NASH · Targeting macrophage CD163 for treatment of non-alcoholic steatohepatitis

Macrophages play a key role in inflammatory diseases. One of the goals of the TROJA ERC program has been to explore drug targeting via the haemoglobin scavenger receptor CD163, which has a high and exclusive expression in macrophages. We have now developed new biodegradable anti-CD163 antibody-drug conjugates by linking drugs directly to anti-CD163 antibody and by encapsulating drugs in liposomes with anti-CD163 antibodies linked to the surface. The CD163-targeting technology has been proven in in vitro and in vivo models. A very promising line of results show that we by use of this technology in a rat inflammation model can show a fifty-fold increase in the potency of synthetic glucocorticoid (dexamethasone). At the same time we observe virtually no systemic effects, which are known to cause the serious glucocorticoids side effects such as bone mobilization, muscle mass loss, infections and metabolic alterations. We now want to investigate the effect of CD163-targeted glucocorticoid in a major inflammatory liver disease. Nonalcoholic steatohepatitis (NASH) is a common, often “silent” disease but anyway a major treat against general health. A fatty liver is an important pathogenic factor in line with the fact that the steady increase in incidence of the disease correlates with changes in life style and obesity. The full-blown NASH with macrophage-driven inflammation and damage of liver tissue is a serious a condition with the risk of lethal liver cirrhosis. There is no current medical treatment of the condition The present approach of targeting the liver macrophages with 'safe' glucocorticoid may effectively dampen the acute inflammation and reduce mortality. The TROJA team expects to have PoC in the NASH indication within 12 month whereafter the project can be taken over by an industrial partner for completion of preclinical validation to obtain approval for clinical testing.""