TCR-mimic bispecific nanobody-based T cell engager targeting intracellular tumor antigens for cancer immunotherapy.

Authors

Ziqiang Ding, Shuyang Sun, Xiaomei Yang, Xianing Huang, Xiaoqiong Hou, Shenxia Xie, Aiqun Liu, Xiaoling Lu

Published in

Signal transduction and targeted therapy. Volume 11. Issue 1. Jun 25, 2026. Epub Jun 25, 2026.

Abstract

T cell engager (TCE) immunotherapies have revolutionized the landscape of cancer treatment; however, their efficacy remains limited by the inaccessibility of intracellular tumor antigens. Conventional bispecific T cell engagers, typically constructed from aggregation-prone single-chain variable fragments (scFvs), suffer from structural instability and an antigenic scope restricted to extracellular targets. To overcome these critical limitations, we presented a proof-of-concept study establishing a modular bispecific VHH‑VHH immunotherapeutic platform. Specifically, we developed a first-in-class TCR-mimic bispecific nanobody (Nb)-based T cell engager (TCRm Bi-NbTE) platform that simultaneously engages CD3ε on T cells and tumor-specific peptide-MHC class I (pMHC I) complexes, exemplified by HLA-A2/WT1_126-134 or HLA-A2/GPC3_144-152. Functional analyses in vitro and in vivo studies demonstrated that TCRm Bi-NbTE exhibits exceptional specificity, potently induces antigen-restricted T cell activation, and mediates selective lysis of pMHC I⁺ tumor cells while sparing antigen-negative cells. In multiple mouse xenograft models, including both cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models, TCRm Bi-NbTE significantly suppressed tumor growth, prolonged survival, and enhanced T cell infiltration without treatment-related adverse effects. By redirecting T cell against intracellular antigens in an HLA-restricted manner, TCRm Bi-NbTE establishes a modular, scalable, and clinically translatable platform for next-generation cancer immunotherapy across a broad spectrum of solid and hematologic malignancies.

PMID:
42342658
Bibliographic data and abstract were imported from PubMed on 25 Jun 2026.

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