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Drug Delivery

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The revolution of Antibody-Drug Conjugates: how this modular macromolecular platform has reshaped chemotherapy

Manuscript deadline
30 November 2023

Cover image - Drug Delivery

Article collection guest advisor(s)

Prof. Gianfranco Pasut, Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padua, Italy
[email protected]

Dr. Tommaso Tedeschini, Italian Institute of Technology, Genoa, Italy
[email protected]

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The revolution of Antibody-Drug Conjugates: how this modular macromolecular platform has reshaped chemotherapy

Antibody-drug conjugates (ADCs) are an established therapeutic option in which a small molecule drug, often called payload, is conjugated to a monoclonal antibody (mAb) via a chemical linker. Hailed as the realization of Paul Elrich’s “magic bullet” notion, these trimodular constructs have been primarily conceived and designed to increase the therapeutic index of chemotherapy drugs by leveraging the antibody carrier’s ability to target tumour-specific antigens and hence to deliver the effect to cancer cells in a selective fashion. In some cases, the antibody contributes to the overall activity of the ADC by, for example, blocking specific cellular receptors or engaging the immune system (e.g., trastuzumab-emtansine). The scenario of ADCs clinical use started in 2000 when gemtuzumab ozogamicin, an anti-CD33-specific IgG4κ mAb conjugated to a calicheamicin derivative, was approved by the US Food and Drug Administration (FDA) for the treatment of leukaemia. ADCs can be considered the first selectively targeted drug delivery system approved for clinical use.

Since then, the field has grown considerably, counting, so far, 14 approved conjugates worldwide and more than 100 candidates in clinical trials. However, the quest for the perfect magic bullet is anything but at an end. The current ADCs present flaws such as the lack of complete responses in some cases, the ineluctable presence of off-target dose-limiting toxicities, the limited drug loading often required to avoid ADC’s instabilities, the ever-present problem of drug resistance, and the problematic penetration in solid tumours.

Consequently, there is still an impellent need for improved ADCs, which can be attained, for example, through engineered designs of the mAb, new precise strategies of drug conjugation, tailored mAb/drug linkers for stable blood circulation and prompt drug release in tumours, altogether with a better understanding of the determinants that are relevant for effective and safe use of this class of drugs.

In this article collection, we welcome original articles and reviews dealing with the ADC topic and focusing on the following aspects:

- ADCs’ design and development
- Conjugation strategies
- New linkers for enhanced drug loading, selective conjugation, or precise drug release
- The mAb format as a suitable platform for the preparation of ADCs
- New payloads for ADCs
- Other therapeutic applications of ADCs beyond anticancer therapy

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All manuscripts submitted to this Article Collection will undergo desk assessment and peer-review as part of our standard editorial process. Guest Advisors for this collection will not be involved in peer-reviewing manuscripts unless they are an existing member of the Editorial Board. Please review the journal Aims and Scope and author submission instructions prior to submitting a manuscript.