A monoclonal antibody (201B) specific to murine thrombomodulin, covalently linked to cyclohexyl diethylenetriaminepentaacetic acid, successfully delivers chelated 213Bi, an α-particle emitter, (213Bi-201B) rapidly to lung vascular endothelium. When injected at doses of 1 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 α (TNF-α), released from damaged tissues, as the pivotal inflammatory cytokine in a cascade of events that culminate in fibrosis. Attempts to prevent the development of pulmonary fibrosis, by using antibodies or soluble receptor (rhuTNFR:Fc) as inhibitors of TNF-α, were unsuccessful. Additionally, mice genetically deficient for TNF-α production developed pulmonary fibrosis following 213Bi-201B treatment. Interestingly, non-tumor-bearing BALB/c mice receiving rhuTNFR:Fc or mice genetically deficient in TNF-α 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, although TNF-α may induce an inflammatory response following α-particle radiation mediated tumor clearance and pulmonary damage, its effects in the post-tumor clearance time period may actually retard the development of fibrosis.


Presented at the “Seventh Conference on Radioimmunodetection and Radioimmunotherapy of Cancer,” October 15–17, 1998, Princeton, NJ. Supported by individual NIH NRSA HL09718 through the National Heart, Lung, and Blood Institute (to I. A. D.) and by the United States Department of Energy under contract DE AC05-96OR22464 with Lockheed Martin Energy Research Corp., DOE/OBER ERKP0038, and National Cancer Institute Grant IAA97-053 from the Office on Women's Health.

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