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Pharmaceuticals
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Recent Insights of Antibody-Drug Conjugate Effectiveness
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Recent Insights of Antibody-Drug Conjugate Effectiveness

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Biopharmaceuticals".

Deadline for manuscript submissions: closed (5 March 2022) | Viewed by 29955

Special Issue Editors

Dr. Jeffrey V. Leyton

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Guest Editor
Department of Nuclear Medicine and Radiobiology Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
Interests: ADC payloads; linkers; linker chemistry; conjugation; ADC modifications
Dr. Mark Barok

E-Mail
Guest Editor
1. Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
2. Laboratory of Molecular Oncology, Biomedicum, University of Helsinki, Helsinki, Finland
Interests: antibody–drug conjugates; extracellular vesicles; drug resistance; breast cancer; gastric cancer

Special Issue Information

Dear Colleagues,

Antibody–drug conjugates (ADCs) are a new type of anti-cancer drug designed to deliver cytotoxic payloads specifically to cancer cells. Nine ADCs have received approval from the U.S. Food and Drug Administration so far, and over 100 ADCs are being investigated in nearly 600 clinical trials currently. In this Special Issue of Pharmaceuticals, we review the current stage of ADC development. We discuss the payloads used in ADCs, the conjugation and linker chemistry, and the clinical applications. We also discuss the limitations of ADC technology, drug resistance to ADCs, and possible strategies to improve the efficacy of these anti-cancer drugs and to decrease their side effects.

Dr. Jeffrey V. Leyton
Dr. Mark Barok
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • antibody–drug conjugate
  • ADC
  • payload
  • linker
  • drug resistance
  • anti-cancer drugs
  • monoclonal antibodies
  • conjugation and linker chemistry
  • clinical applications

Published Papers (3 papers)

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Review

33 pages, 1080 KiB  
Review
Impact of Endocytosis Mechanisms for the Receptors Targeted by the Currently Approved Antibody-Drug Conjugates (ADCs)—A Necessity for Future ADC Research and Development
by Manar Hammood, Andrew W. Craig and Jeffrey V. Leyton
Pharmaceuticals 2021, 14(7), 674; https://doi.org/10.3390/ph14070674 - 15 Jul 2021
Cited by 29 | Viewed by 10560
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Recent Insights of Antibody-Drug Conjugate Effectiveness)
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46 pages, 17334 KiB  
Review
The Chemistry Behind ADCs
by Vesela Kostova, Patrice Désos, Jérôme-Benoît Starck and Andras Kotschy
Pharmaceuticals 2021, 14(5), 442; https://doi.org/10.3390/ph14050442 - 07 May 2021
Cited by 58 | Viewed by 14385
Abstract
Combining the selective targeting of tumor cells through antigen-directed recognition and potent cell-killing by cytotoxic payloads, antibody-drug conjugates (ADCs) have emerged in recent years as an efficient therapeutic approach for the treatment of various cancers. Besides a number of approved drugs already on [...] Read more.
Combining the selective targeting of tumor cells through antigen-directed recognition and potent cell-killing by cytotoxic payloads, antibody-drug conjugates (ADCs) have emerged in recent years as an efficient therapeutic approach for the treatment of various cancers. Besides a number of approved drugs already on the market, there is a formidable follow-up of ADC candidates in clinical development. While selection of the appropriate antibody (A) and drug payload (D) is dictated by the pharmacology of the targeted disease, one has a broader choice of the conjugating linker (C). In the present paper, we review the chemistry of ADCs with a particular emphasis on the medicinal chemistry perspective, focusing on the chemical methods that enable the efficient assembly of the ADC from its three components and the controlled release of the drug payload. Full article
(This article belongs to the Special Issue Recent Insights of Antibody-Drug Conjugate Effectiveness)
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17 pages, 9579 KiB  
Review
Toward Homogenous Antibody Drug Conjugates Using Enzyme-Based Conjugation Approaches
by Ahmad Fawzi Hussain, Armin Grimm, Wenjie Sheng, Chaoyu Zhang, Marwah Al-Rawe, Karen Bräutigam, Mobarak Abu Mraheil, Felix Zeppernick and Ivo Meinhold-Heerlein
Pharmaceuticals 2021, 14(4), 343; https://doi.org/10.3390/ph14040343 - 08 Apr 2021
Cited by 16 | Viewed by 3606
Abstract
In the last few decades, antibody-based diagnostic and therapeutic applications have been well established in medicine and have revolutionized cancer managements by improving tumor detection and treatment. Antibodies are unique medical elements due to their powerful properties of being able to recognize specific [...] Read more.
In the last few decades, antibody-based diagnostic and therapeutic applications have been well established in medicine and have revolutionized cancer managements by improving tumor detection and treatment. Antibodies are unique medical elements due to their powerful properties of being able to recognize specific antigens and their therapeutic mechanisms such as blocking specific pathways, antibody-dependent cellular cytotoxicity, and complement-dependent cytotoxicity. Furthermore, modification techniques have paved the way for improving antibody properties and to develop new classes of antibody-conjugate-based diagnostic and therapeutic agents. These techniques allow arming antibodies with various effector molecules. However, these techniques are utilizing the most frequently used amino acid residues for bioconjugation, such as cysteine and lysine. These bioconjugation approaches generate heterogeneous products with different functional and safety profiles. This is mainly due to the abundance of lysine and cysteine side chains. To overcome these limitations, different site-direct conjugation methods have been applied to arm the antibodies with therapeutic or diagnostics molecules to generate unified antibody conjugates with tailored properties. This review summarizes some of the enzyme-based site-specific conjugation approaches. Full article
(This article belongs to the Special Issue Recent Insights of Antibody-Drug Conjugate Effectiveness)
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