A Novel EGFRvIII T-Cell Bispecific Antibody for the Treatment of Glioblastoma

T-cell bispecific antibodies (TCB) are engineered molecules that bind both the T-cell receptor and tumor-specific antigens. Epider-mal growth factor receptor variant III (EGFRvIII) mutation is a common event in glioblastoma (GBM) and is characterized by the deletion of exons 2-7, resulting in a constitutively active receptor that promotes cell proliferation, angiogenesis, and invasion. EGFR-vIII is expressed on the surface of tumor cells and is not expressed in normal tissues, making EGFRvIII an ideal neoantigen target for TCBs. We designed and developed a novel 2 thorn 1 EGFRvIII-TCB with optimal pharmacologic characteristics and potent antitumor activ-ity. EGFRvIII-TCB showed specificity for EGFRvIII and promoted tumor cell killing as well as T-cell activation and cytokine secretion only in patient-derived models expressing EGFRvIII. Moreover, EGFRvIII-TCB promoted T-cell recruitment into intracranial tumors. EGFRvIII-TCB induced tumor regression in GBM animal models, including humanized orthotopic GBM patient-derived xenograft models. Our results warrant the clinical testing of EGFR-vIII-TCB for the treatment of EGFRvIII-expressing GBMs.

Automated summary

T-cell bispecific antibodies (TCB) are engineered molecules that can bind both the T-cell receptor and tumor-specific antigens, showing potential therapeutic effects for EGFRvIII mutation in glioblastoma (GBM). We designed and developed a novel EGFRvIII-TCB with specificity and potent antitumor activity, promoting T-cell activation and cytokine secretion for tumor cell killing, as well as T-cell recruitment into tumors. In GBM animal models, including humanized orthotopic patient-derived xenograft models, EGFRvIII-TCB induced tumor regression. These results support the clinical testing of EGFRvIII-TCB.