New-Generation Self-Immolative Spacers for the Release of Anticancer Drugs from ADCs

The targeted delivery of cytotoxic agents via antibody-drug conjugates (ADCs) has become a highly attractive method for treating various types of cancers.[1] From the structural viewpoint, traditional ADCs are composed of a monoclonal antibody (mAb) linked to a cytotoxic agent via a protease-cleavable peptide linker and a self-immolative (SI) spacer. In recent years, the significant success of this emerging technology in different types of cancers has stimulated the global effort on finding different ADC’s components and new connections between them, in order to improve the pharmacokinetic properties of the whole ADC construct.[3] For instance, a fast self-immolation mechanism of a proline-based SI spacer for the release of alcohol payloads from carbamate prodrugs[4] has been investigated, through successful new drug-linker syntheses and conjugation on engineered mAb. In this communication, I will describe the structure and activation kinetics of new-generation self-immolative spacers, designed to release hydroxy-bearing drugs. Upon synthesis of the linker-spacer-payload modules and their conjugation to a model antibody, the ADCs were incubated in the presence of a protease and the metabolites were analyzed by LC-MS. In these analyses, the two linker-spacer modules showed markedly different drug release kinetics (Figure 1), providing important structural information for the optimization of new ADC as candidates for follow-up preclinical studies.