作者
Gai Ayalon,Seung-Hye Lee,Oskar Adolfsson,Corinne Foo-Atkins,Jasvinder K. Atwal,Mira Blendstrup,Helen Booler,Joseph Bravo,Robert P. Brendza,Flávia Brunstein,Ruby L.Y. Chan,Pitam Chandra,Jessica A. Couch,Akash Datwani,Barthélemy Demeule,Danielle DiCara,Rich Erickson,James A. Ernst,Oded Foreman,Dongping He,Isidro Hötzel,Michael Keeley,Michael C. M. Kwok,Julien Lafrance‐Vanasse,Han Lin,Yanmei Lu,Wilman Luk,Paul T. Manser,Andreas Muhs,Hai Ngu,Andrea Pfeifer,Maria Pihlgren,Gautham K. Rao,Kimberly Scearce‐Levie,Stephen Schauer,William B. Smith,Hilda Solanoy,Edmond Teng,Kristin R. Wildsmith,Daniela Bumbaca Yadav,Yun Ying,Reina N. Fuji,Geoffrey A. Kerchner
摘要
Tau has become an attractive alternative target for passive immunotherapy efforts for Alzheimer's disease (AD). The anatomical distribution and extent of tau pathology correlate with disease course and severity better than other disease markers to date. We describe here the generation, preclinical characterization, and phase 1 clinical characterization of semorinemab, a humanized anti-tau monoclonal antibody with an immunoglobulin G4 (igG4) isotype backbone. Semorinemab binds all six human tau isoforms and protects neurons against tau oligomer neurotoxicity in cocultures of neurons and microglia. In addition, when administered intraperitoneally once weekly for 13 weeks, murine versions of semorinemab reduced the accumulation of tau pathology in a transgenic mouse model of tauopathy, independent of antibody effector function status. Semorinemab also showed clear evidence of target engagement in vivo, with increases in systemic tau concentrations observed in tau transgenic mice, nonhuman primates, and humans. Higher concentrations of systemic tau were observed after dosing in AD participants compared to healthy control participants. No concerning safety signals were observed in the phase 1 clinical trial at single doses up to 16,800 mg and multiple doses totaling 33,600 mg in a month.