{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T19:13:38Z","timestamp":1793128418000,"version":"4.5.0"},"reference-count":133,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T00:00:00Z","timestamp":1782604800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Antibody\u2013drug conjugates (ADCs) have evolved from early heterogeneous constructs into a mature therapeutic platform with exponential clinical relevance. This review highlights recent advances in ADC design and development, with emphasis on antigen selection, antibody engineering, linker and payload innovation, site-specific conjugation, clinical translation, toxicity, resistance, and emerging data-driven approaches. Methods: The review draws on the literature published from 2019 to the recent clinical and regulatory developments relevant to approved and late-stage ADCs, emphasizing the advances in target biology, antibody formats, linker chemistry, payload classes, conjugation technologies, developability assessment, and computational or artificial intelligence-assisted design strategies. Results: ADC development has evolved with improved target selection, enhanced internalization and tumor selectivity, and the use of engineered, bispecific, biparatopic, and fragment-based antibody formats. Linker and payload innovation has expanded beyond traditional microtubule inhibitors to include topoisomerase I inhibitors, DNA-damaging agents, and emerging dual-payload or non-cytotoxic strategies. Site-specific conjugation and improved control of drug-to-antibody ratio have increased stability, pharmacokinetic performance, and manufacturability. Clinically, ADCs are being used across a broader range of malignancies and treatment settings, although toxicities and resistance mechanisms remain an important limitations. Computational methods and artificial intelligence are increasingly being explored for target discovery, molecular optimization, toxicity prediction, and model-informed clinical development. Conclusions: ADCs are transitioning toward a more integrated, design-driven platform in which antigen biology, antibody format, chemistry, and computational prediction are jointly optimized. Future progress will depend on improved standardization, biomarker-guided development, and interdisciplinary approaches to enhance its therapeutic index and expand its applications beyond oncology.<\/jats:p>","DOI":"10.3390\/cancers18132102","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T02:16:44Z","timestamp":1782699404000},"page":"2102","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Advances and Future Directions in Antibody\u2013Drug Conjugates: From Paradigm Shifts to Data-Driven Design"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1596-9239","authenticated-orcid":false,"given":"Smita","family":"Kumari","sequence":"first","affiliation":[{"name":"Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 500 W. 12th Ave., Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lillian M.","family":"Cool","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 500 W. 12th Ave., Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Howard","sequence":"additional","affiliation":[{"name":"Neuroscience Program, College of Arts and Sciences, The Ohio State University, 230 North Oval Mall, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4675-7784","authenticated-orcid":false,"given":"Jogendra Singh","family":"Pawar","sequence":"additional","affiliation":[{"name":"The Ohio State University Comprehensive Cancer Center\u2014Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, 460 W. 10th Ave., Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Wu, G., Yuan, Z., Chen, M., Tang, X., Wang, F., and Zhang, D. (2026). Antibody\u2013Drug Conjugates (ADCs): A Review of Structural Design, Technological Evolution, and Future Perspectives. 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