Evaluation of microspheres containing cytokine neutralizing antibodies in endotoxemia.
Albumin microspheres are efficient carriers for delivering therapeutic agents to macrophages. In response to endotoxin, macrophages release tumor necrosis factor alpha (TNF alpha) and interleukin-1-beta (IL-1 beta). Blocking the effects of TNF alpha and IL-1 beta decreased lethality due to endotoxin-induced shock. In this study, we compared the efficacy of the microsphere form of TNF alpha and/or IL-1 beta neutralizing antibodies (NAs) with the free form of TNF alpha and/or IL-1 beta NA in preventing lethality due to endotoxemia and evaluated the duration of blockade by the microsphere form of TNF alpha and/or IL-1 beta NA on endotoxin-induced cytokine release. The results indicate that the microsphere form of TNF alpha and/or IL-1 beta NA protected 80% of the rats from lethal endotoxemia, while none of the rats that received the free from of TNF beta and/or IL-1 beta NA survived longer than 48 hr. The microsphere form of TNF alpha and/or IL-1 beta NA attenuated endotoxin-induced cytokine release more potently than the free form of TNF alpha and/or IL-1 beta NA in vivo. In vitro, the microsphere form of TNF alpha and/or IL-1 beta 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.
D'Souza
M J
MJ
Department of Pharmaceutical Sciences, Southern School of Pharmacy, Mercer University, Atlanta, Georgia, USA.
Oettinger
C W
CW
Milton
G V
GV
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004347:Drug Interactions; D019446:Endotoxemia / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000276:immunology / Q000627:therapeutic use*; D008863:Microspheres; D051381:Rats; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*
D000906:Antibodies; D016207:Cytokines; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha