Antibody semorinemab reduces tau pathology in a transgenic mouse model and engages tau in patients with Alzheimer's disease

Sci Transl Med. 2021 May 12;13(593):eabb2639. doi: 10.1126/scitranslmed.abb2639.

Gai Ayalon ¹, Seung-Hye Lee ¹, Oskar Adolfsson ², Corinne Foo-Atkins ³, Jasvinder K Atwal ¹, Mira Blendstrup ⁴, Helen Booler ⁵, Joseph Bravo ⁵, Robert Brendza ¹, Flavia Brunstein ⁶, Ruby Chan ⁷, Priya Chandra ⁸, Jessica A Couch ³, Akash Datwani ⁹, Barthélemy Demeule ¹⁰, Danielle DiCara ¹¹, Rich Erickson ⁹, James A Ernst ⁷, Oded Foreman ¹², Dongping He ¹³, Isidro Hötzel ¹¹, Michael Keeley ³, Michael C M Kwok ⁷, Julien Lafrance-Vanasse ⁷, Han Lin ¹, Yanmei Lu ¹³, Wilman Luk ¹³, Paul Manser ¹⁴, Andreas Muhs ², Hai Ngu ¹², Andrea Pfeifer ², Maria Pihlgren ², Gautham K Rao ⁵, Kimberly Scearce-Levie ¹, Stephen P Schauer ¹⁵, William B Smith ¹⁶, Hilda Solanoy ¹, Edmond Teng ⁴, Kristin R Wildsmith ¹⁵, Daniela Bumbaca Yadav ¹⁷, Yong Ying ⁹, Reina N Fuji ¹⁸, Geoffrey A Kerchner ⁴

Affiliations

1 Department of Neuroscience, Genentech Inc., San Francisco, CA 94080, USA.
2 AC Immune SA, EPFL Innovation Park, Building B, CH-1015 Lausanne, Switzerland.
3 Project Team Leadership, Genentech Inc., San Francisco, CA 94080, USA.
4 Department of Early Clinical Development, Genentech Inc., San Francisco, CA 94080, USA.
5 Department of Safety Assessment, Genentech Inc., San Francisco, CA 94080, USA.
6 Department of Licensing and Early Development Safety, Genentech Inc., San Francisco, CA 94080, USA.
7 Department of Protein Chemistry, Genentech Inc., San Francisco, CA 94080, USA.
8 Department of Clinical Pharmacology, Genentech Inc., San Francisco, CA 94080, USA.
9 Department of Bioanalytical Sciences, Genentech Inc., San Francisco, CA 94080, USA.
10 Department of Late Stage Pharmaceutical Development, Genentech Inc., San Francisco, CA 94080, USA.
11 Department of Antibody Engineering, Genentech Inc., San Francisco, CA 94080, USA.
12 Department of Pathology, Genentech Inc., San Francisco, CA 94080, USA.
13 Department of Biochemical and Cellular Pharmacology, Genentech Inc., San Francisco, CA 94080, USA.
14 Biostatistics, Genentech Inc., San Francisco, CA 94080, USA.
15 Department of Biomarker Development, Genentech Inc., San Francisco, CA 94080, USA.
16 Alliance for Multispecialty Research, University of Tennessee Medical Center, Knoxville, TN 37920, USA.
17 Department of Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc., San Francisco, CA 94080, USA.
18 Department of Safety Assessment, Genentech Inc., San Francisco, CA 94080, USA. [email protected].

PMID: 33980574 DOI: 10.1126/scitranslmed.abb2639

Abstract

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-P99399

Semorinemab

99.90%, Tau Antibody

Tau Protein

Neurological Disease

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