Dr Runcie on the Mechanism of Action of XmAb30819 in ccRCC

“[XmAb30819] is a 2 + 1 bispecific T-cell engager with 2 sites that bind ENPP3 and 1 site that binds CD3. It brings [these] cells together to create a cytotoxic T-cell response.”

Karie Runcie, MD, an assistant professor of medicine at Columbia University Medical Center, discussed the mechanism of action of XmAb30819 for the treatment of patients with clear cell renal cell carcinoma (ccRCC).

XmAb30819 is a bispecific T-cell engager (BiTE) that employs a 2 + 1 design, Runcie began. The BiTE has 2 sites that bind to ENPP3 and another than binds to CD3, she continued. The dual ENPP3 binding sites of XmAb30819 enable the agent to have a strong specificity for the protein on cancer cells and a lower binding affinity to normal tissue, she explained. This mechanism of action brings the ENPP3-positive cancer cells together with T cells to create a cytotoxic response, she concluded.

XmAb30819 being examined for the treatment of patients with advanced clear cell RCC in a phase 1 clinical trial (NCT05433142). The first-in-human study is enrolling patients with ccRCC who experienced disease progression following treatment with standard agents; have measurable disease per RECIST 1.1 criteria; and have an ECOG performance status of 0 or 1. The dual primary end points of the study are safety and tolerability and the incidence of dose-limiting toxicities.

Findings from preclinical studies have shown that XmAb30819 had a tolerable safety profile with dose dependent pharmacodynamics. In vitro, the BiTE demonstrated selective killing of cells with high ENPP3 expression. Moreover, in xenograft mice tumor models of ccRCC, the agent reduced the median tumor volume over time compared with phosphate-buffered saline and an anti–PD-1 monoclonal antibody. Xencor, the developer of XmAb819, plans to share full initial data from the phase 1 study at a medical conference during the 4th quarter of 2025.