Impact of Endocytosis Mechanisms for the Receptors Targeted by the Currently Approved Antibody-Drug Conjugates (ADCs)—A Necessity for Future ADC Research and Development
Biologically-based therapies increasingly rely on the endocytic cycle of internalization and exocytosis of target receptors for cancer therapies. However, receptor trafficking pathways (endosomal sorting (recycling, lysosome localization) and lateral membrane movement) are often dysfunctional in can...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-07-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/7/674 |
| _version_ | 1797526392913526784 |
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| author | Manar Hammood Andrew W. Craig Jeffrey V. Leyton |
| author_facet | Manar Hammood Andrew W. Craig Jeffrey V. Leyton |
| author_sort | Manar Hammood |
| collection | DOAJ |
| description | Biologically-based therapies increasingly rely on the endocytic cycle of internalization and exocytosis of target receptors for cancer therapies. However, receptor trafficking pathways (endosomal sorting (recycling, lysosome localization) and lateral membrane movement) are often dysfunctional in cancer. Antibody-drug conjugates (ADCs) have revitalized the concept of targeted chemotherapy by coupling inhibitory antibodies to cytotoxic payloads. Significant advances in ADC technology and format, and target biology have hastened the FDA approval of nine ADCs (four since 2019). Although the links between aberrant endocytic machinery and cancer are emerging, the impact of dysregulated internalization processes of ADC targets and response rates or resistance have not been well studied. This is despite the reliance on ADC uptake and trafficking to lysosomes for linker cleavage and payload release. In this review, we describe what is known about all the target antigens for the currently approved ADCs. Specifically, internalization efficiency and relevant intracellular sorting activities are described for each receptor under normal processes, and when complexed to an ADC. In addition, we discuss aberrant endocytic processes that have been directly linked to preclinical ADC resistance mechanisms. The implications of endocytosis in regard to therapeutic effectiveness in the clinic are also described. Unexpectedly, information on endocytosis is scarce (absent for two receptors). Moreover, much of what is known about endocytosis is not in the context of receptor-ADC/antibody complexes. This review provides a deeper understanding of the pertinent principles of receptor endocytosis for the currently approved ADCs. |
| first_indexed | 2024-03-10T09:28:54Z |
| format | Article |
| id | doaj.art-8354b71c12c34d6fb3582d301dd6978e |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T09:28:54Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-8354b71c12c34d6fb3582d301dd6978e2023-11-22T04:40:00ZengMDPI AGPharmaceuticals1424-82472021-07-0114767410.3390/ph14070674Impact of Endocytosis Mechanisms for the Receptors Targeted by the Currently Approved Antibody-Drug Conjugates (ADCs)—A Necessity for Future ADC Research and DevelopmentManar Hammood0Andrew W. Craig1Jeffrey V. Leyton2Departément de Medécine Nucléaire et Radiobiologie, Faculté de Medécine et des Sciences de la Santé, Centre Hospitalier Universitaire de Sherbrooke (CHUS), Université de Sherbrooke, Sherbrooke, QC J1H 5N4, CanadaDepartment of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, CanadaDepartément de Medécine Nucléaire et Radiobiologie, Faculté de Medécine et des Sciences de la Santé, Centre Hospitalier Universitaire de Sherbrooke (CHUS), Université de Sherbrooke, Sherbrooke, QC J1H 5N4, CanadaBiologically-based therapies increasingly rely on the endocytic cycle of internalization and exocytosis of target receptors for cancer therapies. However, receptor trafficking pathways (endosomal sorting (recycling, lysosome localization) and lateral membrane movement) are often dysfunctional in cancer. Antibody-drug conjugates (ADCs) have revitalized the concept of targeted chemotherapy by coupling inhibitory antibodies to cytotoxic payloads. Significant advances in ADC technology and format, and target biology have hastened the FDA approval of nine ADCs (four since 2019). Although the links between aberrant endocytic machinery and cancer are emerging, the impact of dysregulated internalization processes of ADC targets and response rates or resistance have not been well studied. This is despite the reliance on ADC uptake and trafficking to lysosomes for linker cleavage and payload release. In this review, we describe what is known about all the target antigens for the currently approved ADCs. Specifically, internalization efficiency and relevant intracellular sorting activities are described for each receptor under normal processes, and when complexed to an ADC. In addition, we discuss aberrant endocytic processes that have been directly linked to preclinical ADC resistance mechanisms. The implications of endocytosis in regard to therapeutic effectiveness in the clinic are also described. Unexpectedly, information on endocytosis is scarce (absent for two receptors). Moreover, much of what is known about endocytosis is not in the context of receptor-ADC/antibody complexes. This review provides a deeper understanding of the pertinent principles of receptor endocytosis for the currently approved ADCs.https://www.mdpi.com/1424-8247/14/7/674endocytosisantibody-drug conjugateCD33CD30CD22CD79b |
| spellingShingle | Manar Hammood Andrew W. Craig Jeffrey V. Leyton Impact of Endocytosis Mechanisms for the Receptors Targeted by the Currently Approved Antibody-Drug Conjugates (ADCs)—A Necessity for Future ADC Research and Development Pharmaceuticals endocytosis antibody-drug conjugate CD33 CD30 CD22 CD79b |
| title | Impact of Endocytosis Mechanisms for the Receptors Targeted by the Currently Approved Antibody-Drug Conjugates (ADCs)—A Necessity for Future ADC Research and Development |
| title_full | Impact of Endocytosis Mechanisms for the Receptors Targeted by the Currently Approved Antibody-Drug Conjugates (ADCs)—A Necessity for Future ADC Research and Development |
| title_fullStr | Impact of Endocytosis Mechanisms for the Receptors Targeted by the Currently Approved Antibody-Drug Conjugates (ADCs)—A Necessity for Future ADC Research and Development |
| title_full_unstemmed | Impact of Endocytosis Mechanisms for the Receptors Targeted by the Currently Approved Antibody-Drug Conjugates (ADCs)—A Necessity for Future ADC Research and Development |
| title_short | Impact of Endocytosis Mechanisms for the Receptors Targeted by the Currently Approved Antibody-Drug Conjugates (ADCs)—A Necessity for Future ADC Research and Development |
| title_sort | impact of endocytosis mechanisms for the receptors targeted by the currently approved antibody drug conjugates adcs a necessity for future adc research and development |
| topic | endocytosis antibody-drug conjugate CD33 CD30 CD22 CD79b |
| url | https://www.mdpi.com/1424-8247/14/7/674 |
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