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A novel LBP-BPI fusion protein with in vivo efficacy and longer half life

Incyte Pharmaceuticals, Palo Alto, CA, USA

J.J. Seilhamer

Incyte Pharmaceuticals, Palo Alto, CA, USA

L. Lin

Incyte Pharmaceuticals, Palo Alto, CA, USA

B.M. McKelligon

Incyte Pharmaceuticals, Palo Alto, CA, USA

J.C. Lane

Incyte Pharmaceuticals, Palo Alto, CA, USA

J.L. Snable

Incyte Pharmaceuticals, Palo Alto, CA, USA

M.T. Kikuchi

Incyte Pharmaceuticals, Palo Alto, CA, USA

R.W. Scott

Incyte Pharmaceuticals, Palo Alto, CA, USA

M.N. Marra

Incyte Pharmaceuticals, Palo Alto, CA, USA

Bactericidal/permeability-increasing protein (BPI) is a neutrophil azurophilic granule protein which binds to and neutralizes the biological activity of Gram-negative bacterial endotoxin both in vitro and in vivo. The therapeutic utility of BPI is hampered by its remarkably short circulating half life. BPI shares 44% sequence identity with lipopolysaccharide binding protein (LBP), an acute phase protein which facilitates endotoxin-mediated cellular responses and has a long circulating half-life. BPI and LBP are members of a family of proteins which regulate LPS activity in vivo. Genetically engineered variants of BPI and LBP were designed to maintain the endotoxin neutralizing properties of BPI but to have an extended circulating half life. One of these, LBP-BPI, is comprised of the N-terminal half of LBP, linked to the C-terminal half of BPI. Like BPI, LBP-BPI had endotoxin neutralizing activity in vitro and in vivo and gave a significant protective effect against lethal endotoxin challenge in mice (90% survival in treated group vs 10% survival in untreated controls P < 0.001). Neither LBP nor the 25 kDa N-terminal fragments of BPI and LBP were protective in this model of lethal endotoxin challenge. Pharmacokinetic studies in CD-1 mice showed that the LBP-BPI variant is cleared 74 times more slowly than BPI. Longer half-life versions of BPI have a broader window of protection and require lower overall doses to maintain therapeutically effective circulating concentrations. Molecules such as the LBP-BPI variant will have greater therapeutic utility than the native BPI molecule by virtue of these properties.

Journal of Endotoxin Research, Vol. 2, No. 3, 209-212 (1995)
DOI: 10.1177/096805199500200310


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