Evaluation of Microspheres Containing Cytokine Neutralizing Antibodies in Endotoxemia

Abstract

Albumin microspheres are efficient carriers for delivering therapeutic agents to macrophages. In response to endotoxin, macrophages release tumor necrosis factor alpha (TNFα) and interleukin-1-beta (IL-1β). Blocking the effects of TNFα and IL-1β decreased lethality due to endotoxin-induced shock. In this study, we compared the efficacy of the microsphere form of TNFα and/or IL-1β neutralizing antibodies (NAs) with the free form of TNFα and/or IL-1β NA in preventing lethality due to endotoxemia and evaluated the duration of blockade by the microsphere form of TNFα and/or IL-1β NA on endotoxin-induced cytokine release. The results indicate that the microsphere form of TNFα and/or IL-1β NA protected 80% of the rats from lethal endotoxemia, while none of the rats that received the free form of TNFβ and/or IL-1β NA survived longer than 48 hr. The microsphere form of TNFα and/or IL-1β NA attenuated endotoxin-induced cytokine release more potently than the free form of TNFα and/or IL-1β NA in vivo. In vitro, the microsphere form of TNFα and/or IL-1β NA blocked endotoxin-induced cytokine release for at least 24 hr. Higher efficacy of the microsphere form of NA in reducing mortality and blocking cytokine release makes it more therapeutically advantageous than the free form of NA in the treatment of lethal endotoxemia.

Key Words:

• Albumin microspheres
• Cytokines
• Endotoxemia
• Interleukin-1-beta
• Macrophages
• Tumor necrosis factor alpha