Single domain antibodies targeting pathological tau protein: Influence of four IgG subclasses on efficacy and toxicity
Erin E. Congdon,
Ruimin Pan,
Yixiang Jiang,
Leslie A. Sandusky-Beltran,
Andie Dodge,
Yan Lin,
Mengyu Liu,
Min-Hao Kuo,
Xiang-Peng Kong,
Einar M. Sigurdsson
Affiliations
Erin E. Congdon
Department of Neuroscience and Physiology, and the Neuroscience Institute, New York University Grossman School of Medicine, 435 East 30th Street, New York, NY 10016, USA
Ruimin Pan
Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA
Yixiang Jiang
Department of Neuroscience and Physiology, and the Neuroscience Institute, New York University Grossman School of Medicine, 435 East 30th Street, New York, NY 10016, USA
Leslie A. Sandusky-Beltran
Department of Neuroscience and Physiology, and the Neuroscience Institute, New York University Grossman School of Medicine, 435 East 30th Street, New York, NY 10016, USA
Andie Dodge
Department of Neuroscience and Physiology, and the Neuroscience Institute, New York University Grossman School of Medicine, 435 East 30th Street, New York, NY 10016, USA
Yan Lin
Department of Neuroscience and Physiology, and the Neuroscience Institute, New York University Grossman School of Medicine, 435 East 30th Street, New York, NY 10016, USA
Mengyu Liu
Department of Biochemistry and Molecular Biology, Michigan State University, 603 Wilson Road, Room 401, East Lansing, MI, 48824, USA
Min-Hao Kuo
Department of Biochemistry and Molecular Biology, Michigan State University, 603 Wilson Road, Room 401, East Lansing, MI, 48824, USA
Xiang-Peng Kong
Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA
Einar M. Sigurdsson
Department of Neuroscience and Physiology, and the Neuroscience Institute, New York University Grossman School of Medicine, 435 East 30th Street, New York, NY 10016, USA; Department of Psychiatry, New York University Grossman School of Medicine, New York, NY 10016, USA; Corresponding author at: Department of Neuroscience and Physiology, and the Neuroscience Institute, New York University Grossman School of Medicine, 435 East 30th Street, New York, NY 10016, USA.
Summary: Background: Eleven tau immunoglobulin G (IgG) antibodies have entered clinical trials to treat tauopathies, including Alzheimer's disease, but it is unclear which IgG subclass/subtype has the ideal efficacy and safety profile. Only two subtypes, with or without effector function, have been examined in the clinic and not for the same tau antibody. The few preclinical studies on this topic have only compared two subtypes of one antibody each and have yielded conflicting results. Methods: We selected two single domain antibodies (sdAbs) derived from a llama immunized with tau proteins and utilized them to generate an array of Fc-(sdAb)2 subclasses containing identical tau binding domains but differing Fc region. Unmodified sdAbs and their IgG subclasses were tested for efficacy in primary cultures and in vivo microdialysis using JNPL3 tauopathy mice. Findings: Unmodified sdAbs were non-toxic, blocked tau toxicity and promoted tau clearance. However, the efficacy/safety profile of their Fc-(sdAb)2 subclasses varied greatly within and between sdAbs. For one of them, all its subtypes were non-toxic, only those with effector function cleared tau, and were more effective in vivo than unmodified sdAb. For the other sdAb, all its subtypes were toxic in tauopathy cultures but not in wild-type cells, suggesting that bivalent binding of its tau epitope stabilizes a toxic conformation of tau, with major implications for tau pathogenesis. Likewise, its subclasses were less effective than the unmodified sdAb in clearing tau in vivo. Interpretation: These findings indicate that tau antibodies with effector function are safe and better at clearing pathological tau than effectorless antibodies, Furthermore, tau antibodies can provide a valuable insight into tau pathogenesis, and some may aggravate it. Funding: Funding for these studies was provided by the National Institute of Health (R01 AG032611, R01 NS077239, RF1 NS120488, R21 AG 069475, R21 AG 058282, T32AG052909), and the NYU Alzheimer's Disease Center Pilot Grant Program (via P30 AG008051).
