Pre-targeting with click chemistry facilitates selective MMAE activation in CEACAM5+ tumors: A first-in-class approach to enhance clinical benefit in targeted therapy

Targeted therapies such as antibody-drug conjugates (ADCs) have transformed the delivery of cytotoxic payloads to tumors, yet their clinical efficacy is often hampered by off-target toxicities. These toxicities arise when the antigen-binding component undergoes systemic catabolic elimination that leads to premature release of the cytotoxic payload in healthy tissues. A pre-targeting approach which separates the targeting binder from the cytotoxic payload and enables them to unite only at the tumor site, offers a promising solution. In this paradigm, the binder is allowed to concentrate at the tumor but clear systemically before the protodrug is administered, It ensures that the payload is activated predominantly where the binder has accumulated-at the tumor-thereby reducing off-target toxicity and increasing the therapeutic index. We present preclinical data on Shasqi's Click Activated Protodrugs Against Cancer (CAPAC®), a click chemistry-based pre-targeting technology that powers tumor-directed in vivo payload activation. The therapeutic candidate consists of a CEACAM5-targeted, clickable small format antibody binder and a chemically attenuated, clickable protodrug of monomethyl auristatin E (MMAE). Upon administration, the binder accumulates at the tumor, and a subsequent protodrug dose 'clicks' specifically with the binder, restoring cytotoxic activity. The CEACAM5 binder showed high affinity (KD 0.046 nM) and binding potency (EC50 3.06 nM) with minimal internalization while retaining its ability to activate protodrugs. The MMAE protodrug was attenuated ~700-fold in vitro and cleared rapidly in vivo (thalf, fast = 6 min, thalf, slow =19 min), minimizing systemic exposure. In multiple CEACAM5+ xenograft models, CAPAC enabled superior tumor control compared to a cognate ADC, including complete responses in highly sensitive tumors (pancreatic and lung) and durable stasis in minimally sensitive tumors (gastric). The treatment also induced marked tumor regression in large mouse tumors. It was well tolerated in naïve rodents. This first-in-class CEACAM5-directed pre-targeting strategy addresses key limitations of conventional targeted therapies by leveraging in vivo click chemistry to selectively concentrate cytotoxic payloads at the tumor. It illustrates robust anti-tumor efficacy in multiple tumor models, including large tumors, more representative of the disease in humans, and a favorable tolerability profile. By decoupling the targeting from the payload delivery, pre-targeting with CAPAC minimizes off-target toxicity, enables higher dosing and has the potential to enhance clinical benefit.