Modeling bispecific monoclonal antibody interaction with two cell membrane targets indicates the importance of surface diffusion.
Modeling bispecific monoclonal antibody interaction with two cell membrane targets indicates the importance of surface diffusion.
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DOI：
10.1080/19420862.2016.1178437
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发表时间：
2016-07
期刊：
影响因子：
5.3
通讯作者：
Sepp A
中科院分区：
文献类型：
--
作者：
Sengers BG;McGinty S;Nouri FZ;Argungu M;Hawkins E;Hadji A;Weber A;Taylor A;Sepp A
我们已经开发了一个数学框架，用于描述双特异性单克隆抗体与两个独立的膜结合的目标，在同一细胞表面上表达的相互作用。溶液中的双特异性抗体首先结合两个靶标中的任一个，然后在细胞表面上时与第二个靶标交联，在单链抗体接合的抗体-抗原复合物的寿命内经历限速横向扩散步骤。在实验密度下，预期在任何时候只有一小部分游离靶标位于抗体结合位点的范围内。使用常微分方程和基于蒙特卡罗模拟的模型，我们验证了这种方法对独立发表的抗CD 4/CD 70 DuetMab实验数据集。作为尺寸减小的结果，预期细胞表面反应如此迅速，使得与实验数据一致，在交联完成之前没有单核苷酸结合的双特异性抗体二元复合物积累。预期双特异性抗体从三元交联复合物的解离显著慢于从任一单核苷酸结合变体的解离。我们估计，双特异性结合的双特异性抗体的有效亲和力比单核苷酸结合的种类提高约4个数量级。这种亲合力增强允许抗CD 4/CD 70 DuetMab与两种靶抗原均阳性的细胞高度特异性结合，而不是仅表达一种或另一种的细胞。我们认为，靶抗原在细胞膜中的侧向扩散在天然抗体和其他二价配体与其各自细胞表面受体相互作用的亲合力效应中也起着关键作用。
We have developed a mathematical framework for describing a bispecific monoclonal antibody interaction with two independent membrane-bound targets that are expressed on the same cell surface. The bispecific antibody in solution binds either of the two targets first, and then cross-links with the second one while on the cell surface, subject to rate-limiting lateral diffusion step within the lifetime of the monovalently engaged antibody-antigen complex. At experimental densities, only a small fraction of the free targets is expected to lie within the reach of the antibody binding sites at any time. Using ordinary differential equation and Monte Carlo simulation-based models, we validated this approach against an independently published anti-CD4/CD70 DuetMab experimental data set. As a result of dimensional reduction, the cell surface reaction is expected to be so rapid that, in agreement with the experimental data, no monovalently bound bispecific antibody binary complexes accumulate until cross-linking is complete. The dissociation of the bispecific antibody from the ternary cross-linked complex is expected to be significantly slower than that from either of the monovalently bound variants. We estimate that the effective affinity of the bivalently bound bispecific antibody is enhanced for about 4 orders of magnitude over that of the monovalently bound species. This avidity enhancement allows for the highly specific binding of anti-CD4/CD70 DuetMab to the cells that are positive for both target antigens over those that express only one or the other We suggest that the lateral diffusion of target antigens in the cell membrane also plays a key role in the avidity effect of natural antibodies and other bivalent ligands in their interactions with their respective cell surface receptors.