Department of Chemistry, University College London, 20 Gordon Street, WC1H 0AJ, London, United Kingdom.
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal.
Bioconjug Chem. 2020 Mar 18;31(3):520-529. doi: 10.1021/acs.bioconjchem.0c00002. Epub 2020 Mar 2.
Diseases are multifactorial, with redundancies and synergies between various pathways. However, most of the antibody-based therapeutics on the market interact with only one target, thus limiting their efficacy. The targeting of multiple epitopes could improve the therapeutic index of treatment and counteract mechanisms of resistance. To this effect, a new class of therapeutics has emerged: bispecific antibodies. Bispecific formation using chemical methods is rare and low-yielding and/or requires a large excess of one of the two proteins to avoid homodimerization and heterogeneity. In order for chemically prepared bispecifics to deliver their full potential, high-yielding, modular, and reliable cross-linking technologies are required. Herein, we describe a novel approach not only for the rapid and high-yielding chemical generation of bispecific antibodies from native antibody fragments, but also for the site-specific dual functionalization of the resulting bioconjugates. Based on orthogonal clickable functional groups, this strategy enables the assembly of functionalized bispecifics with controlled loading in a modular and convergent manner.
疾病是多因素的，各种途径之间存在冗余和协同作用。然而，市场上大多数基于抗体的治疗药物仅与一个靶标相互作用，从而限制了它们的疗效。针对多个表位可以提高治疗的治疗指数并抵抗耐药机制。为此，出现了一类新的治疗药物：双特异性抗体。使用化学方法形成双特异性结构很少见，产量低，或者需要大量过量的两种蛋白质中的一种，以避免同源二聚化和异质性。为了使化学制备的双特异性药物发挥其全部潜力，需要高产、模块化和可靠的交联技术。在此，我们描述了一种新方法，不仅可以从天然抗体片段快速高产地化学生成双特异性抗体，还可以对所得生物缀合物进行特异性双重功能化。基于正交可点击的功能基团，该策略能够以模块化和收敛的方式组装具有受控负载的功能化双特异性抗体。
