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 language | English (US) |
|---|---|
| Pages (from-to) | 5937-5946 |
| Number of pages | 10 |
| Journal | Cancer Research |
| Volume | 54 |
| Issue number | 22 |
| State | Published - Nov 15 1994 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
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. / Goodwin, David A.; Meares, Claude F.; Watanabe, Naoto; McTigue, Maureen; Chaovapong, Warak; Ransone, Charles McK; Renn, Oliver; Greiner, Douglas P.; Kukis, David L.; Kronenberger, Sheila I.
In: Cancer Research, Vol. 54, No. 22, 15.11.1994, p. 5937-5946.Research output: Contribution to journal › Article
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TY - JOUR
T1 - 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
T2 - A model for 90Y radioimmunotherapy
AU - Goodwin, David A.
AU - Meares, Claude F.
AU - Watanabe, Naoto
AU - McTigue, Maureen
AU - Chaovapong, Warak
AU - Ransone, Charles McK
AU - Renn, Oliver
AU - Greiner, Douglas P.
AU - Kukis, David L.
AU - Kronenberger, Sheila I.
PY - 1994/11/15
Y1 - 1994/11/15
N2 - 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.
AB - 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.
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M3 - Article
VL - 54
SP - 5937
EP - 5946
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 22
ER -