ADCs are a class of biopharmaceuticals that combine monoclonal antibodies with potent cytotoxic agents. This article traces their development through three generations, explores reasons behind successes and failures in clinical trials, and underscores the complexity of selecting suitable targets. By integrating technological advances in AI, single-cell sequencing, and combination therapies, researchers aim to widen ADCs' therapeutic window and application scope.
Key points of the review include:

1. Target selection is paramount: Successful ADC development depends heavily on selecting antigens that are highly expressed in tumors but minimally or not at all in normal tissues. However, ideal targets are rare, and many once-promising antigens have later been found in healthy tissues, causing toxicity. Intratumoral heterogeneity and dynamic antigen expression further complicate this challenge.
2. HER2 as a double-edged sword: Although HER2-targeting ADCs like trastuzumab deruxtecan have shown significant efficacy, they carry risks due to HER2 expression in heart and lung tissues. Fatal side effects such as respiratory disease and cardiotoxicity underscore the importance of assessing antigen distribution in non-tumor tissues.
3. Trop2 and EGFR challenges: Trop2 is widely expressed in normal epithelial tissues, leading to broad toxicity profiles despite its therapeutic promise. Similarly, EGFR-targeting ADCs have shown efficacy but also induce severe infusion reactions and eye disorders, indicating a narrow therapeutic window and necessitating precision targeting.
4. Claudin-18 shows promise: Claudin-18, with its restricted expression in normal tissue and high presence in tumors, emerges as a safer ADC target. Clinical trials of Claudin-18-targeting ADCs report minimal adverse effects so far, highlighting its therapeutic potential.

The development of ADCs represents a critical frontier in targeted cancer therapy, but progress is hindered by biological complexity, off-target effects, and resistance mechanisms. This review emphasizes that precise antigen selection, supported by cutting-edge technologies like single-cell sequencing and artificial intelligence, is essential to minimize toxicity and improve efficacy. Future success hinges on integrating these strategies with innovations in antibody engineering and drug-linker chemistry, as well as leveraging combination therapies. Claudin-18 serves as a potential model for safer targeting, while ongoing work continues to refine and expand the ADC toolkit for broader and more effective cancer applications. The work entitled “ The Icarian flight of antibody-drug conjugates: target selection amidst complexity and tackling adverse impacts” was published on Protein & Cell (published on Jan. 15, 2025).
DOI：https://doi.org/10.1093/procel/pwaf002