Preparation, biodistribution and dosimetry of copper-64-labeled anti- colorectal carcinoma monoclonal antibody fragments 1A3-F(ab')2

C. J. Anderson, S. W. Schwarz, J. M. Connett, P. D. Cutler, Wu Guo Li Wu Guo, C. J. Germain, G. W. Philpott, K. R. Zinn, D. P. Greiner, C. F. Meares, M. J. Welch

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52 Scopus citations

Abstract

Antibody fragments labeled with a radiometal using bifunctional chelates generally undergo renal clearance followed by trapping of the metabolites, leading to high radiation doses to the kidneys. Copper-64-labeled BAT-2IT- 1A3-F(ab')2 was recently reported to accumulate in colorectal tumors in an animal model, however, kidney uptake was also high. In this study, the preparation of 64Cu-BAT-2IT-1A3-F(ab')2 was optimized to reduce the renal uptake. Methods: The bifunctional chelate 6-bromoacetamidobenzyl-1,4,8,11- tetraazacyclotetradecane-N,N',N',N''-tetraacetic acid (BAT) was conjugated to 1A3-F(ab')2 using the linking agent 2-iminothiolane (2IT). The conjugation reaction produced 20% of a lower molecular weight (molecular weight) impurity found to be TETA-1A3-Fab'. The conjugation procedure was optimized to include FPLC purification of the BAT-2IT-1A3-F(ab')2 from TETA-1A3-Fab' after conjugation prior to labeling with 64Cu. The biodistribution of 64Cu- labeled FPLC-purified and unpurified conjugates was determined in normal Sprague-Dawley rats and tumor-bearing Golden Syrian hamsters. Human absorbed doses were calculated from rat biodistribution data and PET imaging of a baboon. Results: Upon FPLC purification of the BAT-2IT-1A3-F(ab')2, the immunoreactivity of 64Cu-labeled 1A3-F(ab')2 was significantly improved over that of non-FPLC-purified 64Cu-BAT-2IT-1A3-F(ab')2, and the kidney uptake was decreased in normal rats. The biodistribution in hamsters showed some improvement in both tumor uptake and kidney clearance with FPLC-purified 64Cu-BAT-2IT-1A3-F(ab')2. Conclusion: The improved dosimetry of 64Cu- labeled FPLC purified BAT-2IT-1A3-F(ab')2 should more readily allow this agent to be investigated clinically to image colorectal cancer using PET.

Original languageEnglish (US)
Pages (from-to)850-858
Number of pages9
JournalJournal of Nuclear Medicine
Volume36
Issue number5
StatePublished - 1995
Externally publishedYes

Keywords

  • animal biodistribution
  • colorectal carcinoma
  • copper-64
  • dosimetry
  • Monoclonal antibody fragments

ASJC Scopus subject areas

  • Radiological and Ultrasound Technology

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    Anderson, C. J., Schwarz, S. W., Connett, J. M., Cutler, P. D., Li Wu Guo, W. G., Germain, C. J., Philpott, G. W., Zinn, K. R., Greiner, D. P., Meares, C. F., & Welch, M. J. (1995). Preparation, biodistribution and dosimetry of copper-64-labeled anti- colorectal carcinoma monoclonal antibody fragments 1A3-F(ab')2. Journal of Nuclear Medicine, 36(5), 850-858.