McMaster Immunology Research Center (MIRC), Department of Pathology and Molecular Medicine, and Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4L8, Canada.
ACS Chem Biol. 2020 Apr 17;15(4):1089-1095. doi: 10.1021/acschembio.0c00112. Epub 2020 Mar 13.
Unprecedented progress made in the treatment of cancer using the body's own immune system has encouraged the development of synthetic molecule based immunotherapeutics. An emerging class of these compounds, called Antibody Recruiting Molecules (ARMs) or Antibody Engagers (AEs), functions by reversibly binding antibodies naturally present in human serum and recruiting these to cancer cells. The recruited antibodies then engage immune cells to form quaternary complexes that drive cancer erradication. Despite their promise, the requirement to form quaternary complexes governed by multiple equilibria complicates an understanding of their efficacy. Particularly problematic are low endogenous serum antibody concentrations and rapid clearance of AEs from circulation. Here we describe a new class of trifunctional chemical tools we call covalent immune recruiters (CIRs). CIRs covalently label specific serum antibodies in a selective manner with a target protein binding ligand. CIRs thereby exert well-defined control over antibody recruitment and simplify quaternary complex equilibium, enabling probing of the resultant effects on immune recognition. We demonstrate CIRs can selectively covalently label anti-DNP IgG, a natural human antibody, directly in human serum to drive efficient immune cell recognition of targets. We expect CIRs will be useful tools to probe how quaternary complex stability impacts the immune recognition of cancer , revealing new design principles to guide the development of future AEs.
利用人体自身免疫系统治疗癌症方面取得了前所未有的进展，这促使了基于合成分子的免疫疗法的发展。这些化合物中有一类新兴的化合物，称为抗体募集分子（ARM）或抗体效应器（AE），通过可逆结合人血清中天然存在的抗体并将其募集到癌细胞上来发挥作用。募集的抗体随后与免疫细胞结合形成四级复合物，从而驱动癌症的消除。尽管它们具有很大的潜力，但形成受多个平衡控制的四级复合物使人们对它们的疗效难以理解。特别是内源性血清抗体浓度低和 AE 从循环中快速清除的问题。在这里，我们描述了一类新的三功能化学工具，我们称之为共价免疫招募剂（CIR）。CIR 以选择性的方式将靶蛋白结合配体共价标记到特定的血清抗体上。CIR 因此可以对抗体募集进行明确的控制，并简化四级复合物平衡，从而可以探测对免疫识别的影响。我们证明，CIR 可以直接在人血清中选择性地共价标记抗 DNP IgG，一种天然的人抗体，从而有效地驱动免疫细胞识别靶标。我们预计 CIR 将是有用的工具，可以探测四级复合物稳定性如何影响癌症的免疫识别，为指导未来 AE 的发展提供新的设计原则。
