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Generation and characterization of a mouse/human chimeric antibody directed against extracellular matrix protein tenascin.

Publication ,  Journal Article
He, X; Archer, GE; Wikstrand, CJ; Morrison, SL; Zalutsky, MR; Bigner, DD; Batra, SK
Published in: J Neuroimmunol
July 1994

The murine anti-tenascin monoclonal antibody 81C6, following iodination, has been shown to be an efficient localizing and therapeutic agent in both subcutaneous and intracranial human glioma xenograft models in athymic mice and rats. Similarly, effective monoclonal antibody 81C6 localization has been demonstrated in glioma patients, and Phase I trials with the intact murine IgG2b kappa molecule are currently in progress. In order to maximize the potential for repeated administration by minimizing murine Fc-mediated immunogenicity and reducing Fc-mediated immune effects, we created murine 81C6 variable region/human IgG2 chimeric monoclonal antibodies by the molecular cloning of the variable region genes of mouse 81C6 and their genetic linkage to human constant region exons. The resulting chimeric constructs were introduced into SP2/0 cells, and stable transfectomas were selected by G418 and mycophenolic acid resistance. The resistant clones were screened for anti-tenascin activity on tenascin-coated plates by enzyme-linked immunosorbent assay. The N-terminal amino acid sequence of both heavy and light chains of the purified chimeric 81C6 antibody matched exactly with that of the native mouse 81C6 as well as with that deduced from the nucleotide sequence. The production level of chimeric 81C6 (13.9 mg/ml) from ascites in the highest expressing transfectoma was much higher than that of native mouse 81C6 (2.5 mg/ml). The chimeric antibody showed the same specificity and equivalent affinity for human intact tenascin or tenascin-expressing cells as the native mouse 81C6 antibody. Direct comparison of radioiodinated chimeric and radioiodinated mouse 81C6 biodistribution in subcutaneous and intracranial xenograft-bearing mice showed higher tumor-to-normal tissue ratios for chimeric 81C6 as compared with native mouse 81C6. The improved localizing and clearance characteristics of chimeric 81C6 in xenograft model systems suggests that chimeric 81C6 would be an improved reagent for intracompartmental therapy of tenascin-expressing tumors in the human central nervous system.

Duke Scholars

Published In

J Neuroimmunol

DOI

ISSN

0165-5728

Publication Date

July 1994

Volume

52

Issue

2

Start / End Page

127 / 137

Location

Netherlands

Related Subject Headings

  • Transfection
  • Tissue Distribution
  • Tenascin
  • Neurology & Neurosurgery
  • Nerve Tissue Proteins
  • Molecular Sequence Data
  • Molecular Probes
  • Mice, Nude
  • Mice
  • Immunoglobulin Variable Region
 

Citation

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ICMJE
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He, X., Archer, G. E., Wikstrand, C. J., Morrison, S. L., Zalutsky, M. R., Bigner, D. D., & Batra, S. K. (1994). Generation and characterization of a mouse/human chimeric antibody directed against extracellular matrix protein tenascin. J Neuroimmunol, 52(2), 127–137. https://doi.org/10.1016/0165-5728(94)90106-6
He, X., G. E. Archer, C. J. Wikstrand, S. L. Morrison, M. R. Zalutsky, D. D. Bigner, and S. K. Batra. “Generation and characterization of a mouse/human chimeric antibody directed against extracellular matrix protein tenascin.J Neuroimmunol 52, no. 2 (July 1994): 127–37. https://doi.org/10.1016/0165-5728(94)90106-6.
He X, Archer GE, Wikstrand CJ, Morrison SL, Zalutsky MR, Bigner DD, et al. Generation and characterization of a mouse/human chimeric antibody directed against extracellular matrix protein tenascin. J Neuroimmunol. 1994 Jul;52(2):127–37.
He, X., et al. “Generation and characterization of a mouse/human chimeric antibody directed against extracellular matrix protein tenascin.J Neuroimmunol, vol. 52, no. 2, July 1994, pp. 127–37. Pubmed, doi:10.1016/0165-5728(94)90106-6.
He X, Archer GE, Wikstrand CJ, Morrison SL, Zalutsky MR, Bigner DD, Batra SK. Generation and characterization of a mouse/human chimeric antibody directed against extracellular matrix protein tenascin. J Neuroimmunol. 1994 Jul;52(2):127–137.
Journal cover image

Published In

J Neuroimmunol

DOI

ISSN

0165-5728

Publication Date

July 1994

Volume

52

Issue

2

Start / End Page

127 / 137

Location

Netherlands

Related Subject Headings

  • Transfection
  • Tissue Distribution
  • Tenascin
  • Neurology & Neurosurgery
  • Nerve Tissue Proteins
  • Molecular Sequence Data
  • Molecular Probes
  • Mice, Nude
  • Mice
  • Immunoglobulin Variable Region