Targeted drug delivery is an important strategy to transport a therapeutic selectively to a target-of-interest within the body; with the desire to minimise off-target effects while improving pharmacokinetics and pharmacodynamics.

A myriad of strategies have been developed for self-immolative linker systems that fragment due to a chemical trigger. These can be used in antibody-drug conjugates (ADCs) or in pro-drug approaches to release the therapeutic in its native form.

While linezolid is a highly potent broad-spectrum antibiotic, its off-target toxicity limits its use in treating tuberculosis. By incorporating linezolid in an antibody-drug conjugate, this issue could be resolved. However, the motifs present in the molecule preclude a classical linker attachment, where most approaches utilise free amine or alcohol motifs. To overcome this obstacle, a novel strategy has been developed, paving the way for effective and targeted drug delivery in ADCs.

Despite the prevalence of amides in therapeutic molecules, methods for their use as linker attachment points are underdeveloped, hindering the progress of targeted drug delivery. In this work, we have developed a general strategy of amide-linker attachment that selectively releases the desired drug in its native form. The utility of this approach has been demonstrated by the successful fragmentation of a cathepsin-B cleavable ValCit-linezolid prodrug, with equivalent potency to free linezolid and specific activation only in the presence of cathepsin B. Additionally, this prodrug is stable to physiological conditions and human plasma, indicating its suitability for potential clinical use. Based on these promising results, this linezolid release strategy is currently being incorporated into an ADC with a TB targeting antibody.

Felicity Crawshay-Williams

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