Pizzo ME, Plowey ED, Khoury N, Kwan W, Abettan J, DeVos SL, Discenza CB, Earr T, Joy D, Lye-Barthel M, Roche E, Chan D, Dugas JC, Gadkar K, Meisner R, Sebalusky J, SilvaAmaral AC, Becerra I, Chau R, Chow J, Clemens AJ, Dennis MS, Duque J, Fusaro L, Getz JA, Kariolis MS, Kim DJ, Leung AW, Nguyen HN, Thomsen ER, Sanchez PE, Shan L, Silverman AP, Solanoy H, Tong R, Calvert ME, Watts RJ, Thorne RG, Weinreb PH, Walsh DM, Lewcock JW, Bussiere T, Zuchero YJ. Engineering anti-amyloid antibodies with transferrin receptor targeting improves safety and brain biodistribution. 2024 Jul 26 10.1101/2024.07.26.604664 (version 1) bioRxiv.
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Brown University
Research groups at Denali and Roche have demonstrated encouraging preliminary results in amyloid reduction with lower ARIA rates using plaque-targeting antibodies bound to an antibody transport vehicle targeting the transferrin receptor. Both groups propose broad brain parenchymal antibody distribution with lower binding to vascular Aβ, a key mechanism suspected of underlying the production of inflammation and ARIA. The Denali team used an animal model of amyloid deposition but still needs to conduct this work in AD patients. Their molecular profile seems to mitigate some of the transferrin-related hematological effects. Early data from the Roche trontinemab Phase 1b program shows robust reduction of plaque burden with limited ARIA after just a few doses. This will need to be demonstrated in larger samples with sufficient duration to test for a clinical benefit. Overall these are very encouraging results that could eventually lead to new and safer treatment paradigms for AD.
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