Dr Sweis on Targeting ENPP3 in Clear Cell Renal Cell Carcinoma

“ENPP3 is an extracellular protein that has been found to be uniquely expressed in kidney cancer cells, making it an attractive target for [clear cell] kidney cancer, and also papillary kidney cancer and some other solid tumors such as colorectal cancer.”

Randy F. Sweis, MD, an assistant professor of medicine at the University of Chicago Medicine, discussed the potential utility of ENPP3 as a therapeutic target in renal cell carcinoma (RCC).

ENPP3 is an extracellular protein that is uniquely expressed in multiple RCC subtypes, including clear cell and papillary disease, Sweis began. The expression levels that been observed in these disease settings make it an attractive treatment target in RCC, with other tumor types such as colorectal cancer also displaying some expression of the protein, he added. The physiologic function of ENPP3 is not well understood, although some preclinical studies have identified that it may be related to mast cells, he said. Notably, ENPP3 is not expressed in most normal human tissue, he concluded.

The humanized ENPP3 × CD3 bispecific T-cell engager (BiTE) XmAb30819 is currently being evaluated for the treatment of patients with advanced clear cell RCC. The trial is enrolling patients with clear cell disease 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 clear cell RCC, the agent reduced the median tumor volume over time compared with phosphate-buffered saline and an anti–PD-1 monoclonal antibody.