Dr Sweis on the Mechanism of Action of XmAb819 in RCC

"This is an approach that has been successful in many other types of cancer and is emerging as an active way to treat cancer as an immunotherapy."

Randy F. Sweis, MD, an assistant professor of medicine at the University of Chicago Medicine, discussed the distinctive mechanism of action employed by the XmAb 2+1 ENPP3/CD3-targeted bispecific antibody XmAb819 in renal cell carcinoma (RCC).

XmAb819 is a tumor-targeted, T-cell engaging bispecific antibody intended for use in patients with RCC. The drug functions by engaging the immune system and activating T cells to achieve highly potent and targeted killing of tumor cells that express ENPP3.

The design of XmAb819 is key to its targeted action, as it was engineered as an XmAb 2+1 bispecific antibody. This structure incorporates two binding domains directed against ENPP3, which is highly expressed in clear cell RCC, thus allowing the drug to target the cancer cells more selectively. XmAb819 also has 1 cytotoxic T-cell binding domain targeting CD3, a critical component of the T-cell receptor (TCR) complex.

Sweis noted that the overall approach of utilizing bispecific T-cell engagers has been successful in numerous other cancer types and is emerging as an active strategy for cancer immunotherapy. The foundational idea of loosely binding the CD3 component is a commonly used approach employed by other drugs as well. This loose binding allows the T cells to disengage once they are located within the tumor environment. However, the 2 + 1 design is unique to the XmAb proteins.

The safety, tolerability, and optimal dosage of XmAb819 is currently being evaluated in a phase 1 study (NCT05433142) in patients with advanced RCC whose cancer has progressed despite standard treatments.