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Hemodynamic Evaluation of Recombinant Human Tumor Necrosis Factor (TNF)-α, TNF‐SAM2 and Liposomal TNF‐SAM2 in an Anesthetized Dog Model

Summary We have evaluated the hemodynamic effects of systemically administered recombinant human tumor necrosis factor (TNF)-α, TNF-SAM2 and liposome-bound TNF-SAM2 in an anesthetized mongrel dog model. A dose of 10 μg TNF protein/kg of each formulation was injected in a peripheral vein and mean systemic arterial pressure (SAP), heart rate (HR) and cardiac output (CO) were measured. TNF-α induced a marked drop in SAP in all three dogs (mean decrease = 59.3 ± 5.2 mm Hg; to 61.5% of baseline; p = 0.008); whereas TNF-SAM2 caused a smaller and transient drop in SAP in four dogs (mean decrease = 25.5 ± 10.1 mm Hg; to 81.2% of baseline; p = 0.086). In three dogs administered liposome-bound TNF-SAM2, which retains antitumor activity in vivo, a net slight hypertensive phase and sustained elevated CO occurred, followed by a return to an essentially normotensive state (101.0% of baseline SAP). This model demonstrates that the principal acute systemic toxicity of TNF, i.e., hypotension, can be markedly attenuated by liposomal formulation of a second-generation TNF.