滋养层糖蛋白特异性 5T4-Vδ2 双特异性 T 细胞衔接器招募 Vγ9Vδ2-T 细胞，在多种实体恶性肿瘤中实现肿瘤选择性细胞毒性

5T4 is an oncofetal antigen that is aberrantly expressed across a wide range of malignancies, but only sparsely present in healthy adult tissues. Its tumor-preferential expression pattern has been linked to epithelial-to-mesenchymal transition, invasion, and poor clinical outcome in various tumors, making 5T4 an attractive therapeutic target.

Bispecific T-cell engagers (bsTCEs) have achieved major clinical success in hematological malignancies, yet efficacy in solid tumors has been limited by challenges including on-target off-tumor toxicity. Bispecific Vγ9Vδ2-T cell engagers may overcome this challenge by combining potent anti-tumor activity with reduced toxicity.

Here, we developed high-affinity 5T4-specific VHHs and linked them to a Vδ2 TCR-specific VHH to generate a bsTCE which engages Vγ9Vδ2-T cells to 5T4-expressing tumors and triggers robust proinflammatory cytokine production and target cell lysis.

We demonstrate that 5T4 is expressed in the majority of evaluated solid malignancies and that the 5T4-Vδ2 bsTCE elicits strong Vγ9Vδ2-T cell-mediated anti-tumor activity in both 2D and 3D patient-derived preclinical tumor models.

Importantly, when tested against healthy 5T4-expressing tissue, the bsTCE did not trigger Vγ9Vδ2-T cell cytotoxicity, underscoring its tumor-preferential activity.

These findings support the 5T4-Vδ2 bsTCE as a promising immunotherapeutic candidate for broad clinical application in (solid) tumors.