AB2 Bio - Primary HLH Protein
From Clinical Development
People with HLH usually develop symptoms within the first months or years of life. Symptoms may include fever, enlarged liver or spleen, cytopenia (decreased number of blood cells), and neurological abnormalities. All forms of HLH, including cases treated adequately, may have a high mortality rate. The long-term outlook (prognosis) of familial forms without treatment is poor, with a median survival of less than 2 months to 6 months after diagnosis. These disorders can be either inherited (familial or primary) or secondary to other conditions (rheumatic diseases, cancer or infections) such as Macrophage Activation Syndrome (MAS), a severe complication of rheumatic diseases. NLRC4 mutation and XIAP deficiency can be considered part of primary HLH.
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AB2 Bio is currently conducting a pivotal Phase III clinical trial in patients with IL-18 driven monogenic autoinflammatory conditions: NLRC4 mutation and XIAP deficiency.
NLRC4 mutations. The normal function of the NOD-like receptor C-4 (NLRC4) protein is to detect infections and activate the innate immune system to combat these infections. Gain-of-function mutations in the NLRC4 gene (NLRC4 mutations) have been identified in patients suffering from life threatening systemic inflammation. The continuous and permanent activation of the protein leads to the unnecessary production of IL-18 and to the inability of endogenous IL-18BP to block IL-18 thus resulting in extremely high levels of circulating free IL-18 through the body. In the cases that have been reported, this causes two predominant clinical phenotypes: MAS and/or enterocolitis. The enterocolitis is likely to be a result of the expression of the NLRC4 protein in the gut mucosa where NLRC4 is the main inflammasome present and IL-18 the main effector cytokine.
XIAP deficiency. XIAP deficiency is associated with high levels of IL-18 and free IL-18. One of the functions of the X-linked inhibitor of apoptosis protein (XIAP) is to inhibit the activity of NLRC4. Therefore, a deficiency in XIAP function (loss of function) will result in the same pathophysiology as that seen with a gain in function of the NLRC4 protein. Indeed, XIAP deficiency share many pathological similarities with NLRC4 patients, particularly with respect to MAS and enterocolitis.
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