NextCure, Inc. announced the presentation of preclinical data relating to NC181, a novel humanized antibody targeting ApoE4, for the treatment of Alzheimer?s disease (AD), at the 2nd Annual Neurodegeneration Targets, Drug Discovery for Progressive Central Nervous System Disorders conference. Published research has shown that different forms of the apolipoprotein E (APOE) gene affect the risk of developing AD in distinct ways, with the APOE4 allele most highly associated with and linked to increased risk. The ApoE4 isoform increases ab amyloid plaque formation, promotes Tau spreading, disrupts the blood brain barrier (BBB), promotes neurovasculature leakage, and increases microglia-mediated inflammation, which has been shown to lead to cognitive decline.

Deletion of APOE has been demonstrated to limit disease in multiple AD models. In preclinical AD animal models, NC181 has demonstrated differentiation from amyloid targeted therapies. Key findings from the study include: NC181 binds to amyloid associated ApoE4, resulting in amyloid clearance and prevention of amyloid deposition in mice.

Clearance of the ApoE plaques: Normalizes neuroinflammation and restores neuroimmune homeostasis. Improves vasodilation in amyloid laden blood vessels, which results in less vascular toxicity and lower vascular leakage. In addition to its role in amyloid deposition, ApoE is also a major mediator of a condition known as Cerebral Amyloid Angiopathy (CAA), where deposition of amyloid-b occurs in leptomeningeal and cortical blood vessels.

This results in BBB dysfunction, ischemia, and a risk for microhemorrhages leading to cognitive dysfunction.