{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T04:06:32Z","timestamp":1788581192885,"version":"build-2803163510"},"reference-count":91,"publisher":"SAGE Publications","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2021,3,23]]},"abstract":"<jats:p>Background: Alzheimer\u2019s disease (AD) and other tauopathies are neurodegenerative disorders characterized by cellular accumulation of aggregated tau protein. Tau pathology within these disorders is accompanied by chronic neuroinflammation, such as activation of the classical complement pathway by complement initiation factor C1q. Additionally, about half of the AD cases present with inclusions composed of aggregated alpha-synuclein called Lewy bodies. Lewy bodies in disorders such as Parkinson\u2019s disease and Lewy body dementia also frequently occur together with tau pathology. Objective: Immunotherapy is currently the most promising treatment strategy for tauopathies. However, the presence of multiple pathological processes within tauopathies makes it desirable to simultaneously target more than one disease pathway. Methods: Herein, we have developed three bispecific antibodies based on published antibody binding region sequences. One bispecific antibody binds to tau plus alpha-synuclein and two bispecific antibodies bind to tau plus C1q. Results: Affinity of the bispecific antibodies to their targets compared to their monospecific counterparts ranged from nearly identical to one order of magnitude lower. All bispecific antibodies retained binding to aggregated protein in patient-derived brain sections. The bispecific antibodies also retained their ability to inhibit aggregation of recombinant tau, regardless of whether the tau binding sites were in IgG or scFv format. Mono- and bispecific antibodies inhibited cellular seeding induced by AD-derived pathological tau with similar efficacy. Finally, both Tau-C1q bispecific antibodies completely inhibited the classical complement pathway. Conclusion: Bispecific antibodies that bind to multiple pathological targets may therefore present a promising approach to treat tauopathies and other neurodegenerative disorders.<\/jats:p>","DOI":"10.3233\/jad-201334","type":"journal-article","created":{"date-parts":[[2021,2,13]],"date-time":"2021-02-13T22:29:46Z","timestamp":1613255386000},"page":"813-829","source":"Crossref","is-referenced-by-count":6,"title":["Bispecific Tau Antibodies with Additional Binding to C1q or Alpha-Synuclein"],"prefix":"10.1177","volume":"80","author":[{"given":"Wim Hendricus","family":"Quint","sequence":"first","affiliation":[{"name":"Maptimmune BV, The Hague, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irena","family":"Mate\u010dko-Burmann","sequence":"additional","affiliation":[{"name":"Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden"},{"name":"Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Schilcher","sequence":"additional","affiliation":[{"name":"QPS Austria GmbH, Neuropharmacology, Grambach, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"L\u00f6ffler","sequence":"additional","affiliation":[{"name":"QPS Austria GmbH, Neuropharmacology, Grambach, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Sch\u00f6ll","sequence":"additional","affiliation":[{"name":"Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden"},{"name":"Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden"},{"name":"Department of Neurodegenerative Disease, UCL Queen Square, Institute of Neurology, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn Marcus","family":"Burmann","sequence":"additional","affiliation":[{"name":"Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden"},{"name":"Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Vogels","sequence":"additional","affiliation":[{"name":"Maptimmune BV, The Hague, The Netherlands"},{"name":"Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden"},{"name":"Department of Neurodegenerative Disease, UCL Queen Square, Institute of Neurology, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","reference":[{"key":"10.3233\/JAD-201334_ref1","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.neurol.2018.07.001","article-title":"New classification of tauopathies","volume":"174","author":"Hoglinger","year":"2018","journal-title":"Rev Neurol (Paris)"},{"key":"10.3233\/JAD-201334_ref2","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1016\/j.biopsych.2019.09.019","article-title":"Propagation of tau pathology: Integrating insights from postmortem and in vivo studies","volume":"87","author":"Vogels","year":"2020","journal-title":"Biol Psychiatry"},{"key":"10.3233\/JAD-201334_ref3","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/1750-1326-9-43","article-title":"Alpha-synuclein and tau: Teammates in neurodegeneration?","volume":"9","author":"Moussaud","year":"2014","journal-title":"Mol Neurodegener"},{"key":"10.3233\/JAD-201334_ref4","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/s00401-017-1709-7","article-title":"Interactions of pathological proteins in neurodegenerative diseases","volume":"134","author":"Spires-Jones","year":"2017","journal-title":"Acta Neuropathol"},{"key":"10.3233\/JAD-201334_ref5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1212\/WNL.40.1.1","article-title":"The Lewy body variant of Alzheimer\u2019s disease: A clinical and pathologic entity","volume":"40","author":"Hansen","year":"1990","journal-title":"Neurology"},{"key":"10.3233\/JAD-201334_ref6","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1192\/bjp.162.3.385","article-title":"The Lewy-body variant of Alzheimer\u2019s disease. Clinical and pathological findings","volume":"162","author":"Forstl","year":"1993","journal-title":"Br J Psychiatry"},{"key":"10.3233\/JAD-201334_ref7","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s13195-018-0356-0","article-title":"Improving the identification of dementia with Lewy bodies in the context of an Alzheimer\u2019s-type dementia","volume":"10","author":"Thomas","year":"2018","journal-title":"Alzheimers Res Ther"},{"key":"10.3233\/JAD-201334_ref8","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.3233\/JAD-170914","article-title":"Influence of Lewy pathology on Alzheimer\u2019s disease phenotype: A retrospective clinico-pathological study","volume":"63","author":"Roudil","year":"2018","journal-title":"J Alzheimers Dis"},{"key":"10.3233\/JAD-201334_ref9","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13024-019-0320-x","article-title":"alpha-synuclein in the pathophysiology of Alzheimer\u2019s 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dendritic-like cell in the APP\/PS1 transgenic mouse brains","volume":"1368","author":"Shi","year":"2011","journal-title":"Brain Res"},{"key":"10.3233\/JAD-201334_ref37","doi-asserted-by":"crossref","first-page":"6539","DOI":"10.4049\/jimmunol.1100620","article-title":"Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal beta-catenin pathway function in an Alzheimer\u2019s disease model","volume":"187","author":"Kitazawa","year":"2011","journal-title":"J Immunol"},{"key":"10.3233\/JAD-201334_ref38","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/S0140-6736(15)01124-1","article-title":"Alzheimer\u2019s disease","volume":"388","author":"Scheltens","year":"2017","journal-title":"Lancet"},{"key":"10.3233\/JAD-201334_ref39","doi-asserted-by":"crossref","first-page":"eaay1359","DOI":"10.1126\/scitranslmed.aay1359","article-title":"Brain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys","volume":"12","author":"Kariolis","year":"2020","journal-title":"Sci Transl Med"},{"key":"10.3233\/JAD-201334_ref40","doi-asserted-by":"crossref","first-page":"308","DOI":"10.7150\/thno.17155","article-title":"Bivalent brain shuttle increases antibody uptake by monovalent binding to the transferrin receptor","volume":"7","author":"Hultqvist","year":"2017","journal-title":"Theranostics"},{"key":"10.3233\/JAD-201334_ref41","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/s41573-019-0028-1","article-title":"Bispecific antibodies: A mechanistic review of the pipeline","volume":"18","author":"Labrijn","year":"2019","journal-title":"Nat Rev Drug Discov"},{"key":"10.3233\/JAD-201334_ref42","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1016\/j.molmed.2020.03.012","article-title":"Cell-to-cell transmission of tau and \u03b1-synuclein","volume":"26","author":"Uemura","year":"2020","journal-title":"Trends Mol Med"},{"key":"10.3233\/JAD-201334_ref43","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nature19323","article-title":"The antibody aducanumab reduces Abeta plaques in Alzheimer\u2019s disease","volume":"537","author":"Sevigny","year":"2016","journal-title":"Nature"},{"key":"10.3233\/JAD-201334_ref44","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1007\/s00401-018-1911-2","article-title":"Epitope determines efficacy of therapeutic anti-tau antibodies in a functional assay with human Alzheimer Tau","volume":"136","author":"Courade","year":"2018","journal-title":"Acta Neuropathol"},{"key":"10.3233\/JAD-201334_ref45","doi-asserted-by":"crossref","first-page":"e19338","DOI":"10.1371\/journal.pone.0019338","article-title":"Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease","volume":"6","author":"Masliah","year":"2011","journal-title":"PLoS One"},{"key":"10.3233\/JAD-201334_ref46","doi-asserted-by":"crossref","first-page":"6664","DOI":"10.4049\/jimmunol.181.9.6664","article-title":"Crucial role of aspartic acid at position 265 in the CH2 domain for murine IgG2a and IgG2b Fc-associated effector functions","volume":"181","author":"Baudino","year":"2008","journal-title":"J Immunol"},{"key":"10.3233\/JAD-201334_ref47","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s10858-018-00222-4","article-title":"Increasing the buffering capacity of minimal media leads to higher protein yield","volume":"73","author":"Azatian","year":"2019","journal-title":"J Biomol NMR"},{"key":"10.3233\/JAD-201334_ref48","doi-asserted-by":"crossref","first-page":"26217","DOI":"10.1074\/jbc.M702444200","article-title":"Small ubiquitin-related modifier (SUMO)-specific proteases: Profiling the specificities and activities of human SENPs","volume":"282","author":"Mikolajczyk","year":"2007","journal-title":"J Biol 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tauopathy","volume":"282","author":"Eckermann","year":"2007","journal-title":"J Biol Chem"},{"key":"10.3233\/JAD-201334_ref55","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1093\/jnen\/61.9.797","article-title":"Imaging Abeta plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered Congo red derivative","volume":"61","author":"Klunk","year":"2002","journal-title":"J Neuropathol Exp Neurol"},{"key":"10.3233\/JAD-201334_ref56","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s40478-018-0562-9","article-title":"Enhancement of therapeutic potential of a naturally occurring human antibody targeting a phosphorylated Ser(422) containing epitope on pathological tau","volume":"6","author":"van Ameijde","year":"2018","journal-title":"Acta Neuropathol Commun"},{"key":"10.3233\/JAD-201334_ref57","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s40478-018-0543-z","article-title":"A common antigenic motif recognized by naturally occurring human VH5-51\/VL4-1 anti-tau antibodies with distinct functionalities","volume":"6","author":"Apetri","year":"2018","journal-title":"Acta Neuropathol Commun"},{"key":"10.3233\/JAD-201334_ref58","doi-asserted-by":"publisher","DOI":"10.3791\/58570"},{"key":"10.3233\/JAD-201334_ref59","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/alzrt277","article-title":"Identification of structural determinants on tau protein essential for its pathological function: Novel therapeutic target for tau immunotherapy in Alzheimer\u2019s disease","volume":"6","author":"Kontsekova","year":"2014","journal-title":"Alzheimers Res Ther"},{"key":"10.3233\/JAD-201334_ref60","doi-asserted-by":"crossref","first-page":"5129","DOI":"10.1073\/pnas.97.10.5129","article-title":"Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif ((306)VQIVYK(311)) forming beta structure","volume":"97","author":"von Bergen","year":"2000","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.3233\/JAD-201334_ref61","doi-asserted-by":"crossref","first-page":"48165","DOI":"10.1074\/jbc.M105196200","article-title":"Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure","volume":"276","author":"von Bergen","year":"2001","journal-title":"J Biol Chem"},{"key":"10.3233\/JAD-201334_ref62","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s40478-020-0884-2","article-title":"Pre-clinical characterisation of E2814, a high-affinity antibody targeting the microtubule-binding repeat domain of tau for passive immunotherapy in Alzheimer\u2019s disease","volume":"8","author":"Roberts","year":"2020","journal-title":"Acta Neuropathol Commun"},{"key":"10.3233\/JAD-201334_ref63","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1007\/s00401-017-1705-y","article-title":"Immunological memory to hyperphosphorylated tau in 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