Pharmacokinetics of pretargeted monoclonal antibody 2D12.5 and 88Y-janus-2-(p-nitrobenzyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid (DOTA) in BALB/c mice with KHJJ mouse adenocarcinoma: A model for 90Y radioimmunotherapy

David A. Goodwin, Claude F. Meares, Naoto Watanabe, Maureen McTigue, Warak Chaovapong, Charles McK Ransone, Oliver Renn, Douglas P. Greiner, David L. Kukis, Sheila I. Kronenberger

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Abstract

Three-step pretargeting for radioimmunotherapy in BALB/c mice with KHJJ tumors was done with monoclonal antibody (mAb) 2D12.5, which is specific for yttrium-1,4,7,10-tetraazacyclododecanetetraacetic acid (DOTA) but nonspecific for the tumor. Tumor uptake was by passive diffusion of mAb through leaky neovasculature in the tumor. The three steps were: (a) anti-hapten mAb 2D12.5 (0 h); (b) polyvalent hapten-protein conjugate chase (20 h); and (c) 88Y-labeled monovalent DOTA or bivalent Janus-DOTA haptens (21 h) and organ and tumor bioassay (24 h). Rapid tumor (T) uptake and high tumor:blood ratio (T:BL) was seen 3 h after injection after step c. For monovalent 88Y-DOTA, T = 1.7%/g* and T:BL = 16:1; for bivalent 88Y-Janus-DOTA, T = 4.41%/g* and T:BL = 21:1 at 3 h (*, P < 0.001). Blood and bone plus marrow were <<1%/g, and liver was <1%/g. The 24-h whole body retention was ≈5% of injected dose with 1% in tumor (20% of total), 1.8% in other organs, and 2.2% in carcass; the 24-h whole body retention of covalent nonspecific antibody conjugates was >80% of injected dose. The biological half-life in the tumor of 0.9 μCi 88Y-Janus-DOTA was ≈24 h, measured daily for 5 days. Activity in μCi/g of tumor and blood for 90Y equimolar to the amount of 88Y injected (0.9 0 μCi 88Y = 0.744 pmol = 36.47 μCi 90Y) was used for calculating the area under the curve of tumor and blood in μCi-h/g of 90Y. The 90Y radiation absorbed dose (RAD) from multiplying μCi-h/g x the 90Y absorbed dose constant, 1.99 RAD-g/μCi-h, gave T = 89 RAD and BL = 3.7 RAD. The therapeutic ratio from RAD T:RAD BL = 24:1. These results indicate that pretargeting 90Y hapten-specific mAb for radioimmunotherapy has considerable promise.

Original languageEnglish (US)
Pages (from-to)5937-5946
Number of pages10
JournalCancer Research
Volume54
Issue number22
StatePublished - Nov 15 1994

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Goodwin, D. A., Meares, C. F., Watanabe, N., McTigue, M., Chaovapong, W., Ransone, C. M., Renn, O., Greiner, D. P., Kukis, D. L., & Kronenberger, S. I. (1994). Pharmacokinetics of pretargeted monoclonal antibody 2D12.5 and 88Y-janus-2-(p-nitrobenzyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid (DOTA) in BALB/c mice with KHJJ mouse adenocarcinoma: A model for 90Y radioimmunotherapy. Cancer Research, 54(22), 5937-5946.