Targeting of tau pathology has long been proposed as a potential therapeutic strategy for Alzheimer`s disease (AD). Semorinemab is a humanized IgG4 monoclonal antibody that binds to all known isoforms of full-length tau with high affinity and specificity. Semorinemab`s safety and efficacy have been studied in two Phase 2 randomized, double-blind, placebo-controlled, parallel-group clinical trials: Tauriel (prodromal-to-mild AD; NCT03289143) and Lauriet (mild-to-moderate AD; NCT03828747). CSF was collected from a subset of patients at baseline and after 49 or 73 weeks in Tauriel and baseline and after 49 or 61 weeks in Lauriet. We generated a large proteomics dataset, using more than 250 cerebrospinal fluid (CSF) samples and detecting more than 3500 proteins, to investigate the effects of semorinemab in each trial. Treatment-induced proteomic signatures were defined for each study as a set of proteins significantly elevated in the treatment arm in the respective study. Integration of the corresponding gene signatures with two independent brain single-nucleus RNA-seq datasets from AD and healthy aged controls revealed that Lauriet signature genes were enriched in microglial cells, while Tauriel signature genes were more broadly expressed across major brain cell types. Furthermore, the Lauriet trial gene signature was significantly upregulated in microglia from AD patients as compared to non-demented controls. The elevation of proteins such as CHI3L1 and GPNMB with treatment suggested an activated glial state. Taken together, this study utilizes a large CSF clinical proteomics dataset to assess the pharmacodynamic response of semorinemab and contributes to our understanding of how an anti-tau antibody influences disease-relevant pathophysiology in AD.

All authors are full-time employees and own stock in F. Hoffmann-La Roche Ltd. Edmond Teng is listed as a co-inventor on the patent for semorinemab.

NCT03289143, NCT03828747

The study was funded by F. Hoffmann-La Roche Ltd and Genentech.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All of Ethics committees/IRB listed below gave ethical approval for the Tauriel (NCT03289143) study. [1] NeuroCentrix / Bellberry Human Research Ethics Committees [2] Royal Melbourne Hospital / Melbourne Health Human Research Ethics Committee [3] Royal Melbourne Hospital / Alfred Hospital Ethic Committee [4] Southern Neurology / Bellberry Human Research Ethics Committees [5] Universitair Ziekenhuis Brussel / Ethische Commissie Onderzoek UZ-KU Leuven [6] UZ Leuven / Ethische Commissie Onderzoek UZ-KU Leuven [7] AZ Groeninge / Ethische Commissie Onderzoek UZ-KU Leuven [8] Clinique de la Memoire de l'Outaoua / WCG Clinical [9] Toronto Sunnybrook Hospital / Sunnybrook Health Sciences REB [10] Toronto Memory Program (Neurolog / WCG Clinical [11] Bruyere Continuing Care / Bruyere Continuing Care REB [12] JBN Medical Diagnostic Services Inc. / WCG Clinical [13] Toronto Western Hospital / University Health Network Research Ethics Board [14] CCBR - Vejle - DK / Videnskabsetiske Komite for Region Nordjylland [15] CCBR - AAlborg - DK / Videnskabsetiske Komite for Region Nordjylland [16] Centre pour Personnes AAges / Comite de Protection des Personnes Sud-ouest et Outre-Mer IV [17] CHU Rennes - Pontchaillou / CPP Nord-Ouest III [18] CHU Strasbourg - Hopital Hautepierr / Comite de Protection des Personnes Sud-ouest et Outre-Mer IV [19] Hopital de la Timone / CPP Nord-Ouest III [20] Groupe Hospitalier Pitie-Salpetriere / CPP Nord-Ouest III [21] Hopital des Chapennes / CPP Nord-Ouest III [22] CHU de Lyon - Hopital Neurologique / CPP Nord-Ouest III [23] CHU Lille - Hopital Roger Salengro / Comite de Protection des Personnes Sud-ouest et Outre-Mer IV [24] Klinikum rechts der Isar der TU Muenchen / Ethikkommission der Fakultat fur Medizin der TU Munchen [25] Klinische Forschung Hannover-Mitte / Ethikkommission der Fakultat fur Medizin der TU Munchen [26] Universitatsklinikum Tuebingen / Ethikkommission der Fakultat fur Medizin der TU Munchen [27] Charite - Campus Berlin Buch, Experi / Ethikkommission der Fakultat fur Medizin der TU Munchen [28] Universitatsklinikum Ulm / Ethikkommission der Fakultat fur Medizin der TU Munchen [29] Azienda Ospedaliera Universitaria Po / Comitato etico dell'Azienda Policlinico Umberto I [30] Ospedale San Giovanni Calabita Fate / Comitato Etico Lazio 1 [31] I.R.C.C.S. Neuromed-Istituto Neurolo / Comitato Etico dell'I.R.C.C.S. Neuromed-Istituto Neurologico Mediterraneo [32] Azienda Ospedaliera Card. G. Panico / Comitato Etico della AUSL LE di Lecce [33] Jeroen Bosch Ziekenhuis / Stichting Beoordeling Ethiek Biomedisch Onderzoek [34] Brain Research Center / Stichting Beoordeling Ethiek Biomedisch Onderzoek [35] Centrum Medyczne NeuroProtect / Komisja Bioetyczna przy Dolnoslaskiej Izbie Lekarskiej [36] Podlaskie Centrum Psychogeriatrii / Komisja Bioetyczna przy Dolnoslaskiej Izbie Lekarskiej [37] NZOZ NEURO-KARD, Ilkowski i Par / Komisja Bioetyczna przy Dolnoslaskiej Izbie Lekarskiej [38] Neuro-Care Gabriela Klodowska / Komisja Bioetyczna przy Dolnoslaskiej Izbie Lekarskiej [39] Pratia MCM Krakow / Komisja Bioetyczna przy Dolnoslaskiej Izbie Lekarskiej [40] PALLMED Sp. z o.o. / Komisja Bioetyczna przy Dolnoslaskiej Izbie Lekarskiej [41] Centrum Medyczne AMED Warszawa / Komisja Bioetyczna przy Dolnoslaskiej Izbie Lekarskiej [42] Osrodek Badan Klinicznych EUROME / Komisja Bioetyczna przy Dolnoslaskiej Izbie Lekarskiej [43] NZOZ Wroclawskie Centrum Alzheim / Komisja Bioetyczna przy Dolnoslaskiej Izbie Lekarskiej [44] Novo-Med Zielinski i wspolnicy Sp. j. / Komisja Bioetyczna przy Dolnoslaskiej Izbie Lekarskiej [45] Hospital Perpetuo Socorro / La Fe Department de Salut [46] Hospital Universitario Reina Sofia / La Fe Department de Salut [47] Hospital Universitari i Politecnic La F / La Fe Department de Salut [48] Hospital de la Santa Creu i Sant Pau / La Fe Department de Salut [49] Fundacio ACE / La Fe Department de Salut [50] Hospital Universitario Dr. Peset / La Fe Department de Salut [51] Hospital Universitario Mutua de Terr / La Fe Department de Salut [52] Policlinica Gipuzkoa / La Fe Department de Salut [53] Hospital de Cantoblanco / La Fe Department de Salut [54] Clinica Universidad de Navarra / La Fe Department de Salut [55] Hospital Clinic de Barcelona / La Fe Department de Salut [56] Hospital Universitario Virgen Macare / La Fe Department de Salut [57] Sahlgrenska Universitetssjukhuset, M / Regionala etikprovningnamnden i Stockholm [58] Skanes Universitetssjukhus, Malmo / Regionala etikprovningnamnden i Stockholm [59] Re:Cognition Health Ltd (London) / London - Chelsea Research Ethics Committee [60] The National Hospital for Neurology / London - Chelsea Research Ethics Committee [61] Miami Jewish Health System, Inc / WCG Clinical [62] Southern Illinois University Neurolog / Springfield Committee for Research Involving Human Subjects [63] Neuropsychiatric Research Center of / WCG Clinical [64] Brain Matters Research / WCG Clinical [65] Empire Neurology, PC / Copernicus Group IRB [66] Alexian Brothers Medical Center - Ne / WCG Clinical [67] University of Alabama at Birmingham / WCG Clinical [68] JEM Research Institute / WCG Clinical [69] Synexus Clinical Research US, Inc. - O / Copernicus Group IRB [70] Albany Medical College / WCG Clinical [71] Perlmutter Cancer Center NYU Lango / Columbia University Medical Center IRB [72] Collier Neurologic Specialists, LLC / WCG Clinical [73] Emory University / WCG Clinical [74] Summit Research Network (Oregon) / WCG Clinical [75] Brigham and Women's Hospital / WCG Clinical [76] Premiere Research Institute / Copernicus Group IRB [77] KI Health Partners, LLC / Copernicus Group IRB [78] Bradenton Research Center, Inc. / Copernicus Group IRB [79] Bradenton Research Center, Inc. / WCG Clinical [80] The Memory Clinic / Copernicus Group IRB [81] Alzheimers Disease Center / Copernicus Group IRB [82] Collaborative Neuroscience Network / WCG Clinical [83] Pharmacology Research Institute / WCG Clinical [84] University of Rochester / WCG Clinical [85] Center for Memory and Aging / HealthPartners Institute Institutional Review Board [86] Molecular Neuroimaging / WCG Clinical [87] University of California - Irvine / University of California - Irvine IRB [88] Butler Hospital / Copernicus Group IRB [89] Stanford Hospital and Clinics / Stanford University - Human Subjects IRB [90] Rush University Medical Center-Chic / Rush University Medical Center - Office of Research Affairs [91] Advanced Memory Research Institut / WCG Clinical [92] AMR New Orleans, Formerly New Or / WCG Clinical [93] Neurology Clinic, PC / Copernicus Group IRB [94] Rhode Island Mood & Memory Resea / WCG Clinical [95] Pacific Research Network, Inc / WCG Clinical [96] Georgetown University Medical Cent / Georgetown University Hospital IRB [97] Alzheimer's Research and Treatment / WCG Clinical [98] Abington Neurological Associates / WCG Clinical All of Ethics committees/IRB listed below gave ethical approval for the Lauriet (NCT03828747) study. [1] Brain Matters Research / WCG Clinical [2] Synexus Clinical Research US, Inc. / WCG Clinical [3] Alexian Brothers Medical Center - Neuroscience Research Institute / WCG Clinical [4] Alzheimer's Research and Treatment Center / WCG Clinical [5] JEM Research Institute / WCG Clinical [6] Abington Neurological Associates, LTD / WCG Clinical [7] Neuropsychiatric Research Center of Southwest Florida / WCG Clinical [8] Alzheimers Disease Center / WCG Clinical [9] CHU Rennes - Pontchaillou / CPP Nord-Ouest III [10] Hopital de la Timone / CPP Nord-Ouest III [11] Groupe Hospitalier Pitie-Salpetriere / CPP Nord-Ouest III [12] Hopital Neurologique Bron / CPP Nord-Ouest III [13] Centrum Medyczne NeuroProtect / Komisja Bioetyczna przy Dolnoslaskiej Izbie Lekarskiej [14] Podlaskie Centrum Psychogeriatrii / Komisja Bioetyczna przy Dolnoslaskiej Izbie Lekarskiej [15] NZOZ NEURO-KARD, Ilkowski i Partnerzy Sp. Partn. Lek. / Komisja Bioetyczna przy Dolnoslaskiej Izbie Lekarskiej [16] Osrodek Badan Klinicznych EUROMEDIS / Komisja Bioetyczna przy Dolnoslaskiej Izbie Lekarskiej [17] NZOZ Wroclawskie Centrum Alzheimerowskie / Komisja Bioetyczna przy Dolnoslaskiej Izbie Lekarskiej [18] NZOZ NOVO-MED / Komisja Bioetyczna przy Dolnoslaskiej Izbie Lekarskiej [19] KI Health Partners, LLC / WCG Clinical [20] Miami Jewish Health System, Inc / WCG Clinical [21] Southern Illinois University Neurology Clinic / Springfield Committee for Research Involving Human Subjects [22] Neurology Clinic, PC / WCG Clinical [23] Empire Neurology, PC / WCG Clinical [24] Collier Neurologic Specialists, LLC / WCG Clinical [25] Summit Headlands LLC / WCG Clinical [26] Brigham and Women's Hospital / WCG Clinical [27] Alphab Global Research / WCG Clinical [28] CenExel Collaborative Neuroscience Research / WCG Clinical [29] Pharmacology Research Institute / WCG Clinical [30] University of Rochester - PARENT / WCG Clinical [31] Center for Memory and Aging / HealthPartners Institute Institutional Review Board [32] Stanford Hospital and Clinics / Stanford University - Human Subjects IRB [33] CenExel Advanced Memory Research Institute of NJ / WCG Clinical [34] Pacific Research Network, Inc / WCG Clinical [35] Bradenton Research Center, Inc. / WCG Clinical [36] The Memory Clinic / WCG Clinical [37] Molecular Neuroimaging / WCG Clinical [38] Butler Hospital / WCG Clinical [39] Rush University Medical Center-Chicago / Rush University Medical Center - Office of Research Affairs [40] Rhode Island Mood & Memory Research Institute / WCG Clinical [41] AMR Knoxville, Formerly New Orleans Center for Clinical Research - Knoxville, an AMR company / WCG Clinical [42] Hopital des Chapennes / CPP Nord-Ouest III [43] Hospital Universitari i Politecnic La Fe / La Fe Department de Salut [44] Hospital de la Santa Creu i Sant Pau / La Fe Department de Salut [45] Fundacio ACE / La Fe Department de Salut [46] Hospital Universitario Dr. Peset / La Fe Department de Salut [47] Hospital Clinic de Barcelona / La Fe Department de Salut [48] Hospital Universitario Mutua de Terrasa / La Fe Department de Salut [49] Centrum Medyczne AMED Warszawa Zoliborz / Komisja Bioetyczna przy Dolnoslaskiej Izbie Lekarskiej

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

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