Selective Apoptosis and Regression in CDH17-Positive CRC: The BI 905711 Breakthrough

The TRAILR2 agonistic antibodies have shown promise in inducing tumor cell apoptosis for cancer treatment but have faced challenges with clinical efficacy and liver toxicity. BI 905711 is a novel tetravalent bispecific antibody that targets both TRAILR2 and CDH17, aiming to address these issues. By leveraging CDH17-dependent clustering of TRAILR2, BI 905711 is designed to selectively induce apoptosis in tumor cells that express CDH17, a protein not found in normal liver tissue, thus avoiding liver toxicity.

Preclinical studies have shown that BI 905711 effectively triggers apoptosis in a wide range of CDH17-positive colorectal cancer (CRC) tumor cells. The compound has demonstrated the ability to initiate the apoptosis cascade, as indicated by a significant increase in caspase-8 and caspase-3/7 activity post-treatment. The induction of apoptosis by BI 905711 is strictly CDH17-dependent, as shown using CRC cell line GP2d clones that differ in CDH17 expression.

In vivo studies in CRC patient-derived xenograft (PDX) models have shown that BI 905711 can effectively inhibit tumor growth, with a q14d dosing schedule demonstrating significant tumor growth inhibition. The compound has also shown single-agent tumor regressions in the GP2d CRC xenograft model.

In summary, BI 905711 has been shown to be a first-in-class molecule with a targeted strategy for treating CRC and other CDH17-positive cancers. Its ability to selectively induce apoptosis in CDH17-positive tumor cells, combined with its potential for a favorable safety profile, supports the plan for a phase I clinical trial in patient populations with these cancer types.