Improving antibody-based therapies by chemical engineering of antibodies with multimeric cell-penetrating peptides for elevated intracellular delivery

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 antibodi...

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Bibliographic Details
Published in:Journal of controlled release 2020-06, Vol.322, p.200-208
Main Authors: Sauter, Max, Strieker, Matthias, Kleist, Christian, Wischnjow, Artjom, Daniel, Volker, Altmann, Annette, Haberkorn, Uwe, Mier, Walter
Format: Article
Language:English
Subjects:
Antibody-drug conjugates
Bioconjugation
Cell-penetrating peptides
Monoclonal antibodies
Solid phase peptide synthesis
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Summary: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. [Display omitted] •Conjugation of multimeric cell-penetrating peptides strongly increases the internalization of mAbs and ADCs.•Antibody specificity is retained despite the conjugation of the multimeric cell-penetrating peptides.•Antibody modification leads to improved pharmacokinetic properties.•The elevated internalization increases the cytotoxicity of the ADC conjugates.
ISSN:0168-3659
1873-4995
DOI:10.1016/j.jconrel.2020.03.005