Selected Articles from This Issue

T cell engagers have demonstrated great promise in the treatment of solid tumors, but their use is still impacted by a narrow therapeutic window as well as limited efficacy. Here, Meoni and colleagues identified a novel NANOBODY based molecule, SAR444200, with potent biparatopic binding to GPC3 that engages T cells via a novel TCRαβ binder. SAR444200’s activity in diverse tumor models, wide tolerated dose range and favorable PK profile identified it as a clinical candidate with the potential of further expanding the use of TCE in solid tumors.We developed HRA00129-C004, a novel c-Met targeting antibody-drug conjugate comprising a humanized IgG2 monoclonal antibody with low affinity conjugated to a potent topoisomerase I inhibitor. It selectively binds high c-Met-expressing tumors over normal tissues, enabling efficient internalization and potent payload release. This induces DNA damage and cell apoptosis not only in c-Met positive tumors but also in neighboring negative tumors via a strong bystander effect. Demonstrating robust efficacy in xenograft models and a favorable safety profile in non-human primates, HRA00129-C004 represents a promising therapeutic candidate currently under evaluation in a Phase I clinical trial for advanced solid tumors.Designed to have activity across FGFR3 fusions, activating and gatekeeper resistance alterations while sparing FGFR1/2/4 isoforms, dabogratinib (formerly TYRA-300), an oral, selective FGFR3 inhibitor, has the potential to address key limitations of existing therapies in advanced urothelial carcinoma (mUC), minimizing toxicities and overcoming resistance. In this study, dabogratinib preclinical findings are supported by three clinical case reports from the SURF301 study, which demonstrate early clinical activity in mUC patients with an FGFR3 fusion or activating alteration. This is the first known report of clinical activity with an FGFR3 selective inhibitor in mUC.Stimulator of IFN genes (STING) signaling in the tumor microenvironment (TME) can drive antitumor immunity. Here, Gruber and colleagues designed and synthesized a potent non-cleavable STING agonist linker-payload (ncSTING) for targeted delivery via an antibody drug conjugate (ADC). Across a variety of preclinical murine tumor models, tumor-targeted ncSTING ADCs elicited robust antitumor efficacy with reduced peripheral immune activation compared to systemic delivery of the released payload. These findings highlight that tumor-targeted delivery of a STING agonist via an ADC can decouple antitumor efficacy from toxic systemic inflammation and provide rationale for continued evaluation of immune-agonist drug conjugates.