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Polymyxin b-conjugated-2 macroglobulin as an adjunctive therapy to sepsis: modes of action and impact on lethality

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dc.contributor.author Gerd Birkenmeier
dc.contributor.author Silke Nicklisch
dc.contributor.author Christiane Pockelt
dc.date.accessioned 2020-12-10T14:06:31Z
dc.date.available 2020-12-10T14:06:31Z
dc.date.issued 2006
dc.identifier.uri http://10.140.5.162//handle/123456789/2770
dc.description.abstract A drug targeting both the inflammatory initiators (lipopolysaccharide; LPS) and mediators [tumor necrosis factor- (TNF- )] should have advantage over a “single-factor targeting strategy” in sepsis prevention trials. We have prepared conjugates of polymyxin B (PMB) and the cytokine binding protein 2-macroglobulin (A2M). The conjugate binds TNF- as well as LPS as studied by electrophoresis and phase partitioning. Compared with free PMB, the conjugate is nontoxic to cells and does not affect the viability of human monocytes. The A2M-PMB conjugate binds to the A2M receptor (CD91/low-density lipoprotein receptor-related protein 1) with affinity similar to that of the nonmodified protein. Fluorescein isothiocyanate-labeled LPS in the presence of A2M-PMB is rapidly transported into fibroblasts for degradation via receptor-mediated endocytosis. In vitro, A2M-PMB demonstrated inhibition of LPS-induced secretion of TNF- from isolated monocytes as well as in the whole blood assay. The efficacy of the drug was tested in mice after induction of acute inflammation (LPS model) and after induction of a polymicrobial sepsis by cecal ligation and puncture (CLP) model. Treatment of mice with A2M-PMB up to 250 g/g body weight was not toxic to the animal. When the drug was administered 30 min before or 30 min after the LPS challenge, a survival rate of 90 and 70%, respectively, was obtained compared with the placebo control group (5%). A2M-PMB also protected mice after induction of polymicrobial sepsis when administered 30 min before CLP. These results support our hypothesis that A2M-PMB acts as a polyvalent drug to target different host mediators as well as sepsis inducer at the same time en_US
dc.language.iso en en_US
dc.title Polymyxin b-conjugated-2 macroglobulin as an adjunctive therapy to sepsis: modes of action and impact on lethality en_US
dc.type Article en_US


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