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Immunotoxins that target an oncogenic mutant epidermal growth factor receptor expressed in human tumors.

Publication ,  Journal Article
Lorimer, IA; Wikstrand, CJ; Batra, SK; Bigner, DD; Pastan, I
Published in: Clin Cancer Res
August 1995

Human cancers arise from a series of mutations, many of which direct the expression of mutant proteins with altered functions. These aberrant proteins are attractive targets for new therapeutic agents. One such protein is a mutant epidermal growth factor receptor (EGFRvIII) that has an in-frame deletion near the NH2 terminus of its extracellular domain. This protein was first identified in human gliomas, but has also been shown to be present in lung and breast carcinomas. The deletion results in a receptor with constitutive tyrosine kinase activity that enhances the tumorigenicity of glioblastomas in vivo. The deletion also creates a tumor-specific cell-surface sequence at the deletion junction. Three specific anti-EGFRvIII mAbs have been isolated following immunization with a mixture of a deletion junction synthetic peptide and EGFRvIII as present on cell membranes. We have constructed immunotoxins by conjugating a modified version of Pseudomonas exotoxin A to these mAbs. Immunotoxins were tested on cells that had been transfected with cDNA for the EGFRvIII receptor and expressed receptor protein at 5 x 10(5) receptors/cell. All three immunotoxins were cytotoxic to these cells, with 50% inhibition of protein synthesis occurring in a 15-50 pM range. The immunotoxins specifically targeted EGFRvIII, as their cytotoxicity could be blocked by their respective free antibody. They showed little or no cytotoxicity to cells expressing high levels of normal epidermal growth factor receptors, demonstrating that they are able to discriminate between cells expressing the mutant receptor and those expressing the wild-type receptor. Immunotoxins targeted to mutant epidermal growth factor receptors are promising candidates for further development as tumor cell-specific therapeutic agents.

Duke Scholars

Published In

Clin Cancer Res

ISSN

1078-0432

Publication Date

August 1995

Volume

1

Issue

8

Start / End Page

859 / 864

Location

United States

Related Subject Headings

  • Transfection
  • Sequence Deletion
  • Recombinant Proteins
  • Protein Sorting Signals
  • Oncology & Carcinogenesis
  • Oligopeptides
  • Mutagenesis, Site-Directed
  • Mice
  • Lung Neoplasms
  • Immunotoxins
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Lorimer, I. A., Wikstrand, C. J., Batra, S. K., Bigner, D. D., & Pastan, I. (1995). Immunotoxins that target an oncogenic mutant epidermal growth factor receptor expressed in human tumors. Clin Cancer Res, 1(8), 859–864.
Lorimer, I. A., C. J. Wikstrand, S. K. Batra, D. D. Bigner, and I. Pastan. “Immunotoxins that target an oncogenic mutant epidermal growth factor receptor expressed in human tumors.Clin Cancer Res 1, no. 8 (August 1995): 859–64.
Lorimer IA, Wikstrand CJ, Batra SK, Bigner DD, Pastan I. Immunotoxins that target an oncogenic mutant epidermal growth factor receptor expressed in human tumors. Clin Cancer Res. 1995 Aug;1(8):859–64.
Lorimer, I. A., et al. “Immunotoxins that target an oncogenic mutant epidermal growth factor receptor expressed in human tumors.Clin Cancer Res, vol. 1, no. 8, Aug. 1995, pp. 859–64.
Lorimer IA, Wikstrand CJ, Batra SK, Bigner DD, Pastan I. Immunotoxins that target an oncogenic mutant epidermal growth factor receptor expressed in human tumors. Clin Cancer Res. 1995 Aug;1(8):859–864.

Published In

Clin Cancer Res

ISSN

1078-0432

Publication Date

August 1995

Volume

1

Issue

8

Start / End Page

859 / 864

Location

United States

Related Subject Headings

  • Transfection
  • Sequence Deletion
  • Recombinant Proteins
  • Protein Sorting Signals
  • Oncology & Carcinogenesis
  • Oligopeptides
  • Mutagenesis, Site-Directed
  • Mice
  • Lung Neoplasms
  • Immunotoxins