Document resource
Background The approval of Catumaxomab, the first T cell engager (TCE) for solid tumors in 2009 brought hope that TCEs could achieve both high response rates and durable benefits in solid tumor patients. However, over the following 15 years, efforts to develop TCEs for solid tumors have led to the approval of only two additional drugs: the TCR-based Tebentafusp and the antibody-based Tarlatamab. The limited progress in this field is largely attributed to challenges such as high on-target, off-tumor toxicity and severe cytokine release syndrome (CRS), which contribute not only to adverse effects but also to reduced efficacy. Recent advances in prodrug technology have renewed interest in TCEs, offering the potential for a new and potent therapeutic format that could become a cornerstone of solid tumor treatment. Carbonic anhydrase 9 (CAIX, CA9), along with VEGF, is a key downstream pathway activated by hypoxia—a hallmark of cancer. CA9 is highly expressed in several cancers, including KIRC, CHOL, PAAD, LUSC, LUAD, HNSC, BLCA, ESCA, COAD, READ, SCLC, STAD, MESO and CESC.Methods Using its proprietary LogicBee platform for the design of prodrugs with tumor-specific protease-mediated activation, Vibrant Therapeutics has developed VIB193, the first masked TCE prodrug targeting both CA9 and CD3. Crucially, VIB193 remains inactive until its masking moiety is removed within the tumor microenvironment, preventing premature T-cell activation.Results In preclinical studies VIB193 effectively inhibited tumor growth and eradicated tumors without causing significant signs of toxicity including severe cytokine release syndrome. These rendered VIB193 a high therapeutic window not observed with conventional TCEs. It is noteworthy that, due to high TCE’s high potency, VIB193 was able to achieve complete responses (per mRECIST criteria) at low doses.Conclusions VIB193 holds promise for the treatment of a wide range of solid tumors and represents a significant step forward toward overcoming the challenges traditionally associated with TCEs for solid tumors.Ethics Approval Ethical committee approval ID number for the animal work 20250206C02, Guangzhou, China.