Xencor Reports Initial Phase 1 Results for XmAb819 ENPP3 x CD3 Bispecific in Clear Cell Renal Cell Carcinoma
核心洞察
Xencor presented initial Phase 1 dose-escalation data for XmAb819, a first-in-class ENPP3 (搜索) x CD3 (搜索) bispecific T-cell engager targeting clear cell renal cell carcinoma (搜索) patients.
The most common treatment-emergent adverse events were cytokine release syndrome (搜索), rash, and gastrointestinal toxicities, primarily Grade 1 or 2 in severity.
Dosing preparation errors led to higher than expected drug concentrations in 18 patients, resulting in increased Grade 3 cytokine release syndrome (搜索) rates.
Xencor has released initial Phase 1 dose-escalation results for XmAb819, a first-in-class ENPP3 (搜索) x CD3 (搜索) bispecific T-cell engaging antibody being developed for patients with clear cell renal cell carcinoma (搜索) (ccRCC). The data was presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.
Safety Profile and Adverse Events
The most common treatment-emergent adverse events (TEAE) observed were cytokine release syndrome (搜索) (CRS), 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. Grade 3 TEAEs related to treatment included rash (16%), liver enzyme elevations (7%) and CRS (4%).
One dose-limiting toxicity of Grade 4 elevated liver enzymes was deemed related to treatment. Notably, no cases of treatment-related immune effector cell-associated neurotoxicity syndrome (ICANS) were observed, and no Grade 5 events were reported.
Four patients (6%) required dose reduction due to treatment-related adverse events, while three patients (4%) discontinued treatment due to treatment-related AEs. The discontinuations included two patients who experienced elevated liver enzymes and one patient who experienced a non-fatal myocardial infarction in the presence of hypotension and CRS.
Dosing Preparation Issues Impact Safety
A significant finding emerged regarding dosing preparation errors that affected patient safety outcomes. While 51 patients received the correct priming dose of XmAb819, higher than expected serum levels were observed in 18 patients. This was investigated during early 2025 and linked to priming dose preparation errors that resulted from use of certain ports and syringes during drug dilution.
The impact of these dosing errors was substantial: of the 51 patients receiving the correct priming dose, 2 (4%) experienced Grade 3 CRS. However, of the 18 patients that were found to have a 3- to 8-fold higher than expected concentration of study drug post-priming dose, 5 (28%) experienced Grade 3 CRS.
Xencor has implemented mitigation measures through site retraining and plans to eliminate the root cause of these errors through the introduction of a low concentration formulation to be implemented during the first half of 2026.
XmAb819 Mechanism and Design
XmAb819 is a first-in-class, tumor-targeted, T-cell engaging XmAb 2+1 bispecific antibody specifically designed for patients with clear cell renal cell carcinoma (搜索). The drug engages the immune system and activates T cells for highly potent and targeted lysis of tumor cells expressing ENPP3 (搜索), an antigen highly expressed on kidney cancers.
ENPP3 (搜索) represents a differentially expressed target, with high level expression in renal cell carcinoma (搜索) and low-level expression on normal tissues. With two tumor-antigen binding domains and one T-cell binding domain, Xencor's XmAb 2+1 format enables antibodies to bind more avidly and selectively kill tumor cells with higher antigen density, potentially sparing normal cells.
Clinical Development Program
Xencor is conducting a Phase 1 study to evaluate XmAb819 in patients with advanced ccRCC (ClinicalTrials.gov Identifier: NCT05433142). The company submitted a placeholder abstract with limited detail based on a previous data-cut from the ongoing dose-escalation study, which contained a high-level safety summary across all dosing cohorts.
The presentation of an updated dataset at the conference included a detailed safety analysis along with efficacy results from the target dose range. Xencor hosted a webcast to discuss the initial results outlined in their findings.
The ongoing clinical development represents part of Xencor's broader pipeline, with more than 20 candidates engineered with the company's XmAb technology currently in clinical development, and multiple XmAb medicines already marketed by partners.