Mechanism of ARIA following Anti-Amyloid Immunotherapy

PROJECT SUMMARY Monoclonal antibody (Ab)-based immunotherapy to remove amyloid-beta (Aβ) holds great promise for treating AD patients. However, potential severe consequences, including excessive inflammation, increased risk of bleeding in the brain, and potential death, have raised concerns regarding the safety of anti-amyloid immunotherapy. To develop efficient strategies to safely administer anti-amyloid immunotherapy, it is critical to identify the mechanisms leading to Amyloid-Related Imaging Abnormalities (ARIA), such as cerebral edema and microhemorrhages that are induced by immunotherapy. To address this, we cloned the human anti-Aβ antibody Aducanumab (Adu) and Lecanemab (Lec) and further murinized them on mouse IgG2a. While these chAbs were effective in reducing Aβ in the brain, the chronic administration of these chimeric Abs (chAbs) recapitulated MRI- detectable ARIA events in AD model mice. Our preliminary studies found genes associated with vascular inflammation that were dysregulated in brain endothelial cells, and that the elimination of chAbs from the brain was significantly reduced in aged AD model mice. Thus, it is reasonable to surmise that the prolonged retention of immunogenic chAbs in the brain may cause excessive vascular inflammation. We hypothesize that the low clearance of anti-amyloid Abs in the AD brain is directly linked to the development of ARIA events through increased vascular inflammation. Using clinically relevant but conformationally distinct ChAbs raised against dense plaques (ChAdu) and protofibrils (ChLec) of Aβ, Aim 1 focuses on determining the elimination pathway and the mechanism of clearance for chAbs in AD mouse models. In Aim 2, using a biophase PK/PD model, we will examine how ARIA events develop in AD model mice receiving chronic administration of two conformational ChAbs. We will assess PK/PD relationships between chAbs and ARIA profiles, cognitive function, and immunotherapy associated exacerbation of CAA in AD model mice with and without ARIA. In Aim 3, we will examine the mechanisms of vascular inflammation that exacerbate vascular deposition of Aβ aggregates in immunotherapy treated animals. Understanding vascular inflammation profiles between ARIA-positive and ARIA-negative mice will identify the inflammatory pathways involved in the development of ARIA in AD model mice receiving immunotherapy, which may allow for adjunctive anti- inflammatory treatments to reduce risk. The completion of this project will provide insights into the mechanisms underlying ARIA events caused by clinically relevant anti-Aβ antibodies directed against two distinct conformations of Aβ. Ultimately, this project will contribute to the development of management strategies to ensure the safe application of immunotherapy in AD patients.