| Popis: |
The Click Activated Protodrugs Against Cancer (CAPACTM) platform enables activation of powerful cancer drugs at tumor sites, maximizing efficacy and minimizing systemic toxicity. CAPAC utilizes a potent click chemistry reaction between tetrazine and trans-cyclooctene, called tetrazine ligation. The reaction between the activator, linked to a tumor targeting agent, and the protodrug leads to targeted activation of the drug. In this study, activation is accomplished either by intratumoral injection of a tetrazine-modified hyaluronic acid biopolymer (SQL70) or by systemic infusion of a tetrazine-modified HER2-targeting antigen-binding fragment (SQT01). The drug used is monomethyl auristatin E (MMAE), a cytotoxic agent hindered in its clinical use by severe toxicity. MMAE modification with a trans-cyclooctene moiety to form the protodrug SQP22 reduced its cytotoxicity in vitro and in vivo. Treatment of SQP22 paired with SQL70 biopolymer demonstrated anti- tumor effects in Karpas 299 and RENCA murine tumor models, establishing the requirement of click chemistry for protodrug activation. Furthermore, SQP22 paired with SQT01 induced anti-tumor effects in the HER2-positive NCI-N87 murine tumor model, showing that activation could be accomplished by systemic dosing of a tumor-targeting antibody conjugate. Observed toxicities were limited to modest, transient myelosuppression and moderate body weight loss in these tumor models. This study further delineates the capabilities of the CAPAC platform by demonstrating anti-tumor activity of SQP22 with two differentiated targeting approaches and underscores the power of click chemistry to precisely control the activation of cancer drugs at tumor sites. |
