The use of therapeutic monoclonal antibodies is constrained because single antigen targets often do not provide sufficient selectivity to distinguish diseased from healthy tissues. We present HexElect^®, an approach to enhance the functional selectivity of therapeutic antibodies by making their activity dependent on clustering after binding to two different antigens expressed on the same target cell. lmmunoglobulin G (lgG)-mediated clustering of membrane receptors naturally occurs on cell surfaces to trigger complement- or cell-mediated effector functions or to initiate intracellular signaling. We engineer the Fc domains of two different lgG antibodies to suppress their individual homo-oligomerization while promoting their pairwise hetero-oligomerization after binding co-expressed antigens. We show that recruitment of complement component C1q to these hetero-oligomers leads to clustering-dependent activation of effector functions such as complement mediated killing of target cells or activation of cell surface receptors. HexElect allows selective antibody activity on target cells expressing unique, potentially unexplored combinations of surface antigens.

治疗性单克隆抗体的使用受到限制，因为单一抗原靶点通常不能提供足够的选择性来区分患病组织和健康组织。我们推出了 HexElect ^® ，这是一种增强治疗性抗体功能选择性的方法，通过使治疗性抗体的活性依赖于与同一靶细胞上表达的两种不同抗原结合后的聚类。免疫球蛋白 G (IgG) 介导的膜受体聚集自然发生在细胞表面，以触发补体或细胞介导的效应功能或启动细胞内信号传导。我们设计了两种不同 IgG 抗体的 Fc 结构域，以抑制其各自的同源寡聚化，同时在结合共表达抗原后促进其成对的异源寡聚化。我们发现，补体成分 C1q 向这些异源寡聚物的募集会导致效应功能的簇依赖性激活，例如补体介导的靶细胞杀伤或细胞表面受体的激活。 HexElect 允许对表达独特的、潜在未开发的表面抗原组合的靶细胞进行选择性抗体活性。