免疫毒素GB13通过激活高尔基体到内质网逆向转运通路靶向GBM和H3.3K27M DIPG

GB13, an IL13Ra2-targeted immunotoxin, shows potent therapeutic potential against Glioblastoma (GBM) and H3.3K27M mutant Diffuse Midline Glioma (DIPG). The toxin, comprising Pseudomonas exotoxin A and IL-13 mutein, binds to IL13Ra2, which is frequently overexpressed on the surface of GBM and DIPG with histone 3.3 (H3.3) K27M mutation. GB13 is internalized through this binding and processed via Golgi-to-ER pathway. The active domain of the toxin is translocated to ADP-ribosylating eukaryotic elongation factor 2 (eEF-2) and halts protein synthesis, inducing apoptosis. In vitro drug dose-response assays demonstrated a 280-300 fold differential response in patient-derived GBM and DIPG models. Sensitivity correlated with IL13RA2 abundance and the H3.3K27M mutation. Gene Set Enrichment Analysis confirmed that sensitivity is linked to activated Golgi-to-ER retrograde transport pathways, the required trafficking route for GB13's cytotoxic release. Furthermore, these transport pathway scores negatively correlate with patient age in the TCGA-GBM dataset, suggesting demographic dependence. PBT29, the most sensitive H3.3K27M mutant DIPG line, showed the highest transport pathway enrichment. GB13's selective activity and its association with a Golgi-to-ER retrograde transport, as a predictive signature make it a highly promising candidate for these devastating diseases. The presence of these molecular signatures of vulnerability (mSov) could serve as an inclusion criterion for patient enrollment in clinical trials.