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A Rationally Designed Fully Human EGFRvIII:CD3-Targeted Bispecific Antibody Redirects Human T Cells to Treat Patient-derived Intracerebral Malignant Glioma.

Publication ,  Journal Article
Gedeon, PC; Schaller, TH; Chitneni, SK; Choi, BD; Kuan, C-T; Suryadevara, CM; Snyder, DJ; Schmittling, RJ; Szafranski, SE; Cui, X; Healy, PN ...
Published in: Clin Cancer Res
August 1, 2018

Purpose: Conventional therapy for malignant glioma fails to specifically target tumor cells. In contrast, substantial evidence indicates that if appropriately redirected, T cells can precisely eradicate tumors. Here we report the rational development of a fully human bispecific antibody (hEGFRvIII-CD3 bi-scFv) that redirects human T cells to lyse malignant glioma expressing a tumor-specific mutation of the EGFR (EGFRvIII).Experimental Design: We generated a panel of bispecific single-chain variable fragments and optimized design through successive rounds of screening and refinement. We tested the ability of our lead construct to redirect naïve T cells and induce target cell-specific lysis. To test for efficacy, we evaluated tumor growth and survival in xenogeneic and syngeneic models of glioma. Tumor penetrance following intravenous drug administration was assessed in highly invasive, orthotopic glioma models.Results: A highly expressed bispecific antibody with specificity to CD3 and EGFRvIII was generated (hEGFRvIII-CD3 bi-scFv). Antibody-induced T-cell activation, secretion of proinflammatory cytokines, and proliferation was robust and occurred exclusively in the presence of target antigen. hEGFRvIII-CD3 bi-scFv was potent and target-specific, mediating significant lysis of multiple malignant glioma cell lines and patient-derived malignant glioma samples that heterogeneously express EGFRvIII. In both subcutaneous and orthotopic models, well-engrafted, patient-derived malignant glioma was effectively treated despite heterogeneity of EGFRvIII expression; intravenous hEGFRvIII-CD3 bi-scFv administration caused significant regression of tumor burden (P < 0.0001) and significantly extended survival (P < 0.0001). Similar efficacy was obtained in highly infiltrative, syngeneic glioma models, and intravenously administered hEGFRvIII-CD3 bi-scFv localized to these orthotopic tumors.Conclusions: We have developed a clinically translatable bispecific antibody that redirects human T cells to safely and effectively treat malignant glioma. On the basis of these results, we have developed a clinical study of hEGFRvIII-CD3 bi-scFv for patients with EGFRvIII-positive malignant glioma. Clin Cancer Res; 24(15); 3611-31. ©2018 AACR.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

August 1, 2018

Volume

24

Issue

15

Start / End Page

3611 / 3631

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • T-Lymphocytes
  • Single-Chain Antibodies
  • Recombinant Proteins
  • Oncology & Carcinogenesis
  • Mice
  • Male
  • Lymphocyte Activation
  • Immunotherapy
  • Humans
 

Citation

APA
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Gedeon, P. C., Schaller, T. H., Chitneni, S. K., Choi, B. D., Kuan, C.-T., Suryadevara, C. M., … Sampson, J. H. (2018). A Rationally Designed Fully Human EGFRvIII:CD3-Targeted Bispecific Antibody Redirects Human T Cells to Treat Patient-derived Intracerebral Malignant Glioma. Clin Cancer Res, 24(15), 3611–3631. https://doi.org/10.1158/1078-0432.CCR-17-0126
Gedeon, Patrick C., Teilo H. Schaller, Satish K. Chitneni, Bryan D. Choi, Chien-Tsun Kuan, Carter M. Suryadevara, David J. Snyder, et al. “A Rationally Designed Fully Human EGFRvIII:CD3-Targeted Bispecific Antibody Redirects Human T Cells to Treat Patient-derived Intracerebral Malignant Glioma.Clin Cancer Res 24, no. 15 (August 1, 2018): 3611–31. https://doi.org/10.1158/1078-0432.CCR-17-0126.
Gedeon PC, Schaller TH, Chitneni SK, Choi BD, Kuan C-T, Suryadevara CM, et al. A Rationally Designed Fully Human EGFRvIII:CD3-Targeted Bispecific Antibody Redirects Human T Cells to Treat Patient-derived Intracerebral Malignant Glioma. Clin Cancer Res. 2018 Aug 1;24(15):3611–31.
Gedeon, Patrick C., et al. “A Rationally Designed Fully Human EGFRvIII:CD3-Targeted Bispecific Antibody Redirects Human T Cells to Treat Patient-derived Intracerebral Malignant Glioma.Clin Cancer Res, vol. 24, no. 15, Aug. 2018, pp. 3611–31. Pubmed, doi:10.1158/1078-0432.CCR-17-0126.
Gedeon PC, Schaller TH, Chitneni SK, Choi BD, Kuan C-T, Suryadevara CM, Snyder DJ, Schmittling RJ, Szafranski SE, Cui X, Healy PN, Herndon JE, McLendon RE, Keir ST, Archer GE, Reap EA, Sanchez-Perez L, Bigner DD, Sampson JH. A Rationally Designed Fully Human EGFRvIII:CD3-Targeted Bispecific Antibody Redirects Human T Cells to Treat Patient-derived Intracerebral Malignant Glioma. Clin Cancer Res. 2018 Aug 1;24(15):3611–3631.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

August 1, 2018

Volume

24

Issue

15

Start / End Page

3611 / 3631

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • T-Lymphocytes
  • Single-Chain Antibodies
  • Recombinant Proteins
  • Oncology & Carcinogenesis
  • Mice
  • Male
  • Lymphocyte Activation
  • Immunotherapy
  • Humans