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Antibody drug conjugates (ADCs) combine the specificity of monoclonal antibodies with potent antineoplastic small molecules, and promise efficacy without the systemic toxicity of chemotherapy. Despite this tremendous potential, most clinical ADCs have failed to provide sufficient therapeutic benefit before the onset of off-target dose-limiting platform toxicities. Here we report the development of proprietary protease cleavable N-acyl sulfonamide linked hemiasterlin and auristatin payloads, Zymelink, that allow the generation of an efficacious ADC platform with improved tolerability. Both Zymelink drug-linkers were conjugated via maleimides to endogenous cysteines. As Zymelink drug-linkers are more polar than maleimide valine citrulline monomethyl auristatin E drug-linker, the resulting ADCs can be produced with potential advantages in PK, efficacy and safety. The resulting ADCs exhibit potent in vitro cytotoxicity. A trastuzumab-based ADC prepared with Zymelink drug-linker and demonstrated at least equivalent efficacy compared to a trastuzumab-based ADC prepared with MMAE, promoting durable complete regressions in a patient-derived xenograft model. Zymelink hemiasterlin and auristatin ADCs were tolerated at 5-6 fold higher doses compared to a MMAE ADC in cynomolgus monkeys. The maximum tolerated dose of the MMAE ADC was just 3 mg/kg based on severe neutropenia. Zymelink hemiasterlin ADC was tolerated at 15 mg/kg with no evidence of neutropenia or elevations in transaminases. Zymelink auristatin ADC was tolerated at 18 mg/kg based on increased levels of transaminases at 24 mg/kg. Moreover, Zymelink ADCs exhibited greater serum exposure at equivalent doses. These results suggest Zymelink ADCs have a greatly expanded therapeutic window compared to MMAE conjugates. Citation Format: Stuart Barnscher, John Babcook, Jamie Rich, Geoff Winters, Graham Garnett, Andrea Hernandez, Vincent Fung, Kevin Yin, Kevin Hamblett, Rupert Davies. Zymelink drug conjugate platform: redefining the therapeutic window for ADCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 61. doi:10.1158/1538-7445.AM2017-61