Abstract 7215: Nectin-4 targeted therapy with MMAE protodrug results in anti-tumor efficacy mediated by click chemistry
Authors: Coricor George , McFarland Jesse M. , Srinivasan Sangeetha , Wagner Stefanie , Yee Nathan , Nguyen Tri-Hung , Mejia Oneto Jose M. 
Published: March 2024

Abstract
Shasqi is advancing the Click Activated Protodrugs Against Cancer (CAPAC®) platform based on click chemistry, a Nobel Prize winning technology. The platform is modular and comprises 1) an activator that target specific antigens, and 2) inert cancer drugs, protodrugs, which are selectively activated at tumors via click chemistry. The CAPAC technology separates the tumor targeting function from the payload and reunite them at the tumor creating the flexibility to optimize activity while limiting toxicity during preclinical and clinical development. The modularity of the platform enables the rapid development of new therapies as well as unlocking unique treatment benefits such as tunable combinations and payload cycling. We envision that CAPAC will expand the scope of potential targets, widen the therapeutic index of antibody drug conjugates (ADCs). Here we present a Nectin-4-targeting activator with a monomethyl auristatin E (MMAE) payload.
Nectin-4 is a clinically validated tumor target expressed in a wide range of solid tumors, making Nectin-4 an attractive target for developing new therapeutic approaches for cancer patients. Substantial numbers of Nectin-4 targeting drugs are being developed but exhibit high rates of drug toxicities and highlight the need for alternative approaches that are efficacious and safe. We have developed a Nectin-4 Fab binder conjugated with tetrazine (~2.3 tetrazines per protein), SQT03, and tested it in combination with SQP22, an attenuated protodrug of MMAE conjugated to trans-cyclooctene (TCO). The reaction between tetrazine and TCO moieties releases MMAE at the tumor site. We have previously demonstrated that SQP22 is highly attenuated in vivo at doses that are &gt; 20x the toxic dose of free MMAE, and in combination with a HER2 targeting activator, led to significant tumor growth inhibition in NCI-N87 gastric cancer xenograft model. The separation of an antigen-targeting activator from the payload by CAPAC technology allowed the rapid development and subsequent testing of SQT03 in combination with SQP22 in vitro and in vivo. SQT03 displayed &lt;10nM binding affinity to Nectin-4 positive cells by flow cytometry analysis. In vivo, dosing of SQT03 occurs 8-24hrs prior to SQP22 to reduce systemic activation and to enable specific release of the active cytotoxic payload at the tumor site. In the T47D breast cancer xenograft model, a single dose of SQP22 at 8-24hrs after SQT03 led to tumor regression without body weight loss, in contrast to the 5% of body weight loss presented by two doses of Enfortumab-vedotin required to lead to similar activity.
The presented data illustrates how the CAPAC platform can be used to test various therapeutic combinations, accelerating development, and reducing the time it takes to bring treatments to the clinic. The results support further development and testing of MMAE protodrug with Nectin-4 targeting agent in clinical settings.
Citation Format: George Coricor, Jesse M. McFarland, Sangeetha Srinivasan, Stefanie Wagner, Nathan Yee, Tri-Hung Nguyen, Jose M. Mejia Oneto. Nectin-4 targeted therapy with MMAE protodrug results in anti-tumor efficacy mediated by click chemistry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7215.