University of California, San Francisco has received a USD 1.64 million National Cancer Institute R01 award to develop a bispecific T cell engager (TCE) targeting ALPPL2, a cell surface antigen reported to have highly restricted expression in normal adult tissues while being expressed across multiple solid tumor types.
The scientific rationale centers on ALPPL2's near-exclusive expression in cancers including mesothelioma, ovarian, lung, gastric, pancreatic, and testicular malignancies. Unlike tumor-associated antigens, which are typically overexpressed in cancer but retain baseline expression in normal tissue, ALPPL2 has been reported to exhibit highly restricted expression in normal adult tissues, making it an attractive candidate for improving the therapeutic index of TCEs. The research team, led by principal investigator Bin Liu, will engineer a bispecific T cell engager (BiTE) with one arm targeting ALPPL2 and a second engaging CD3 on T cells. Critically, the CD3-binding arm will be engineered at reduced affinity to separate the thresholds for tumor cell killing and cytokine release — a strategy intended to widen the therapeutic window and limit cytokine release syndrome, a dose-limiting complication with existing BiTE therapies.
The program also addresses molecular architecture as a variable affecting both manufacturability and clinical performance, applying what the investigators describe as a systems engineering approach to identify an optimized lead molecule for clinical translation.