SQ3370 Activates Cytotoxic Drug via Click Chemistry at Tumor and Elicits Sustained Responses in Injected & Non-injected Lesions

Abstract

While systemic immuno-oncology therapies have shown remarkable success, only a limited subset of patients benefit from them. Our Click Activated Protodrugs Against Cancer (CAPAC™) Platform is a click chemistry-based approach that activates cancer drugs at a specific tumor with minimal systemic toxicity. CAPAC Platform is agnostic to tumor characteristics that can vary across patients and hence applicable to several types of tumors. We describe the benefits of SQ3370 (lead candidate of CAPAC) to achieve systemic anti-tumor responses in mice bearing two tumors. SQ3370 consists of a biopolymer, injected in a single lesion, followed by systemic doses of an attenuated protodrug of doxorubicin (Dox). SQ3370 was well-tolerated at 5.9-times the maximum dose of conventional Dox, increased survival by 63% and induced a systemic anti- tumor response against injected and non-injected lesions. The sustained anti-tumor response also correlated with immune activation measured at both lesions. SQ3370 could potentially benefit patients with micro-metastatic lesions.

Pretargeted Imaging Beyond the Blood-Brain-Barrier

“…Development of controlled drug delivery by means of Tz-triggered decaging of TCO-drug conjugates or vice versa (click-to-release) makes this chemistry even more attractive. 24,[34][35][36] Recently, we performed a systematic study of the relationship between the physicochemical properties of Tzs and their in vivo click performance in a colon tumor model. This study revealed that only hydrophilic Tzs with fast click kinetics were suitable for pretargeted imaging.…”

Uncovering the key role of distortion in tetrazine ligations guides the design of bioorthogonal tools that defy the reactivity/stability tradeoff

“…[2][3] Very recently, bioorthogonal chemistry has entered Phase 1 clinical trials, with Tz/TCO-reactions currently being tested in humans, aiming for locally restricted prodrug activation to improve the selectivity of chemotherapeutics. [9][10] In recent years, a variety of differently substituted tetrazines has been used for bioorthogonal reactions and in vivo chemistry, including bis-alkyl-substituted Tz, [11][12][13][14][15] alkyl-aryl-Tz, [16][17][18][19] mono-alkyl-Tz [20] (alkyl-H-Tz) as well as highly reactive bisheteroaryl [21][22] and mono-aryl [23][24][25][26] derivatives (aryl-H-Tz). These applications have motivated and fueled the development of advanced procedures for the synthesis of tetrazine scaffolds.…”

Origin of Increased Reactivity in Rhenium-Mediated Cycloadditions of Tetrazines

“…[9][10][11] A targeted drug delivery system based on this cycloaddition is currently in phase 1 clinical studies. 12,13 Commonly used tetrazines include mono-and di-substituted derivatives with alkyl or aryl groups. [14][15][16][17] Due to the inverse electrondemand nature of the initial, rate limiting [4+2] cycloaddition, electron withdrawing substituents increase reactivity.…”