Anti-Tau Monoclonal Antibodies Derived from Soluble and Filamentous Tau Show Diverse Functional Properties in vitro and in vivo

Article type: Research Article

Authors: Vandermeeren, Marc^{a; 1} | Borgers, Marianne^{a; 1} | Van Kolen, Kristof^{a; *} | Theunis, Clara^a | Vasconcelos, Bruno^a | Bottelbergs, Astrid^a | Wintmolders, Cindy^a | Daneels, Guy^a | Willems, Roland^a | Dockx, Koen^b | Delbroek, Lore^a | Marreiro, André^a | Ver Donck, Luc^a | Sousa, Cristiano^a | Nanjunda, Rupesh^c | Lacy, Eilyn^c | Van De Casteele, Tom^d | Van Dam, Debby^{e; f} | De Deyn, Peter Paul^{e; f; g; h} | Kemp, John A.^{a; i} | Malia, Thomas J.^c | Mercken, Marc H.^a

Affiliations: [a] Neuroscience Department, Janssen Research and Development, Beerse, Belgium | [b] Discovery Sciences, Janssen Research and Development, Beerse, Belgium | [c] Biologics Research, Janssen Research and Development, Spring House, PA, USA | [d] Non-Clinical Statistics, Janssen Research and Development, Beerse, Belgium | [e] Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium | [f] Department of Neurology and Alzheimer Research Center, University Medical Center Groningen (UMCG), Groningen, The Netherlands | [g] Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium | [h] Biobank, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium | [i] Syndesi therapeutics, Belgium

Correspondence: [*] Correspondence to: Kristof Van Kolen, Neuroscience Department, Janssen Research and Development, 2340 Beerse, Belgium. E-mail: kvkolen@its.jnj.com.

Note: [1] These authors contributed equally to this work.

Abstract: The tau spreading hypothesis provides rationale for passive immunization with an anti-tau monoclonal antibody to block seeding by extracellular tau aggregates as a disease-modifying strategy for the treatment of Alzheimer’s disease (AD) and potentially other tauopathies. As the biochemical and biophysical properties of the tau species responsible for the spatio-temporal sequences of seeding events are poorly defined, it is not yet clear which epitope is preferred for obtaining optimal therapeutic efficacy. Our internal tau antibody collection has been generated by immunizations with different tau species: aggregated- and non-aggregated tau and human postmortem AD brain-derived tau fibrils. In this communication, we describe and characterize a set of these anti-tau antibodies for their biochemical and biophysical properties, including binding, tissue staining by immunohistochemistry, and epitope. The antibodies bound to different domains of the tau protein and some were demonstrated to be isoform-selective (PT18 and hTau56) or phospho-selective (PT84). Evaluation of the antibodies in cellular- and in vivo seeding assays revealed clear differences in maximal efficacy. Limited proteolysis experiments support the hypothesis that some epitopes are more exposed than others in the tau seeds. Moreover, antibody efficacy seems to depend on the structural properties of fibrils purified from tau Tg mice- and postmortem human AD brain.

Keywords: Epitope mapping, immunotherapy, in vivo seeding, tau antibodies

DOI: 10.3233/JAD-180404

Journal: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 265-281, 2018