4.6 Article

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

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MOLECULAR CANCER THERAPEUTICS
卷 21, 期 10, 页码 1499-1509

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AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-22-0201

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资金

  1. Fundacion Asociacion Espanola contra el Cancer (AECC)
  2. FERO (EDM)
  3. Ramon Areces Foundation
  4. Cellex Foundation
  5. BBVA (CAIMI)
  6. ISCIII
  7. FIS [PI19/00318]
  8. William K. Bowes Jr Foundation
  9. German Research Foundation [AB 1234/1-1]
  10. Office of Biological and Environmental Research of the U.S. Department of Energy Atmospheric System Research Program [DE-SC0000001]
  11. National Institute of Health Research UK
  12. UK-China Research and Innovation Partnership Fund through the Met Office Climate Science for Service Partnership (CSSP) China as part of the Newton Fund
  13. NIH [U12AB123456, R01AB123456]

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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.
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.

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