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Chemists, biologists and clinicians, among other scientists, are partnering their expertise to improve their design, synthesis, efficacy and precision as they strive to advance this paradigm of personalized and targeted medicine to treat cancer patients more effectively and to expand its scope to other indications. Just as Alexander Fleming's penicillin, and the myriad other bioactive natural products that followed its discovery and success in the clinic, ignited a revolution in medicine after the Second World War, so did calicheamicin \u03b3<jats:sub>1<\/jats:sub><jats:sup>I<\/jats:sup>, and other highly potent naturally occurring antitumor agents, play a pivotal role in enabling the advent of this new paradigm of \u201cbiological\u2010small molecule hybrid\u201d medical intervention. Today there are four clinically approved drugs from the ADC paradigm, Mylotarg, Adcetris, Kadcyla and Besponsa, in order of approval, the first and the last of which carry the same calicheamicin \u03b3<jats:sub>1<\/jats:sub><jats:sup>I<\/jats:sup>\u2010derived payload. Covering oncological applications, and after a brief history of the emergence of the field of antibody\u2013drug conjugates triggered more than a century ago by Paul Ehrlich's \u201cmagic bullet\u201d concept, this Review is primarily focusing on the chemical synthesis aspects of the ADCs multidisciplinary research enterprise.<\/jats:p>","DOI":"10.1002\/anie.201903498","type":"journal-article","created":{"date-parts":[[2019,4,23]],"date-time":"2019-04-23T06:30:08Z","timestamp":1556001008000},"page":"11206-11241","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":97,"title":["The Role of Organic Synthesis in the Emergence and Development of Antibody\u2013Drug Conjugates as Targeted Cancer Therapies"],"prefix":"10.1002","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5332-2511","authenticated-orcid":false,"given":"K. 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