Abstract: The invention provides for the expression and purification of a recombinant form of FABP (Fh15) exhibiting a similar suppressive effect on TLR-stimulation and inflammatory cytokine expression from macrophages than those previously demonstrated for the native molecule. Fh15 suppresses the expression of IL-1? and TNF? in murine macrophages and THP1 Blue CD14 cells. Additionally, Fh15 suppress the LPS-induced TLR4 stimulation. This effect was not impaired by a thermal denaturing process or blocked by the presence of anti-Fh12 antibodies. Fh15 also suppressed the stimulation of various TLRs in response to whole bacteria extracts so that Fh15 could be an excellent alternative for an anti-inflammatory drug in preclinical studies in the near future.

Abstract: The present disclosure reports that (1) recombinant Fh15 significantly prevented bacteremia, suppressed LPS levels in plasma and the production of C-reactive protein and procalcitonin, which are key signatures of inflammation and bacterial infection, respectively; (2) reduced the production of pro-inflammatory cytokines; and (3) increased innate immune cell populations in blood, which suggests a role in promoting a prolonged steady state in rhesus macaques even in the presence of inflammatory stimuli. This is the first report demonstrating that a F. hepatica-derived molecule possesses potential as anti-inflammatory drug against sepsis in an NHP-model. Prophylactic effects of rFh15 administered in a non-human preclinical primate model of sepsis support its use as a biotherapeutic.

Abstract: Toll-like receptor 4 (TLR4), the innate immunity receptor for bacterial endotoxins, plays a pivotal role in the induction of inflammatory responses. There is a need to develop molecules that block either activation through TLR4 or the downstream signaling pathways to inhibit the storm of inflammation typically elicited by bacterial lipopolysaccharide (LPS), which is a major cause of the high mortality associated with bacterial sepsis. The present invention provides that a single intraperitoneal injection of 15 ?g Fasciola hepatica fatty acid binding protein (Fh12) 1 hour before exposure to LPS suppressed significantly the expression of serum inflammatory cytokines in a model of septic shock using C57BL/6 mice. Whereas Fh12 alone did not induce cytokine expression, it significantly suppressed the expression of IL12, TNF?, IL6 and IL1? cytokines as well as iNOS2 in bmM?s, and also impaired the phagocytic capacity of bmM?s.