Frontiers in Antibody–Drug Conjugates: Mechanisms, Design Innovations, and Clinical Applications in Targeted Cancer Therapy

TL;DR

This paper reviews antibody-drug conjugates (ADCs), a targeted cancer therapy that uses antibodies to deliver toxic drugs directly to tumor cells, reducing side effects.

Contribution

The paper provides a comprehensive overview of ADC mechanisms, design innovations, and clinical applications, emphasizing recent advancements and future directions.

Findings

ADCs use monoclonal antibodies to deliver cytotoxic agents to tumor cells, minimizing systemic toxicity.

Approved ADCs like gemtuzumab ozogamicin and trastuzumab emtansine have redefined cancer treatment.

Ongoing research addresses ADC challenges like tumor heterogeneity and resistance through new conjugation and payload technologies.

Abstract

Antibody–drug conjugates (ADCs) represent a transformative class of targeted therapies designed to deliver potent cytotoxic agents specifically to tumor cells, minimizing systemic toxicity. This review provides a comprehensive overview of ADCs, detailing their mechanisms of action, design strategies, and clinical advancements. ADCs utilize monoclonal antibodies to selectively bind tumor-associated antigens, enabling the precise delivery of toxic payloads to cancer cells. The review explores the critical components of ADCs, including the antibody, linker, and payload, and highlights how these elements can be optimized to improve efficacy and minimize off-target effects. We examine the evolution of ADC design from early constructs to the latest innovations and the development of novel payloads that extend therapeutic possibilities beyond traditional cytotoxic agents. Additionally, we discuss the clinical success of ADCs, with examples from approved therapies such as gemtuzumab ozogamicin, brentuximab vedotin, and trastuzumab emtansine, which have redefined the treatment landscape for various cancers. Despite their success, ADCs face challenges such as tumor heterogeneity, resistance mechanisms, and toxicity, which are actively being addressed through ongoing research. The review concludes with an outlook on the future of ADCs, highlighting emerging strategies in conjugation technology, payload design, and combination therapies that are poised to enhance their therapeutic potential across oncology and other disease areas.

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