小柯机器人

荷兰Genmab公司Rob N. de Jong研究团队开发出选择性地作用于共同表达两种抗原细胞的逻辑门控抗体对。这一研究成果于2022年7月25日在线发表在国际学术期刊《自然—生物技术》上。

研究人员提出了HexElect，这是一种提高治疗性抗体功能选择性的方法，使其活性取决于与同一靶标细胞上表达的两种不同抗原结合后的聚集。免疫球蛋白G（lgG）介导的膜受体聚集自然发生在细胞表面，从而触发补体或细胞介导的效应器功能或启动细胞内信号。研究人员对两种不同lgG抗体的Fc结构域进行设计来抑制其单独的同源寡聚化，同时在结合共同表达的抗原后促进其成对的异源寡体化。

结果表明，补体成分C1q被招募到这些异源寡聚体上，导致聚集依赖性的激活效应功能，如补体介导的目标细胞的杀伤或细胞表面受体的激活。HexElect能够对表达独特的、潜在未开发的表面抗原组合的靶标细胞进行选择性的抗体活性。

据悉，治疗性单克隆抗体的使用受到限制，因为单一抗原靶点往往不能提供足够的选择性来区分疾病和健康组织。

附：英文原文

Title: Logic-gated antibody pairs that selectively act on cells co-expressing two antigens

Author: Oostindie, Simone C., Rinaldi, Derek A., Zom, Gijs G., Wester, Michael J., Paulet, Desiree, Al-Tamimi, Kusai, van der Meijden, Els, Scheick, Jennifer R., Wilpshaar, Tessa, de Jong, Bart, Hoff-van den Broek, Marloes, Grattan, Rachel M., Oosterhoff, Janita J., Vignau, Julie, Verploegen, Sandra, Boross, Peter, Beurskens, Frank J., Lidke, Diane S., Schuurman, Janine, de Jong, Rob N.

Issue&Volume: 2022-07-25

Abstract: 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.

DOI: 10.1038/s41587-022-01384-1

Source: https://www.nature.com/articles/s41587-022-01384-1

Nature Biotechnology：《自然—生物技术》，创刊于1996年。隶属于施普林格·自然出版集团，最新IF：68.164
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