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Infection and Immunity, April 1994, p. 1185-1191, Vol. 62, No. 4
0019-9567/1994/$04.00+0     DOI:

research-article

Competition between rBPI23, a recombinant fragment of bactericidal/permeability-increasing protein, and lipopolysaccharide (LPS)-binding protein for binding to LPS and gram-negative bacteria.

H Gazzano-Santoro, K Mészáros, C Birr, S F Carroll, G Theofan, A H Horwitz, E Lim, S Aberle, H Kasler, and J B Parent

Department of Sepsis Research, XOMA Corporation, Berkeley, California 94710.

ABSTRACT

Lipopolysaccharide (LPS)-binding protein (LBP) and bactericidal/permeability-increasing protein (BPI) are two structurally related lipid A-binding proteins with divergent functional activities. LBP mediates activation of macrophage and other proinflammatory cells. In contrast, BPI has potent bactericidal and LPS-neutralizing activities. A recombinant fragment of BPI (rBPI23) retains the potent biological activities of the holo protein and may represent a novel therapeutic agent for the treatment of gram-negative infections, sepsis, and endotoxemia. For therapeutic effectiveness in many clinical situations, rBPI23 will have to successfully compete with high serum levels of LBP for binding to endotoxin and gram-negative bacteria. The relative binding affinities of rBPI23 and human recombinant LBP (rLBP) for lipid A and gram-negative bacteria were evaluated. The binding of both proteins to lipid A was specific and saturable with apparent Kds of 2.6 nM for rBPI23 and 58 nM for rLBP. rBPI23 was approximately 75-fold more potent than rLBP in inhibiting the binding of 125I-rLBP to lipid A. The binding affinity of rBPI23 (Kd = 70 nM) for Escherichia coli J5 bacteria was also significantly higher than that of rLBP (Kd = 1,050 nM). In addition, rBPI23 at 0.2 micrograms/ml was able to inhibit LPS-induced tumor necrosis factor release from monocytes in the presence of 20 micrograms of rLBP per ml. These results demonstrate that rBPI23 binds more avidly to endotoxin than does rLBP and that, even in the presence of a 100-fold weight excess of rLBP, rBPI23 effectively blocks the proinflammatory response of peripheral blood mononuclear cells to endotoxin.

Infection and Immunity, April 1994, p. 1185-1191, Vol. 62, No. 4
0019-9567/1994/$04.00+0     DOI:




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