Huhn Anna, Nissley Daniel, Wilson Daniel B, Kutuzov Mikhail A, Donat Robert, Tan Tiong Kit, Zhang Ying, Barton Michael I, Liu Chang, Dejnirattisai Wanwisa, Supasa Piyada, Mongkolsapaya Juthathip, Townsend Alain, James William, Screaton Gavin, van der Merwe P Anton, Deane Charlotte M, Isaacson Samuel A, Dushek Omer
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
Oxford Protein Informatics Group, Department of Statistics, University of Oxford, Oxford, UK.
Nat Commun. 2025 Jan 2;16(1):338. doi: 10.1038/s41467-024-54916-5.
Key functions of antibodies, such as viral neutralisation, depend on high-affinity binding. However, viral neutralisation poorly correlates with antigen affinity for reasons that have been unclear. Here, we use a new mechanistic model of bivalent binding to study >45 patient-isolated IgG1 antibodies interacting with SARS-CoV-2 RBD surfaces. The model provides the standard monovalent affinity/kinetics and new bivalent parameters, including the molecular reach: the maximum antigen separation enabling bivalent binding. We find large variations in these parameters across antibodies, including reach variations (22-46 nm) that exceed the physical antibody size (~15 nm). By using antigens of different physical sizes, we show that these large molecular reaches are the result of both the antibody and antigen sizes. Although viral neutralisation correlates poorly with affinity, a striking correlation is observed with molecular reach. Indeed, the molecular reach explains differences in neutralisation for antibodies binding with the same affinity to the same RBD-epitope. Thus, antibodies within an isotype class binding the same antigen can display differences in molecular reach, substantially modulating their binding and functional properties.
抗体的关键功能，如病毒中和作用，依赖于高亲和力结合。然而，病毒中和作用与抗原亲和力之间的相关性较差，其原因尚不清楚。在这里，我们使用一种新的二价结合机制模型，研究了45种以上患者分离的IgG1抗体与严重急性呼吸综合征冠状病毒2（SARS-CoV-2）受体结合域（RBD）表面的相互作用。该模型提供了标准的单价亲和力/动力学以及新的二价参数，包括分子作用范围：实现二价结合的最大抗原间距。我们发现这些参数在不同抗体之间存在很大差异，包括超过物理抗体大小（约15纳米）的作用范围差异（22-46纳米）。通过使用不同物理大小的抗原，我们表明这些较大的分子作用范围是抗体和抗原大小共同作用的结果。尽管病毒中和作用与亲和力的相关性较差，但却与分子作用范围存在显著相关性。事实上，分子作用范围解释了具有相同亲和力且结合相同RBD表位的抗体在中和作用上的差异。因此，同一同种型类别中结合相同抗原的抗体在分子作用范围上可能存在差异，从而显著调节其结合和功能特性。
