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

Research output: Contribution to journalArticle

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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

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Radioimmunotherapy
Adenocarcinoma
Pharmacokinetics
Monoclonal Antibodies
Neoplasms
Haptens
Radiation
1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
Yttrium
Biological Assay
Area Under Curve
Half-Life

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 journalArticle

Goodwin, DA, Meares, CF, Watanabe, N, McTigue, M, Chaovapong, W, Ransone, CM, Renn, O, Greiner, DP, Kukis, DL & Kronenberger, SI 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, vol. 54, no. 22, pp. 5937-5946.
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. / 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. In: Cancer Research. 1994 ; Vol. 54, No. 22. pp. 5937-5946.
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title = "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",
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.",
author = "Goodwin, {David A.} and Meares, {Claude F.} and Naoto Watanabe and Maureen McTigue and Warak Chaovapong and Ransone, {Charles McK} and Oliver Renn and Greiner, {Douglas P.} and Kukis, {David L.} and Kronenberger, {Sheila I.}",
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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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