Radioimmunotherapy Using Vascular Targeted 213Bi: The Role of TNF-Alpha in the Development of Pulmonary Fibrosis

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A monoclonal antibody (201B) specific to murine thrombomodulin, covalently linked to CHX-b-DTPA, successfully delivers chelated 213Bi, an {alpha}-particle emitter, (213Bi-201B) rapidly to lungvascular endothelium. When injected at doses of l MBq/mouse, 213Bi-201B destroyed most of the 100 colonies of EMT-6 mammary carcinomas growing as lung tumors of up to 2000 cells/colony. Some mice were cured of lung tumors and others had extended life-spans compared to untreated control animals but eventually succumbed to tumor recurrence. At injected doses of 4-6 MBq/mouse, 100% of lung tumor colonies were eliminated; however, 3-4 months later these mice developed pulmonary fibrosis and died. The mechanisms ... continued below

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19 Pages

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Davis, I.A. & Kennel, S.J. October 14, 1998.

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A monoclonal antibody (201B) specific to murine thrombomodulin, covalently linked to CHX-b-DTPA, successfully delivers chelated 213Bi, an {alpha}-particle emitter, (213Bi-201B) rapidly to lungvascular endothelium. When injected at doses of l MBq/mouse, 213Bi-201B destroyed most of the 100 colonies of EMT-6 mammary carcinomas growing as lung tumors of up to 2000 cells/colony. Some mice were cured of lung tumors and others had extended life-spans compared to untreated control animals but eventually succumbed to tumor recurrence. At injected doses of 4-6 MBq/mouse, 100% of lung tumor colonies were eliminated; however, 3-4 months later these mice developed pulmonary fibrosis and died. The mechanisms leading to the fibrotic response in other pulmonary irradiation models strongly implicate tumor necrosis factor-alpha (TNF-{alpha}), released from damaged tissues, as the pivotal inflammatory cytokine in a cascade of events which culminate in fibrosis. Attempts to prevent the development of pulmonary fibrosis, by using antibodies or soluble receptor (Enbrel{trademark}) as inhibitors of TNF-{alpha}, were unsuccessful. Additionally, mice genetically deficient for TNF-{alpha} production developed pulmonary fibrosis following 213Bi-201B treatment. Interestingly, non-tumor bearing BALB/c mice receiving Enbrel{trademark} or mice genetically deficient in TNF-{alpha} production and treated with 213Bi-201B, had significantly reduced life spans compared to mice receiving no treatment or 213Bi-201B alone. We speculate that, in normal mice, while TNF-{alpha} may induce an inflammatory response following {alpha}-particle radiation mediated tumor clearance and pulmonary damage, its effects in the post-tumor clearance time period may actually retard the development of fibrosis.

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19 Pages

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  • 7th Conference on Radioimmunodetection and Radioimmunotherapy of Cancer, Princeton, NJ, Oct. 14-18, 1998

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  • Other: DE00002950
  • Report No.: ORNL/CP-100716
  • Grant Number: AC05-96OR22464
  • Office of Scientific & Technical Information Report Number: 2950
  • Archival Resource Key: ark:/67531/metadc674821

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  • October 14, 1998

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  • July 25, 2015, 2:20 a.m.

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  • Nov. 4, 2015, 2:30 p.m.

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Davis, I.A. & Kennel, S.J. Radioimmunotherapy Using Vascular Targeted 213Bi: The Role of TNF-Alpha in the Development of Pulmonary Fibrosis, article, October 14, 1998; United States. (digital.library.unt.edu/ark:/67531/metadc674821/: accessed September 26, 2017), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT Libraries Government Documents Department.