Abstract 6245: SQ3370 enhances the safety and therapeutic index of cytotoxic agents via local activation therapy with improved local and systemic immune response
Authors: Yee Nathan , Srinivasan Sangeetha , Mahmoodi Amir , Zakharian Michael , Royzen Maksim , Oneto Jose Mejia 
Published: September 2020

Abstract
With systemic chemotherapy, only 1-2% of the administered dose reaches a localized tumor, while the remaining leads to adverse off-target toxicities, including immunosuppression. Hence, there is a critical need to locally deliver cytotoxics directly to the tumor. Our patented approach (SQ3370) consists of:
1. SQL70 - a drug-activating biomaterial carrying no payload
2. SQP33 - a chemically-modified prodrug of doxorubicin (Dox) with attenuated activity.
SQL70 is injected at the tumor site followed by SQP33 administered systemically. The prodrug is first captured by the biomaterial due to their complementary chemical reactivities. The active drug is then spontaneously released, providing local delivery directly to the tumor region while reducing systemic side effects.
Previously, we have shown that the greater safety of SQP33 allows it to be given at over 38 times the dose of standard Dox in SQL70-injected mice. Pharmacokinetic and biodistribution studies in SQ3370-treated rodents and dogs show highly efficient capture and activation of the prodrug, likely due to the rapid reaction of SQP33 with SQL70. Without SQL70, SQP33 shows minimal spontaneous conversion to activated Dox. Additionally, after SQL70 injection, increased dosing of SQP33 led to higher active drug levels at the injection site but not to other tissues. These studies indicate that a single injection of SQL70 can selectively activate multiple doses of SQP33 at the target site, maximizing the local therapeutic index.
Recent studies demonstrate that SQ3370 treatment enhances therapeutic response and survival in tumor-bearing mice: In a syngeneic MC38 colorectal cancer model, SQ3370 treatment showed significantly improved anti-tumor response and overall survival compared to conventional Dox therapy.
In mice bearing two tumors, we observed that SQL70 injection at one tumor site followed by systemic SQP33 treatment induced an anti-tumor response in both the injected and non-injected tumors. Furthermore, we found that SQ3370 increased CD4 and CD8 TILs and decreased regulatory T-cells in both injected and non-injected tumors. These findings suggest that SQ3370 is capable of inducing an immune-mediated anti-tumor effect, thus expanding potential treatment options in the clinic and highlighting the advantages of immune-sparing cytotoxic therapy.
Collectively, our results demonstrate that SQ3370 enables delivery of cytotoxic drugs to a target site while limiting exposure in off-target tissues in small and large animals, leading to improvements in both safety and efficacy.
Citation Format: Nathan Yee, Sangeetha Srinivasan, Amir Mahmoodi, Michael Zakharian, Maksim Royzen, Jose Mejia Oneto. SQ3370 enhances the safety and therapeutic index of cytotoxic agents via local activation therapy with improved local and systemic immune response [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6245.