Department of Nuclear Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
Department of Nuclear Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
J Control Release. 2020 Jun 10;322:200-208. doi: 10.1016/j.jconrel.2020.03.005. Epub 2020 Mar 14.
Monoclonal antibodies (mAbs) are increasingly exploited as vehicles for the targeted delivery of cytotoxic drugs. In antibody-drug conjugates (ADCs) antibodies specifically deliver cytotoxic compounds to cancer cells. Here, we present a technology for elevating the intracellular delivery of antibodies by the conjugation of tetrameric cell-penetrating peptides (tCPPs). The solid phase synthesis of tCPPs and their application in a chemical modification strategy for mAbs provides constructs that attain up to fourfold elevated internalization rates while retaining the mAbs target specificity. The antigen independent internalization is accompanied by beneficial pharmacokinetics limiting off-target accumulation. Applicability was proven for matuzumab, trastuzumab and the ADC Kadcyla®. Cytotoxicity studies of tCPP-conjugates of Kadcyla® resulted in a sixfold increased cytotoxicity proving the potential of chemical modification strategies to extend the applicability of biologicals. This constitutes a significant step towards next-generation antibody-based therapeutics.
单克隆抗体（mAbs）越来越多地被用作靶向递送细胞毒性药物的载体。在抗体药物偶联物（ADCs）中，抗体将细胞毒性化合物特异性递送到癌细胞中。在这里，我们提出了一种通过连接四聚体细胞穿透肽（tCPPs）来提高抗体细胞内递呈的技术。tCPPs 的固相合成及其在 mAbs 化学修饰策略中的应用提供了构建体，这些构建体可实现高达四倍的内化率，同时保留 mAbs 的靶特异性。抗原非依赖性内化伴随着有益的药代动力学，限制了脱靶积累。该方法适用于马妥珠单抗、曲妥珠单抗和 ADC Kadcyla®。tCPP 缀合物的细胞毒性研究导致 Kadcyla®的细胞毒性增加了六倍，证明了化学修饰策略有潜力扩展生物制剂的适用性。这是迈向下一代基于抗体的治疗方法的重要一步。
