Factor C for treating gram-negative bacterial infection

US7939492B2 · kind B2 · utility

Assignee

• NATIONAL UNIVERSITY OF SINGAPORE · SG

Inventors

• Jeak Ling Ding · Singapore, SG
• Bow Ho · Singapore, SG
• Nguan Soon Tan · Singapore, SG

Key dates

• Filing date: Oct 12, 2007
• Grant date: May 10, 2011
• Expiry date: Jul 29, 2029

Classification

• Technology area (CPC Y): Emerging Cross-Sectional Technologies
• CPC primary: Y10T436/25375
• WIPO field: Pharmaceuticals
• WIPO sector: Chemistry

Abstract

Recombinant fragments of Factor C are disclosed. These proteins and peptides show great potency in recognizing, binding to, neutralizing and removing endotoxin. These molecules can thus be used for anti-microbial, anti-endotoxin, and anti-sepsis therapy. SSCrFCES is a 38 kDa protein representing the LPS-binding domain of Factor C. The ability of SSCrFCES to bind lipid A was analyzed using an ELISA-based assay as well as surface plasmon resonance. Surface plasmon resonance similarly carried out for SSCrFC-sushi-1,2,3-GFP, SSCrFC-sushi-1GFP, and SSCrFC-sushi-3GFP confirmed their superior affinity for endotoxin. The 50% endotoxin-neutralizing concentration of SSCrFCES against 200 EU of endotoxin is 0.069 μM, suggesting that SSCrFCES is an effective inhibitor of LAL coagulation cascade. Although partially attenuated by human serum, as low as 1 μM of SSCrFCES inhibits the LPS-induced secretion of hTNF-α and hIL-8 by THP-1 and human pheripheral blood mononuclear cells with a potency more superior than polymyxin B. SSCrFCES is non-cytotoxic, with a clearance rate of 4.7 ml/minute. The LD90 of SSCrFCES for LPS lethality in mice is achieved at 2 μM. These results demonstrate the endotoxin-n…