Three years after demonstrating the first-ever in vivo use of click chemistry by safely delivering 12 times the standard dose of doxorubicin directly to tumors, Shasqi is again pushing boundaries. Its CAPAC platform, which initially relied on intratumoral injections, now targets CEACAM5, a cell-surface antigen overexpressed in lung, gastric, pancreatic, colorectal, esophageal/HNSCC, and cervical cancers, with a systemically administered MMAE. Early data in rats reveal a 300-fold improvement in tolerability of their activated MMAE protodrug compared with conventional MMAE at 50x the dose.
Typically, “less than 1% of the ADC dose actually reaches the tumor,” CEO José Mejía Oneto, MD, Ph.D. said. “This is true for small molecules and biologics.” The biologic has to break down into smaller pieces, releasing the payload over multiple days. “That prolonged exposure can lead to toxicity,” Mejía Oneto said. While developers have tried making ADCs more stable, “that doesn’t solve the fundamental problem of so little drug getting to the tumor,” Mejía Oneto said. Shasqi aims to reduce efficacy-limiting toxicities seen with conventional MMAE antibody-drug conjugates (ADCs) by decoupling tumor targeting from payload activation. “We have a manuscript that was accepted, and we’re hoping to have a commentary,” Mejía Oneto said. “Overall, it underscores the significance of using click chemistry in human patients.”
More drug to tumors can translate to less toxicity
A slide from Shasqi’s JPM presentation
José Mejía Oneto, MD, Ph.D.
“If you look at the complete responses … the real question is how to unlock those. Reducing off-target toxicity is key. You can’t stop 99% of the drug from going places it doesn’t need to be, but If you reduce toxicity to the rest of the body, you can get more drug to tumor, and achieve more complete responses.,” said biotech veteran Sadie Whittaker, Ph.D., who has consulted with Shasqi for the past two years.
An alliance with J&J
In 2023, SHASQI strengthened a pact with J&J that focused on CAPAC, an abbreviation for Click-Activated Protodrugs Against Cancer. Since its debut with intratumoral biopolymers before that, Shasqi has honed the CAPAC platform into a two-step, systemically administered strategy—one that can reach difficult-to-access tumors and spare patients from direct injections. Not every patient has a lesion that can be safely injected; by pivoting to an infusion-based approach, Shasqi has expanded the potential number of patients who can benefit. In the updated workflow, an antigen-specific binder infuses through the bloodstream, anchoring to tumors that overexpress targets such as CEACAM5 (lung, gastric, pancreatic, colorectal, esophageal/HNSCC, and cervical) or HER2 (human epidermal growth factor receptor 2; notable in breast and gastric cancer). A masked protodrug is then administered systemically; once these components converge in the tumor, a click-chemistry reaction activates the cytotoxic payload. “The core idea is pre-targeting: How do you get more drug to the tumor and less to normal tissues? We use a binder with a click chemistry component. It binds tumor antigen, accumulates in the tumor, and then clears from circulation. Next, we infuse the payload, which clicks to the binder in the tumor,” Mejía Oneto said.
By keeping the binder and payload separate, CAPAC is designed to deliver higher local doses without saturating normal tissues. As Mejía Oneto noted of the Johnson & Johnson partnership: “It’s going really well. They’ve validated a lot of our results on their side and are now defining how they want to proceed with this approach.”
At JPM, Shasqi showed the potential of complete tumor regression with the single-dose CEACAM5 Program, outperforming tusamitamab ravtansine by a wide margin in terms of mean tumor volume reduction.
700-fold less active before activation relative to conventional MMAE
Based on research presented at the Society for Immunotherapy of Cancer (SITC) Annual Meeting 2024 (Abstract #1278, “Attenuated MMAE therapeutic activated by click chemistry at the tumor evokes potent immune responses”), Shasqi’s attenuated monomethyl auristatin E (MMAE) protodrug is 700-fold less active before activation compared with conventional MMAE, offering significantly reduced toxicity. Once activated, it shows 300-fold better tolerability than standard MMAE—even at 50 times the dose. CEACAM5’s characteristics as a poorly internalizing target make it particularly well-suited for Shasqi’s approach. While this property typically limits ADC efficacy by preventing adequate internalization, CAPAC activates on the cell surface. Recent data illustrates this advantage—a single dose of CEACAM5-targeted MMAE using CAPAC achieved complete tumor regressions and showed superiority to tusamitamab ravtansine (Sanofi’s CEACAM5-ADC that advanced to Phase 3 before being halted). Shasqi’s modular design can also be applied to chelated radioisotopes; clinical data are now emerging in soft tissue sarcoma patients using a doxorubicin-based iteration of the platform (Abstract #624, “Doxorubicin-based click chemistry therapeutic activates potent cytotoxic immune responses in advanced sarcoma patients in a Phase 1/2a clinical trial”).
Shasqi recently welcomed industry veteran Travis Biechele, Ph.D.—formerly of Seagen (acquired by Pfizer in late 2023) and Merck—as VP of Research to accelerate pipeline development. “Shasqi’s technology is highly differentiated and has the potential to greatly improve the therapeutic index of cancer drugs,” Biechele said in a press release upon joining. “While sharing some of the fundamental principles, Shasqi’s technology was thoughtfully designed to solve many of the shortcomings of ADCs.”
Since 2021, Shasqi has secured more than $8 million in NIH grants. Mejía Oneto said, “We aim to secure funding from different sources, each with its own priorities. The NCI is huge for supporting more exploratory or pipeline-expanding projects. Venture capital is interested in validation and technology expansion that drives investor value. The third avenue of funding is BD partnerships. We are in discussions with a number of big pharma companies who are focused on targeted therapies. They are interested in how they might collaborate on the CAPAC technology. Our technology is flexible enough to tap into all three avenues.”
Filed Under: Oncology
