Xilio's Masked T Cell Engager Data Signal New Approach to Solid Tumor Toxicity

Xilio Therapeutics has disclosed preclinical data for XTX601, a masked T cell engager targeting claudin 18.2 (CLDN18.2), that could reshape how the industry approaches systemic toxicity in solid tumor bispecifics. Presented at the AACR Annual Meeting on April 17, 2026, the data showed protease-dependent, tumor-selective activation and potent anti-tumor activity across multiple xenograft models, while non-human primate (NHP) studies showed no evidence of cytokine release syndrome or liver enzyme changes. For development teams working on T cell engager platforms, the findings highlight a potential path toward wider therapeutic indices in a drug class historically constrained by on-target, off-tumor toxicity.

XTX601 uses Xilio's advanced tumor-activated cell engager (ATACR) format, which masks the CD3-targeting domain to limit systemic T cell engagement in healthy tissue. The molecule also incorporates a conditional half-life modulation element designed to confer antibody-like pharmacokinetics in its masked state and a short half-life upon activation in the tumor microenvironment, further reducing peripheral exposure. In preclinical models, XTX601 demonstrated dose-dependent anti-tumor activity in GSU gastric carcinoma and OE19 esophageal adenocarcinoma xenograft models engrafted with human T cells, with effective tumor cell killing observed in both high- and low-CLDN18.2-expression settings.

Integration of drug exposure data from murine tumor models and NHP tolerability studies indicated what Xilio described as a favorable, positive therapeutic index. Uli Bialucha, Ph.D., chief scientific officer of Xilio Therapeutics, noted that the company's modular masked T cell engager architecture allows parallel evaluation of multiple designs, including masking of the CLDN18.2 binding domain and optional addition of a co-stimulatory domain, to optimize the clinical profile of the molecule.

Xilio plans to advance the CLDN18.2-targeting masked T cell engager program into IND-enabling studies and submit an investigational new drug (IND) application in 2027. CLDN18.2 is a tumor-associated antigen expressed in gastric, pancreatic, and esophageal cancers, and the target has drawn significant pipeline activity across the industry. The ability to decouple anti-tumor potency from systemic toxicity through masking technology will be a key differentiator as multiple CLDN18.2-directed programs compete for clinical proof of concept.

Source: Xilio Therapeutics press release via GlobeNewswire, April 17, 2026.