Shasqi uses click chemistry, a Nobel Prize winning technology, to advance the Click Activated Protodrugs Against Cancer (CAPAC®) platform. The platform is modular and comprises 1) tumor-targeting activators, and 2) attenuated cancer drugs, dubbed protodrugs, which are selectively activated at tumors via click chemistry. The CAPAC technology separates tumor targeting from payload activation, creating the flexibility to optimize activity while limiting toxicity during preclinical and clinical development. The modularity of the platform leverages the library of components to enable the rapid development of new therapies as well as unlock unique treatment benefits such as tunable combinations and payload cycling. We envision that CAPAC will expand the scope of potential targets, widen the activity window, and enhance the safety of antibody drug conjugates (ADCs). Here we present proof of concept for a HER2-targeting activator with a monomethyl auristatin E (MMAE) payload.
The activator SQT01 is composed of a HER2-binding Fab conjugated with tetrazines. The protodrug SQP22 is formed by coupling trans-cyclooctene to MMAE, a cytotoxic spindle poison. SQP22 was evaluated in vitro and in vivo for stability, activation with tetrazine and potency attenuation. The activity of SQT01 with SQP22 was tested in HER2+ NCI-N87 xenografts to identify the optimal dosing schedule and measure tumor exposure.
SQP22 was found to be stable in plasma and had minimal cytotoxicity in the absence of the activator. In the NCI-N87 model, the administration of SQT01 followed by SQP22 resulted in a significant inhibition of tumor growth on day 29 (80% TGI) as compared to a non-binding control (28% TGI) or the ADC disitamab vedotin (47% TGI), which targets HER2 and carries MMAE. No body weight loss was observed. Analysis of NCI-N87 tumors confirmed the presence of both Fab and tetrazine up to 24 hours post SQT01 dosing. A time course study has identified 24 hours as the optimal schedule of SQP22 administration following SQT01 dosing. Analysis of tumors showed MMAE at >100 ng/g within 15 minutes of SQP22 injection. The intratumoral exposure profile of MMAE will be presented. Thus, the rate of MMAE accumulation in tumors is highly differentiated from the profile reported with vedotin ADCs.
These results confirm that click chemistry selectively activates an auristatin protodrug and provides a new avenue to get cytotoxic agents directly to tumors.

Tri-Hung Nguyen

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