Lysosomal-Cleavable Peptide Linkers in Antibody–Drug Conjugates
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 via a linker. The success of currently used ADCs has been largely attributed to the develo...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-11-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/11/3080 |
| _version_ | 1797460034342354944 |
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| author | Seetharamsing Balamkundu Chuan-Fa Liu |
| author_facet | Seetharamsing Balamkundu Chuan-Fa Liu |
| author_sort | Seetharamsing Balamkundu |
| collection | DOAJ |
| description | 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 via a linker. The success of currently used ADCs has been largely attributed to the development of linker systems, which allow for the 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 for the design of ADC linker systems. As a well-established linker, valine-citrulline-<i>p</i>-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 the preclinical evaluation of 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 ValCitPABC, the GGFG tetrapeptidyl-aminomethoxy linker is also cathepsin-cleavable and is used in the highly successful ADC drug, DS8201a. 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. |
| first_indexed | 2024-03-09T16:59:24Z |
| format | Article |
| id | doaj.art-5306da6e88a14aa28beb3e7eab36fc10 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-09T16:59:24Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-5306da6e88a14aa28beb3e7eab36fc102023-11-24T14:31:25ZengMDPI AGBiomedicines2227-90592023-11-011111308010.3390/biomedicines11113080Lysosomal-Cleavable Peptide Linkers in Antibody–Drug ConjugatesSeetharamsing Balamkundu0Chuan-Fa Liu1School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, SingaporeSchool of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, SingaporeAntibody–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 via a linker. The success of currently used ADCs has been largely attributed to the development of linker systems, which allow for the 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 for the design of ADC linker systems. As a well-established linker, valine-citrulline-<i>p</i>-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 the preclinical evaluation of 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 ValCitPABC, the GGFG tetrapeptidyl-aminomethoxy linker is also cathepsin-cleavable and is used in the highly successful ADC drug, DS8201a. 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.https://www.mdpi.com/2227-9059/11/11/3080antibody–drug conjugatelysosomecathepsinlegumainself-immolationpayload release |
| spellingShingle | Seetharamsing Balamkundu Chuan-Fa Liu Lysosomal-Cleavable Peptide Linkers in Antibody–Drug Conjugates Biomedicines antibody–drug conjugate lysosome cathepsin legumain self-immolation payload release |
| title | Lysosomal-Cleavable Peptide Linkers in Antibody–Drug Conjugates |
| title_full | Lysosomal-Cleavable Peptide Linkers in Antibody–Drug Conjugates |
| title_fullStr | Lysosomal-Cleavable Peptide Linkers in Antibody–Drug Conjugates |
| title_full_unstemmed | Lysosomal-Cleavable Peptide Linkers in Antibody–Drug Conjugates |
| title_short | Lysosomal-Cleavable Peptide Linkers in Antibody–Drug Conjugates |
| title_sort | lysosomal cleavable peptide linkers in antibody drug conjugates |
| topic | antibody–drug conjugate lysosome cathepsin legumain self-immolation payload release |
| url | https://www.mdpi.com/2227-9059/11/11/3080 |
| work_keys_str_mv | AT seetharamsingbalamkundu lysosomalcleavablepeptidelinkersinantibodydrugconjugates AT chuanfaliu lysosomalcleavablepeptidelinkersinantibodydrugconjugates |