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Understanding the Preclinical Efficacy of Antibody-Drug Conjugates

Antibody-drug conjugates (ADCs) represent a therapeutic modality that guides chemotherapies to tumoral cells by using antibodies against tumor-associated antigens (TAAs). The antibody and the chemotherapy or payload are attached by a chemical structure called the linker. The strategy for the develop...

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Bibliographic Details
Published in:International journal of molecular sciences 2024-12, Vol.25 (23), p.12875
Main Authors: Díaz-Tejeiro, Cristina, López de Sá, Alfonso, Poyatos-Racionero, Elisa, Ballestín, Pablo, Bartolomé, Jorge, Calvo, Emiliano, Moreno, Víctor, Moris, Francisco, Pérez-Segura, Pedro, Gyorffy, Balazs, Pandiella, Atanasio, Ocaña, Alberto
Format: Article
Language:English
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Summary:Antibody-drug conjugates (ADCs) represent a therapeutic modality that guides chemotherapies to tumoral cells by using antibodies against tumor-associated antigens (TAAs). The antibody and the chemotherapy or payload are attached by a chemical structure called the linker. The strategy for the development of this type of drug was based on several rational pillars, including the use of a very potent payload and the use of specific antibodies acting only on antigens expressed on tumoral cells. In this article, by using data from all approved ADCs that have received regulatory approval, we analyze the potential contribution of each ADC component to preclinical activity. We suggest that payload potency and the drug-to-antibody ratio (DAR) have a less relevant role in relation to efficacy than previously considered. Additionally, we have observed that some ADCs have been developed against antigens also present in non-transformed tissues, which could suggest that TAA specificity is not a mandatory requirement. Finally, we have identified that ADCs with payloads harboring more favorable physicochemical characteristics showed better potential activity. In this article, we also review other aspects that should be taken into consideration for ADC design, including linker structure, stability, conjugation type, pharmacokinetics, receptor internalization, and recycling. Based on currently available data, our study summaries different concepts that should be considered in the design of novel ADCs in the future.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms252312875