XmAb819 (ENPP3 x CD3)
Ongoing Phase 1 clinical trial in patients with advanced renal cell carcinoma (RCC) and additional ENPP3+ tumors
XmAb819 is a tumor-targeted, T-cell engaging XmAb® 2+1 bispecific antibody in development for patients with clear cell renal cell carcinoma (ccRCC) and additional ENPP3+ tumors. XmAb819 engages the immune system and activates T cells for highly potent and targeted killing of tumor cells expressing ENPP3 (ectonucleotide pyrophosphatase/phosphodiesterase 3). ENPP3 is differentially expressed between several tumor types (high expression) and normal tissues (low expression). In order to attack tumor cells selectively, XmAb819 was engineered as an XmAb 2+1 bispecific antibody with two binding domains against ENPP3 and one cytotoxic T-cell binding domain against CD3, a component of the T-cell receptor (TCR) complex. Xencor’s XmAb Bispecific Fc Domain serves as the scaffold for these binding domains and provides for long circulating half-life, stability and ease of manufacture.
Clinical Evaluation
XmAb819 is being evaluated for the treatment of patients with ENPP3+ tumors in a Phase 1 clinical study (Clinicaltrials.gov Identifier: NCT05433142). Initial results from dose-escalation in advanced ccRCC were presented during the AACR-NCI-EORTC Conference on Molecular Targets and Cancer Therapeutics in October 2025. Currently:
- Expansion cohorts are evaluating intravenous doses to support selection of a dose for the planned Phase 3 pivotal study for patients with advanced ccRCC,
- Dose escalation of subcutaneous administration in advanced ccRCC is ongoing,
- A sub-study for patients with ENPP3+ advanced colorectal cancer, non-small cell lung cancer and papillary renal cell carcinoma opened to enrollment in the second quarter of 2026, and
- A sub-study for patients with intermediate- or poor-risk advanced ccRCC who have progressed after nivolumab in combination with ipilimumab as a first-line treatment (IO doublet therapy) is planned to open to enrollment in the third quarter of 2026.
Xencor plans to select a recommended Phase 3 dose during 2026 to support initiation of a pivotal study in advanced ccRCC during 2027.
XmAb® 2+1 Bispecific Antibodies
T-cell engaging bispecific antibodies with single tumor-antigen binding domains (1+1 formats) cannot always be designed to selectively target tumor antigens, particularly when the antigen is expressed on normal tissues. Limited selectivity for tumor cells may lead to the killing of normal tissues that express the antigen at lower levels, including critical organs, which can cause poor tolerability in clinical testing.
With two tumor-antigen binding domains and one T-cell binding domain, Xencor’s multivalent XmAb 2+1 format enables antibodies to bind more avidly to – and selectively kill – tumor cells with higher antigen density, potentially sparing normal cells. 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.