Chemically Cleavable Antibody–Drug Conjugates: Drug Release in One Click
In the new SYNFORM category “Emerging Technologies” Marc Robillard reports on the development of chemically cleavable antibody–drug conjugates.
Since the introduction of the Staudinger ligation, the field of bioorthogonal chemistry has grown rapidly, and today’s bioorthogonal toolbox includes a plethora of reactions that are highly selective and function in aqueous and complex media at physiological pH. Among these, the inverse-electron-demand Diels–Alder (IEDDA) cycloaddition between strained alkenes and tetrazines (TZs) has proven to be an extraordinary tool due to exceptional speed allowing very low reagent concentrations, potentially enabling in vivo click chemistry for medical applications. This reaction has already been applied in a range of fields, such as materials chemistry, chemical bio-logy (protein modification in vivo, study of dynamic processes in living cells, and high-resolution imaging, among others) and nuclear medicine (radiolabeling of sensitive molecules, and pretargeted radioimmunoimaging and therapy). At first, the IEDDA reaction was viewed only as a powerful ligation tool. Until a few years ago when, in 2013, Marc Robillard from Tagworks Pharmaceuticals (The Netherlands) and co-workers developed a bioorthogonal bond cleavage reaction, the IEDDA pyridazine elimination, to enable selective elimination chemistry in living systems.
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