Antibody-Drug Conjugate-Based Therapeutics: State of the Science
Cet article passe en revue les évolutions techniques des différents éléments structurels des conjugués anticorps-médicaments puis analyse les résultats cliniques de quatre conjugués-médicaments ayant reçu une autorisation de mise sur le marché ainsi que les résultats prometteurs d'anticorps-médicaments actuellement en cours de développement et destinés aux traitements de tumeurs solides et de cancers hématologiques
Antibody-drug conjugates (ADCs) are complex engineered therapeutics consisting of monoclonal antibodies, directed toward tumor-associated antigens, to which highly potent cytotoxic agents are attached using chemical linkers. This targeted drug delivery strategy couples the precision of the antibody targeting moiety with the cytocidal activity of the payload, which is generally too toxic on its own to be systemically administered. In this manner, ADCs confer a means to reduce off-target toxicities in patients by limiting the exposure of normal tissues to the payload, thus broadening the potential therapeutic window compared with traditional chemotherapy. The pace of ADC development is accelerating, with the number of investigational agents in human trials having more than tripled over the past 5 years, underscoring the enthusiasm for this transformative approach to cancer treatment. Here, we review the key structural elements of ADC design (antibody, linker, and payload), highlighting critical aspects and technological advances that have impacted the clinical effectiveness of this class of biopharmaceuticals. The ADC field continues to evolve, including ongoing efforts aimed at improving target selection, developing payloads with varied mechanisms of action and increased potency, designing innovative bioconjugation strategies, as well as maximizing efficacy and tolerability in patients. An overview of the current clinical trial landscape is provided, with emphasis on the clinical experience of the four ADCs to have received regulatory approval to date, as well as additional promising candidates currently in late-stage clinical development in both solid tumor and hematological malignanices.
Journal of the National Cancer Institute , article en libre accès, 2018