Antibody-drug Conjugates in Cancer Treatment: An Overview

Abstract

The development of antibody-drug conjugates (ADCs) has significantly impacted cancer therapy, progressing from foundational discoveries in the late 19th century to contemporary clinical applications. With the approval of the first ADC in 2000 and subsequent advancements, including over 30 ADCs in advanced clinical development, the therapeutic landscape for cancer patients has undergone a notable transformation. From initial cleavable linker technologies to the latest third-generation ADCs, continuous innovation in ADC design has been evident. Novel conjugation and linker technologies, alongside the identification of specific target antigens in solid cancers, have reinvigorated prospects for treating challenging malignancies. However, challenges such as off-target toxicity and heterogeneous antigen expression persist. The prevailing empirical approach to systemic cancer therapy administration presents challenges, including potential under-treatment of aggressive disease and over-treatment of indolent conditions, along with frequent adverse effects. Robust prognostic markers are essential to differentiate disease aggressiveness levels, guide treatment decisions, and anticipate adverse effects. Companion diagnostics for targeted therapies, such as HER-2 status for trastuzumab in breast cancer and BCR–ABL mutations for imatinib resistance in CML, enable personalized treatment strategies. Similarly, BRCA mutations predict response to PARP inhibitors in breast and ovarian cancers, while BRAF mutations guide treatment with BRAF inhibitors in melanoma. Patient selection strategies for clinical trials involving ADCs rely on prospective selection or retrospective analysis, each with its merits and challenges.