XmAb819 (ENPP3 x CD3)
Ongoing Phase 1 clinical trial in patients with renal cell carcinoma (RCC)
XmAb819 is a tumor-targeted, T-cell engaging XmAb® 2+1 bispecific antibody in development for patients with renal cell carcinoma (RCC). XmAb819 engages the immune system and activates T cells for highly potent and targeted killing of tumor cells expressing ENPP3, an antigen highly expressed on kidney cancers.
ENPP3 (ectonucleotide pyrophosphatase/phosphodiesterase 3) is differentially expressed between RCC (high expression) and normal tissues (low expression). In order to attack RCC 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.
Xencor is conducting a Phase 1 study of XmAb819 in patients with advanced clear cell renal cell carcinoma (ccRCC).
- October 2025 Update: Xencor presented initial results from the Phase 1 study at the AACR-NCI-EORTC Conference on Molecular Targets and Cancer Therapeutics. (Oncology Update, Oct. 24, 2025). As of the data cut-off, 69 patients had received XmAb819 across 15 dose cohorts; patients were heavily pre-treated, having received a median of 4 prior lines of therapy. All patients received prior anti-PD1 therapy and prior VEGF-TKI therapy, and 36% of patients were previously treated with a HIF2α inhibitor. XmAb819 demonstrated evidence of anti-tumor activity and an acceptable safety profile that was generally well tolerated across dose levels. Of the 20 efficacy-evaluable patients treated at the dose levels that were preclinically predicted to be within the target dose range, 25% achieved a partial response (PR, per RECIST v1.1) as best response with a 70% disease control rate. The most common treatment-emergent adverse events (AEs) were cytokine release syndrome, rash and gastrointestinal-related toxicities that were primarily Grade 1 or 2 in severity and predominantly associated with prime-step dosing in the first four weeks of treatment. No cases of treatment-related immune effector cell-associated neurotoxicity syndrome (ICANS) were observed. No Grade 5 events were reported. Four patients (6%) were dose-reduced due to treatment-related AEs, and three patients (4%) discontinued treatment due to treatment-related AEs.
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.