位点，能够针对各种疾病。然而，由于在高浓度下通常会出现粘度增加，因此为适合患者自我给药而配制稳定溶液通常具有挑战性。在这里，我们通过对自缔合抗体存在时出现的聚集体的特性进行表征，在抗体溶液的微观分子细节与其产生的性质之间建立了联系。具体而言，我们发现可以通过基于存在此类聚集体的先前用于研究聚合物和胶体物体的分析模型来解释实验小角度 X 射线散射数据。这些聚集体由理论计算确定，并得到了粗粒度最小模型的计算机模拟的支持，其中抗体被视为 Y 形胶体分子，而吸引力域被设计为补丁。使用理论预测的聚集体尺寸分布，我们能够在广泛的浓度和盐条件下描述实验结构因子。因此，我们提供了微观证据，证明了粘度随浓度增加的事实源于聚集体的存在。我们的研究结果为单克隆抗体的自组装提供了新的见解，可用于指导稳定有效的抗体溶液的配方。
