Angewandte Chemie International Edition · 2022 · 46 citations · 48 references
PharmacyBiotechnologyMedicinal ChemistryAntibody EngineeringDrug DeliveryDrug DesignAntibody ConjugatesAntibody ConjugationAntibody DiscoveryAntibody StructureAntibody-drug ConjugatesTherapeutic Antibody DevelopmentAcyl Transfer ReactionsAntibodiesAntibody - Toxin ConjugatesAntibody-toxin ConjugatesLigand-mediated ReleaseSite-specific Antibody ConjugationTargeting Ligand ConjugationThermal Stability
Direct chemical modification of native antibodies in a site-specific manner remains a great challenge. Ligand-directed conjugation can achieve the selective modification of antibodies, but usually requires multiple extra steps for ligand release and cargo assembly. Herein, we report a novel, traceless strategy to enable the facile and efficient one-step synthesis of site-specific antibody-drug conjugates (ADCs) by harnessing a thioester-based acyl transfer reagent. The designed reagent, consisting of an optimized Fc-targeting ligand, a thioester bridge and a toxin payload, directly assembles the toxin precisely onto the K251 position of native IgGs and simultaneously self-releases the affinity ligand in one step. With this method, we synthesized a series of K251-linked ADCs from native Trastuzumab. These ADCs demonstrated excellent homogeneity, thermal stability, and both in vitro and in vivo anti-tumor activity. This strategy is equally efficient for IgG1, IgG2, and IgG4 subtypes.
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Convergent Solutions to Binding at a Protein-Protein Interface
Warren L. DeLano, Mark Ultsch, Abraham M. de et al. · Science · 2000 · 682 citations