On January 27, 2021 Shasqi, a clinical-stage biotechnology company developing precision oncology therapeutics with its proprietary Click Activated Protodrugs Against Cancer (CAPACTM) platform, reported the publication of two preclinical studies highlighting the potential of the company’s click chemistry-based approach to the development of treatments for a range of solid cancers (Press release, Shasqi, JAN 27, 2021, View Source [SID1234574359]). The paper, "Click activated protodrugs against cancer increase the therapeutic potential of chemotherapy through local capture and activation" was published in the journal Chemical Science on January 5, 2021 and the paper, "SQ3370 Activates Cytotoxic Drug via Click Chemistry at Tumor and Elicits Sustained Responses in Injected and Non–Injected Lesions” was published in the journal Advanced Therapeutics on January 20, 2021. Shasqi is currently advancing its lead clinical candidate, SQ3370, a click-activated protodrug therapy, in a phase 1 clinical trial.
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"A goal of targeted cancer treatments is to achieve high tumor specificity with minimal side effects. The limitations of targeted therapies, which benefit only a small subset of patients, make this goal difficult to achieve in practice," said José M. Mejía Oneto, M.D., Ph.D., Founder and CEO of Shasqi. "We believe our platform has the potential to overcome these limitations and benefit patients regardless of biomarker status or genetics. The published evidence reinforces the ability of our lead candidate, SQ3370, to do that in preclinical models. We are now in the process of evaluating this approach in our first clinical trial and look forward to sharing data later this year."
Click Activated Protodrugs Against Cancer Increase the Therapeutic Potential of Chemotherapy through Local Capture and Activation. Wu, K., et. al., Chemical Science. January 5, 2021
Protodrugs of various chemotherapy agents were tested in vitro to evaluate cytotoxicity, solubility, stability and activation. These studies rendered the protodrug of doxorubicin, SQP33, as the most promising candidate for in vivo studies. In mice, the maximum tolerated dose of SQP33 in combination with locally injected tetrazine-modified biopolymer (SQL70) was 19.1-times the maximum-tolerated dose of conventional doxorubicin. Pharmacokinetics studies in rats show that a single injection of SQL70 efficiently captures multiple SQP33 protodrug doses given cumulatively at 10.8-times the maximum-tolerated dose of conventional doxorubicin with greatly reduced systemic toxicity. Combined treatment with SQL70 and SQP33 (together called SQ3370) showed antitumor activity in a syngeneic tumor model in mice.
SQ3370 Activates Cytotoxic Drug via Click Chemistry at Tumor and Elicits Sustained Responses in Injected and Non–Injected Lesions. Srinivasan, S., et. al.. Advanced Therapeutics. January 20, 2021
This study found that the Shasqi’s Click Activated Protodrugs Against Cancer (CAPAC) platform is capable of developing medicines to treat a range of tumor types and that SQ3370 is tolerated well above the maximum dose of conventional doxorubicin. In preclinical models, SQ3370 increased survival by 63 percent over conventional doxorubicin and induced a potent systemic anti–tumor response against injected as well as non–injected lesions. The sustained anti–tumor response correlated with activation of the immune system which was measured at both lesions.
SQ3370 is the first click chemistry-based treatment to be tested in humans. This study, SQ3370-001, is currently enrolling patients with advanced sarcomas and other solid tumors in the United States and Australia (ClinicalTrials.gov NCT04106492). The company presented preclinical and trial-in-progress data from the SQ3370 program in late 2020.
CAPAC and SQ3370
SQ3370 utilizes Shasqi’s proprietary Click Activated Protodrugs Against Cancer (CAPAC) platform, a click chemistry-based approach that activates cancer drugs at a specific tumor with minimal systemic toxicity. The platform utilizes the biocompatible chemical reaction between an attenuated trans-cyclooctene-modified protodrug and a tetrazine-modified biopolymer. The biopolymer is injected into the target tumor lesion, where it precisely captures and activates an infused protodrug. Unlike traditional targeted therapies, the CAPAC platform is agnostic to tumor characteristics that can vary from patient to patient, such as biomarker expression and enzymatic activity. CAPAC is highly modular and can be applied to a wide variety of cancer therapeutics.