Development of amyloid conformer-targeting technologies in type 2 diabetes mellitus

PROJECT SUMMARY Type 2 diabetes mellitus (T2DM) represents a significant and escalating global health crisis, with a profound impact on millions of lives and healthcare systems worldwide. Central to the pathogenesis of T2DM is the deposition of islet amyloid polypeptide (IAPP) aggregates, which are implicated in the dysfunction and loss of pancreatic β-cells, leading to the progressive failure of insulin production. Despite the critical role of amyloid aggregation in T2DM and its complications, therapeutic strategies targeting this process remain underexplored and represent a substantial unmet medical need. The founders of Aggregate Biosciences have developed an innovative platform technology for discovering conformation- specific, anti-protofibril monoclonal antibodies (mAbs) that target intermediate amyloid aggregates. Resulting mAbs have shown the ability to target and clear hIAPP aggregates in vivo, leading to improved biomarkers in a mouse model of amyloid-induced diabetes. Building on this innovative approach, we hypothesize that removing toxic hIAPP protofibrils in prediabetic or early diabetic patients could significantly improve β-cell health and delay T2DM progression. However, given the recent lackluster results from FDA-approved therapeutics targeting soluble amyloid intermediates, we hypothesize that specific amyloid conformers are the predominant strains driving disease pathogenesis. Our platform offers a unique opportunity to isolate these amyloid conformers and discover conformation-specific mAbs targeting these conformer strain groups. By employing our lead pan-conformer chaperone-like amyloid modulating protein (CLAMP), nucleobindin-1 (NUCB1), we aim to develop a novel conformer-specific mAb screening platform and an optimized NUCB1- immunoglobulin fusion protein (NUCBody) for targeting a wide range of amyloid conformers. The successful development of this platform and subsequent proof-of-concept studies detecting 'conformer space' in disease could introduce a groundbreaking approach for categorizing amyloid strains, potentially leading to revolutionary diagnostic strategies and therapeutics. By focusing on the identification of disease-specific amyloid conformers, this project addresses a critical gap in current research and treatment methodologies, with the potential to revolutionize the management and treatment of T2DM and other amyloid-related disorders.