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Improving antibody-based therapies by chemical engineering of antibodies with multimeric cell-penetrating peptides for elevated intracellular delivery.
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2020-03-14 , DOI: 10.1016/j.jconrel.2020.03.005 Max Sauter 1 , Matthias Strieker 2 , Christian Kleist 2 , Artjom Wischnjow 2 , Volker Daniel 3 , Annette Altmann 4 , Uwe Haberkorn 5 , Walter Mier 2
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2020-03-14 , DOI: 10.1016/j.jconrel.2020.03.005 Max Sauter 1 , Matthias Strieker 2 , Christian Kleist 2 , Artjom Wischnjow 2 , Volker Daniel 3 , Annette Altmann 4 , Uwe Haberkorn 5 , Walter Mier 2
Affiliation
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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.
中文翻译：
通过用多聚体穿透细胞的肽对抗体进行化学工程来提高细胞内递送的化学工程来改善基于抗体的疗法。
单克隆抗体（mAb）越来越多地被用作靶向递送细胞毒性药物的载体。在抗体-药物缀合物（ADC）中，抗体将细胞毒性化合物特异性地递送至癌细胞。在这里，我们提出了一种通过结合四聚体细胞穿透肽（tCPPs）来提高抗体在细胞内递送的技术。tCPP的固相合成及其在mAb的化学修饰策略中的应用提供了在保持mAb靶标特异性的同时，可实现高达四倍的内在化速率的构建体。抗原独立的内在化伴随着限制离靶积累的有益药代动力学。已证明适用于马妥珠单抗，曲妥珠单抗和ADCKadcyla®。Kadcyla®的tCPP结合物的细胞毒性研究导致细胞毒性增加了六倍，证明了化学修饰策略可扩展生物制剂的应用范围。这是迈向下一代基于抗体的治疗方法的重要一步。
更新日期：2020-03-16
中文翻译：
通过用多聚体穿透细胞的肽对抗体进行化学工程来提高细胞内递送的化学工程来改善基于抗体的疗法。
单克隆抗体（mAb）越来越多地被用作靶向递送细胞毒性药物的载体。在抗体-药物缀合物（ADC）中，抗体将细胞毒性化合物特异性地递送至癌细胞。在这里，我们提出了一种通过结合四聚体细胞穿透肽（tCPPs）来提高抗体在细胞内递送的技术。tCPP的固相合成及其在mAb的化学修饰策略中的应用提供了在保持mAb靶标特异性的同时，可实现高达四倍的内在化速率的构建体。抗原独立的内在化伴随着限制离靶积累的有益药代动力学。已证明适用于马妥珠单抗，曲妥珠单抗和ADCKadcyla®。Kadcyla®的tCPP结合物的细胞毒性研究导致细胞毒性增加了六倍，证明了化学修饰策略可扩展生物制剂的应用范围。这是迈向下一代基于抗体的治疗方法的重要一步。
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