On June 22, 2020 Shasqi, a leader in chemistry based locally-activated cancer drugs, reported data showing that the company’s lead candidate SQ3370 produced robust anti-tumor responses both at the target site and at distal lesions in a preclinical cancer model (Press release, Shasqi, JUN 22, 2020, View Source [SID1234561411]). The study, titled "SQ3370, a Local Activation Therapy of Cytotoxic Agents, Produces Sustained Responses in Target and Distal Lesions via Immune Activation," was presented in a poster with audio at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II.
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Shasqi’s SQ3370 is a novel investigational drug product that uses bioorthogonal "click" chemistry reactions to capture and activate an attenuated anthracycline prodrug at the target tumor site enabling higher doses of the cancer drug while reducing side effects commonly experienced with conventional chemotherapy. Unlike other therapeutic approaches, Shasqi’s technology is solely based on chemistry and is independent of tumor biology such as biomarker expression and enzymatic activity.
This new therapeutic modality can precisely control the duration of exposure and magnitude of activated drugs at a specific area in the body. This allows the exploration of therapeutic benefits of a drug that had been previously limited by existing routes of administration in the clinic (oral, intravenous, direct injection or controlled release).
"SQ3370 is powered by an innovative chemistry based approach to precisely deliver high doses of a cancer drug locally and potentially activate the immune system against human tumors, independent of biological markers," said Carolyn R. Bertozzi, Ph.D., professor of chemistry and HHMI investigator at Stanford University.
SQ3370 consists of two components – SQL70, a hyaluronic acid-based biomaterial and SQP33, a prodrug of Doxorubicin, a commonly used chemotherapy. During treatment, SQL70 biomaterial is first injected at the target tumor site. SQP33 prodrug is then given systemically through daily IV infusions for 5 days. SQP33 prodrug remains in attenuated form in the body until it reaches the target tumor site and is captured by SQL70. Once captured, SQP33 is converted and released as active Doxorubicin at the target tumor.
In the study, Shasqi’s scientists evaluated SQ3370 in a preclinical cancer model in mice bearing two tumors, where the target lesion was injected with the SQL70 biomaterial and the distal lesion was not.
Treatment with SQ3370 significantly prolonged overall survival by reducing target lesions compared to controls. Interestingly, SQ3370 also reduced tumor growth at the distal lesion, which was not injected with the SQL70 biomaterial. Together, this suggests SQ3370 can induce both local and systemic anti-tumor responses.
"Our data demonstrate that SQ3370 can significantly reduce tumor size in both, tumors injected with the biomaterial, and at distal lesions. The preclinical data suggests that our approach can be relevant against the critical challenges facing clinicians today: undetectable lesions or widely disseminated solid tumors," said Nathan Yee, Ph.D., Senior Scientist at Shasqi and an author of the study.
Immune biomarker analysis indicates that SQ3370 triggers an immune response as shown by an increase in cytotoxic and helper T cells, and a decrease in regulatory T cells in both target and distal lesions. To further validate the immune activating properties, combination treatment with SQ3370 and an immune-activating agent led to more robust and sustained anti-cancer responses than controls with conventional Doxorubicin.
Additionally, in a separate study in rats, SQ3370 reduced adverse exposure to heart, kidney and liver tissue compared to conventional Doxorubicin treatment, indicating lower off-target toxic effects.
"Because of its highly modular nature, we can use our platform on numerous cancer drugs with doses traditionally limited due to toxicity and uncover new pharmacological benefits," said José M. Mejía Oneto, M.D., Ph.D., Founder and CEO of Shasqi. "To evaluate the translation of our findings to humans, we are initiating our first clinical trial of SQ3370 as a monotherapy in advanced solid tumors, and expect to dose our first patient shortly."
The entire AACR (Free AACR Whitepaper) poster presentation plus an audio description of the data by Dr. Yee, can be found here. In addition, the abstract for the poster can be found here.