CEACAM5-targeted activation of potent chemotherapeutics via bioorthogonal click chemistry - Abstract Shasqi, Inc. is utilizing its innovative Click Activated Protodrugs Against Cancer (CAPAC®) platform to improve the therapeutic efficacy of cancer treatments by facilitating precise and localized activation of potent cytotoxic drugs. Many standard-of-care therapies lack tumor specificity and often require high doses to achieve a therapeutic benefit, which result in significant toxicity and adverse drug events (ADEs). Similarly, antibody-drug conjugates (ADCs), while designed as targeted therapeutics, deliver less than 2% of the active drug to the tumor site. A much larger fraction of the dose is distributed to and degraded in healthy tissues, resulting in off-target toxicities, limiting the therapeutic index. Shasqi’s CAPAC platform overcomes these challenges by using bioorthogonal click chemistry to activate drugs precisely at the tumor site. The platform is made up of a two- component system: a tetrazine-modified antigen-targeting conjugate and a trans-cyclooctene-modified prodrug (a.k.a. protodrug). The first component, the tetrazine conjugate, is designed to bind specifically to tumor- associated antigens, such as CEACAM5, and is otherwise inert until paired with the second component. The second component, the protodrug, is inactive until it encounters the tetrazine conjugate at the tumor site. Upon meeting, a highly specific and rapid chemical reaction occurs between the two components, releasing the active drug only in the localized area of the tumor, maximizing efficacy and reducing systemic toxicity. This Direct-to- Phase II project targets CEACAM5, which is an antigen whose expression has been well established in several cancers with significant unmet need. CEACAM5 has been found in over 90% of colorectal, gastric and pancreatic cancer cases, and in 25% of non-small-cell lung cancers (NSCLC) cases. CEACAM5 is ideal for localized drug activation, not just because of its slow internalization kinetics, but also due to its high tumor specificity and minimal expression in normal tissues. By optimizing CEACAM5-targeted activating agents and conducting preclinical studies focused on pharmacokinetics, efficacy and tolerability, this project aims to develop a novel platform for targeted drug delivery. The specific aims of this projects are: 1) Develop and characterize CEACAM5-targeted activating agent conjugates, 2) Evaluate pharmacokinetic/pharmacodynamic (PK/PD) properties of preferred conjugates, 3) Demonstrate antitumor efficacy of CEACAM5-binders with MMAE protodrug in multiple murine tumor models of lung carcinoma and 4) Perform a non-GLP toxicology study in naïve rats. Aside from cancer therapy, the CAPAC platform also has the potential for adoption by other therapeutic areas, such as infectious diseases and autoimmune disorders, since it offers improved therapeutic outcomes with minimal toxicity.
