Dr Kotecha on the Potential of ENPP3 as a Therapeutic Target in ccRCC

"When we think about [targeting] something specific in kidney cancer, we want to find something that, for example, is highly expressed in clear cell [RCC] and generally not expressed in any normal tissue. And if it is expressed in some normal tissue, [we want to understand] where that [expression occurs], such as a vital organ."

Ritesh R. Kotecha, MD, an assistant attending physician at Memorial Sloan Kettering Cancer Center, discussed the rationale for targeting ENPP3 in clear cell renal cell carcinoma (ccRCC) and the potential role of XmAb819, a novel bispecific T-cell engager, being evaluated in the phase 1 XmAb819-01 trial (NCT05433142).

XmAb819 is designed to bind CD3 on T cells and ENPP3 on tumor cells to facilitate T-cell–mediated cytotoxicity in ccRCC, a tumor type characterized by high ENPP3 expression. Kotecha noted that ENPP3 expression in normal tissue is minimal and largely restricted to mast cells and basophils, with low expression in the gastrointestinal tract and little to no enrichment in vital organs. This differential expression profile, he explained, makes ENPP3 a promising and potentially safe target for developing therapies in ccRCC.

The ongoing phase 1 trial is enrolling patients with relapsed or refractory ccRCC to evaluate the safety, tolerability, and preliminary activity of XmAb819. Early data from this study are not yet mature, but Kotecha emphasized that preliminary observations support continued dose escalation. The agent’s unique mechanism of action could offer an alternative approach for patients whose disease has progressed on VEGF TKIs and immune checkpoint inhibitors.

Kotecha further elaborated on the need for novel therapeutic strategies in the relapsed/refractory RCC setting. For patients whose tumors are refractory to VEGF inhibition or immunotherapy, current treatment options are often limited to sequential VEGF TKIs. Although these agents retain some efficacy, he noted, their benefit tends to diminish over time and is often accompanied by chronic toxicity.

As such, the development of bispecific agents like XmAb819 represents a broader effort to diversify treatment mechanisms beyond VEGF and immune checkpoint blockade. Kotecha concluded that future treatment strategies for ccRCC will benefit from the integration of targeted immunotherapies that engage the immune system through distinct, antigen-directed pathways.