CRD5500: Targeting Tumors with a Multi-Modal STING Agonist Approach

CRD5500 is a next-generation compound with the capability to be administered via intra-tumoral injection, systemic routes like intravenous (IV) or subcutaneous (SC), or as an antibody-drug conjugate (ADC) with Trastuzumab. This ADC strategy aims to target tumors systemically with minimal systemic payload exposure, potentially enhancing the therapeutic index in clinical settings.

The compound was evaluated through various methods, including reporter gene assays in HEK293T cells with human STING variants, immunoblots to verify phosphorylation of STING, TBK1, and IRF3, and real-time PCR and ELISA to monitor cytokine induction in human tumor cell lines, peripheral blood mononuclear cells (PBMCs), and dendritic cells. Direct binding to STING was confirmed by Cellular Thermal Shift Assays and in vitro kinase assays.

CRD5500 was found to activate multiple human STING variants, leading to the phosphorylation of key proteins and the release of cytokines such as IFNβ and TNFα. In vivo studies demonstrated tumor regression in syngenic tumors with human STING, with CRD5500 showing the abscopal effect and synergistic effects when combined with checkpoint inhibitors. Additionally, non-conjugated pre-antibody constructs, when administered intravenously, were able to eliminate tumors in combination with an anti-CTLA4 antibody.

The conjugation of CRD5500 with Trastuzumab was successful, and the resulting ADC was tested in HER2-expressing cells to evaluate the release of the free payload. Overall, CRD5500, as a STING agonist, holds promise for generating anti-tumor immune responses and is a candidate for further development as a versatile anti-cancer agent.