Antigen-targeted activation of Topo1 inhibitors via click chemistry - Most drugs are administered systemically and spread throughout the body. Due to lack of specificity for the pathological site, high doses are required to achieve effective therapeutic concentrations, causing toxicity and adverse drug effects (ADEs) at sites of the body where they are not needed. Each year, there are approximately 1.2 million reports of ADEs in the U.S. alone, representing over 5% of all hospitalized patients. ADEs also contribute to the 90% failure rate of drug candidates due to the inability to achieve therapeutic concentrations at the target site or intolerable side effects, thus leading to high drug development costs and prices. Toxicity and ADEs are extremely common in chemotherapeutic compounds administered systemically, such as exatecan, a potent inhibitor of topoisomerase I. While these compounds exhibit potent anti-tumor activity, their use and efficacy are hindered by severe and dose-limiting toxicities, including neutropenia and liver dysfunction. However, even specific targeting by addition of antibody conjugation to these drugs (antibody-drug conjugates; ADCs), such as Trastuzumab-deruxtecan (an exatecan analogue) have multiple limitations including systemic release of the chemotherapy payload, poor penetration into solid tumors and limited internalization into tumor cells. Additional factors such as low receptor copy numbers, required internalization for payload activation, and inefficient subcellular trafficking to the lysosome all further limit the potential development of new ADCs. Shasqi is developing a platform to activate drugs at a specific site in the body, thus enhancing their efficacy while minimizing systemic toxicity and adverse drug events (ADEs). Shasqi’s modular click activated prodrug (CAP) platform addresses a critical need and broad commercial opportunity for new technologies capable of efficient activation of therapeutics with spatiotemporal control, making drugs more efficacious by increasing target site concentrations while also improving safety by reducing systemic exposure. This platform also has the potential to enable the reinvestigation and repurposing of drug candidates that may have previously been shelved due to high levels of toxicity. To achieve the aims of this Direct to Phase II study, Shasqi will first characterize and test a novel CEACAM5-targeted activating agent conjugates with attenuated exatecan and deruxtecan prodrugs in a CEACAM5+ xenograft mouse model of colorectal cancer. Then, the efficacy of the platform will be confirmed and challenged within a low expressing CEACAM5+ cancer models and subsequently evaluate pharmacokinetics in naïve rats. Finally, Non-GLP toxicology studies of the selected exatecan and deruxtecan conjugates in naïve rats will be performed prior to the final step of GLP manufacturing for the final conjugate and protodrug in advance of IND-enabling toxicology studies. The above will identify novel antigen-targeted structures for use in Shasqi’s Gen2 CAP and will advance an initial product toward the clinic, which could also be used in future to develop site-directed treatments for other indications, including antibiotics for site-specific infections, autoimmunity, and localized anti-inflammatory and pain management.
