Review
Version 1
Preserved in Portico This version is not peer-reviewed
Lysosomal Cleavable Peptide Linkers in Antibody-Drug Conjugates
Version 1
: Received: 15 May 2023 / Approved: 16 May 2023 / Online: 16 May 2023 (04:51:34 CEST)
A peer-reviewed article of this Preprint also exists.
Balamkundu, S.; Liu, C.-F. Lysosomal-Cleavable Peptide Linkers in Antibody–Drug Conjugates. Biomedicines 2023, 11, 3080. Balamkundu, S.; Liu, C.-F. Lysosomal-Cleavable Peptide Linkers in Antibody–Drug Conjugates. Biomedicines 2023, 11, 3080.
Abstract
Antibody-Drug Conjugates (ADCs) are a powerful therapeutic modality for cancer treatment. ADCs are multi-functional biologics in which a disease-targeting antibody is conjugated to an effector payload molecule through a linker. The success of currently used ADCs has been largely attributed to the development of linker systems which allow targeted release of cytocidal payload drugs inside cancer cells. Many lysosomal proteases are over-expressed in human cancers. They can effectively cleave a variety of peptide sequences, which can be exploited in the design of ADC linker systems. As a well-established linker, valine-citrulline-p-aminobenzyl carbamate (ValCitPABC) is used in many ADCs that are already approved or under preclinical and clinical development. Although ValCitPABC and related linkers are readily cleaved by cathepsins in the lysosome while remaining reasonably stable in human plasma, many studies have shown that they are susceptible to carboxylesterase 1C (Ces1C) in mouse and rat plasma, which hinders preclinical evaluation of the ADCs. Furthermore, neutropenia and thrombocytopenia, two of the most commonly observed dose-limiting adverse effects of ADCs, are believed to result from the premature hydrolysis of ValCitPABC by human neutrophil elastase. In addition to cathepsin-cleavable linkers, there is also growing interest in legumain-sensitive linkers for ADC development. Increasing plasma stability while maintaining lysosomal cleavability of ADC linkers is an objective of intensive current research. This review reports recent advances in the design and structure-activity relationship studies of various peptide/peptidomimetic linkers in this field.
Keywords
antibody-drug conjugate; lysosome; cathepsin; legumain; self-immolation; payload release; peptidomimetic; linker
Subject
Medicine and Pharmacology, Medicine and Pharmacology
Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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