The success of seven clinically-approved therapeutic antibody-drug conjugates (ADCs) demonstrates targeted delivery of cytotoxic payloads to tumors as an effective clinical approach. However, a significant number of ADCs have failed in the clinic due to acute toxicity in subjects. Such dose-limiting toxicities in large part originate form a premature release of cytotoxin prior to reaching tumor cells. While recent improvements of ligation approaches have partly mitigated the protein-cytotoxin deconjugation problem, the apparent instability of the commonly used enzymatically-cleavable peptide linkers is yet to be fully addressed. A typical linker design incorporates dipeptides that are readily cleaved upon internalization by lysosomal proteases. However, they are also susceptible to cleavage by promiscuous enzymes during circulation. Herein, we describe development of a novel type of stable and effective linker for ADCs that requires two consecutive cleavage events to release cytotoxin intracellularly. We demonstrate that this approach, combined with our SMARTag® site-specific conjugation technology, allows the production of ADCs with improved stability in plasma, low toxicity, and favorable pharmacokinetic profile.

Development of dual-cleavage linkers for next generation antibody-drug conjugates with expanded therapeutic window

ACS Fall 2020 Virtual Meeting

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