CD19-ReTARG(TPR)：一种用于抗 CMV 细胞毒性 T 细胞生理性结合 CD19 表达恶性肿瘤的新型融合蛋白

Background/Objectives : The physiological activation of cytotoxic CD8 pos T cells (CTLs) relies on the engagement of the TCR/CD3 complex with cognate peptide-HLA class I (pHLA-I) on target cells, triggering cell lysis with appropriate cytokine release and minimized off-target toxicity.

In contrast, current immunotherapies for CD19-expressing hematological malignancies, such as chimeric antigen receptor (CAR) T cells and bispecific T cell engagers (BiTEs) , bypass TCR/pHLA interactions, resulting in CTL hyperactivation and excessive cytokine release, which frequently cause severe immune-related adverse events (irAEs).

Thus, there is a pressing need for T cell-based therapies that preserve physiological activation while maintaining antitumor efficacy. Methods : To address this, we developed CD19-ReTARG TPR , a novel fusion protein consisting of the immunodominant cytomegalovirus (CMV) pp65-derived peptide TPRVTGGAM (TPR) covalently presented by a soluble HLA-B*07:02/ 2-microglobulin complex fused to a high-affinity CD19-targeting Fab antibody fragment.

The treatment of CD19-expressing cancer cells with CD19-ReTARG TPR makes them recognizable for pre-existing anti-CMV pp65 CTLs via physiological TCR-pHLA engagement. Results : Our preclinical data demonstrate that CD19-ReTARG TPR efficiently redirects anti-CMV CTLs to eliminate CD19-expressing cancer cells, including both established cell lines and primary chronic lymphocytic leukemia (CLL) cells.

Unlike CD19-directed CAR T cells or the CD19/CD3 BiTE blinatumomab, CD19-ReTARG TPR mediated robust cytotoxic activity without triggering supraphysiological cytokine release .

Importantly, this approach retained efficacy even against cancer cells with low CD19 expression. Conclusions : In summary, we provide a robust proof-of-concept study and show that CD19-ReTARG TPR offers a promising alternative strategy for T cell redirection, enabling the selective and effective killing of CD19-expressing malignancies while minimizing cytokine-driven toxicities through physiological CTL activation pathways.