XmAb819 (ENPP3 x CD3)

ENPP3 x CD3 bispecific T-cell engager in Phase 1 development for advanced clear cell renal cell carcinoma and other ENPP3-expressing tumors

XmAb819 is an investigational, potential first-in-class ENPP3 x CD3 bispecific T-cell engager in development for patients with advanced clear cell renal cell carcinoma (ccRCC) and other tumors with high ENPP3 expression, including colorectal cancer, non-small cell lung cancer and papillary renal cell carcinoma. XmAb819 is designed to redirect T cells to target and kill tumor cells expressing ENPP3 (ectonucleotide pyrophosphatase/phosphodiesterase 3).

XmAb819 incorporates Xencor’s XmAb® 2+1 bispecific antibody format, with two ENPP3-binding domains and one CD3-binding domain. ENPP3 is expressed at high levels in renal cell carcinoma and at lower levels in normal tissues. The XmAb 2+1 format is designed to enable more avid binding to tumor cells with higher antigen density, supporting selective tumor-cell killing while potentially sparing normal cells.

Clinical Evaluation

Xencor is evaluating XmAb819 in a Phase 1 clinical study in patients with advanced ccRCC and other ENPP3-expressing tumors (ClinicalTrials.gov Identifier: NCT05433142). Updated dose-expansion results in advanced ccRCC were presented at the European Society for Medical Oncology (ESMO) Congress in October 2026. Currently:

  • Expansion cohorts evaluating intravenous doses to support selection of a dose for the planned Phase 3 pivotal study for patients with advanced ccRCC have completed enrollment.
  • Dose escalation of subcutaneous administration in advanced ccRCC is ongoing.
  • Cohorts evaluating every-three-week intravenous dosing and reduced hospitalization requirements are planned.

Proof-of-concept sub-studies to enable expansion of development are ongoing. Currently:

  • Part C of the ongoing Phase 1 study is enrolling patients with ENPP3+ advanced papillary RCC, colorectal cancer and non-small cell lung cancer.
  • Part D of the ongoing Phase 1 study is enrolling patients with IMDC intermediate- to poor-risk advanced ccRCC, who have progressed after nivolumab in combination with ipilimumab as a first-line treatment and who are naïve to VEGFR TKI therapy.
  • Part F of the ongoing Phase 1 study is planned as a safety study for the combination of XmAb819 with nivolumab to potentially enable front-line development.

XmAb® 2+1 Bispecific Antibodies

Selectively targeting tumor antigens can be challenging when those antigens are also expressed on normal tissues. Xencor’s XmAb 2+1 bispecific antibody format incorporates two tumor-antigen binding domains and one T-cell binding domain. This multivalent design is intended to enable more avid binding to—and selective killing of—tumor cells with higher antigen density, potentially sparing normal cells with lower antigen expression.

Xencor’s XmAb Bispecific Fc Domain provides the scaffold for these binding domains, maintaining full-length antibody properties and supporting production and purification using standard antibody manufacturing methods.

The XmAb 2+1 bispecific antibody format may be a particularly powerful tool for developing drug candidates against solid tumors. XmAb 2+1 bispecific antibodies include XmAb819 (ENPP3 x CD3), XmAb808 (B7-H3 x CD28) and XmAb541 (CLDN6 x CD3), in addition to several programs being developed by partners.

Additional Resources