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Immunomodulatory and Toxic Effects of Free and Liposome-encapsulated Tumor Necrosis Factor in Rats¹

Robert J. Debs², Henry J. Fuchs, Ramila Philip, Elisa N. Brunette, Nejat Düzgüne, Judd E. Shellito, Denny Liggitt and John R. Patton

Cancer Research Institute [R. J. D., R. P., E. N. B., N. D.], Cardiovascular Research Institute [J. E. S.], and Department of Pharmaceutical Chemistry [N. D.], University of California, San Francisco, California 94143 Respiratory Care Section, VA Medical Center San Francisco, 94121 [J. E. S.]; and Department of Pharmacology, Genentech Inc., South San Francisco, California 94080 [H. J. F., D. L., J. S. P.]

Tumor necrosis factor has potent immunomodulatory and antitumor activity, but its therapeutic applications may be limited by its significant host toxicity. We showed that liposome-encapsulated recombinant human tumor necrosis factor (rHuTNF-) retained full anticellular activity in vitro. We then assessed the immunomodulatory and toxic effects of two different doses of i.v. free or liposome-encapsulated rHuTNF- in normal rats. Both free and liposome-encapsulated rHuTNF- significantly enhanced alveolar macrophage- and blood monocyte-mediated interleukin 1 release and tumor cell lysis, as well as natural killer cell cytotoxicity, when compared to buffer-treated controls. However, administration of rHuTNF- in liposomes substantially reduced tumor necrosis factor -mediated toxicity. Animals receiving liposome-encapsulated rHuTNF- showed significantly less tissue injury, gastric retention, and circulating leukocyte shifts than animals receiving free rHuTNF-. In addition, liposome-based delivery significantly increased lung and liver uptake of rHuTNF-. Therefore, liposome-encapsulated rHuTNF- retains immunomodulatory activity, significantly reduces toxic inflammatory effects, and may allow targeting of tumor necrosis factor to selected organs after i.v. administration.

¹ This work was supported by funds provided by grants from the State of California, as recommended by the Universitywide Task Force on AIDS (R. J. D. and N. D.), and by NIH Grants AI 26128 (R. J. D.) and AI 25534 (N. D.).

² To whom requests for reprints should be addressed.

Received 12/ 6/88. Revised 3/27/89. Revised 6/22/89. Revised 8/29/89. Accepted 10/11/89.

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