Affibody-Mediated Sequestration of Amyloid β Demonstrates Preventive Efficacy in a Transgenic Alzheimer's Disease Mouse Model

Allal Boutajangout; Hanna Lindberg; Abdulaziz Awwad; Arun Paul; Rabaa Baitalmal; Ismail Almokyad; Ingmarie Höidén-Guthenberg; Elin Gunneriusson; Fredrik Y Frejd; Torleif Härd; John Löfblom; Stefan Ståhl; Thomas Wisniewski

doi:10.3389/fnagi.2019.00064

Affibody-Mediated Sequestration of Amyloid β Demonstrates Preventive Efficacy in a Transgenic Alzheimer's Disease Mouse Model

Front Aging Neurosci. 2019 Mar 22:11:64. doi: 10.3389/fnagi.2019.00064. eCollection 2019.

Authors

Allal Boutajangout^{1

2

3

4}, Hanna Lindberg⁵, Abdulaziz Awwad⁶, Arun Paul^{1

2}, Rabaa Baitalmal^{1

2}, Ismail Almokyad^{1

2}, Ingmarie Höidén-Guthenberg⁷, Elin Gunneriusson⁷, Fredrik Y Frejd⁷, Torleif Härd⁸, John Löfblom⁵, Stefan Ståhl⁵, Thomas Wisniewski^{1

2

3

9}

Affiliations

¹ Center for Cognitive Neurology, New York University Langone Health, New York, NY, United States.
² Department of Neurology, New York University Langone Health, New York, NY, United States.
³ Department of Psychiatry, New York University Langone Health, New York, NY, United States.
⁴ Department of Physiology & Neuroscience, New York University Langone Medical Center, New York, NY, United States.
⁵ Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, Sweden.
⁶ School of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
⁷ Affibody AB, Solna, Sweden.
⁸ Department of Chemistry and Biotechnology, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
⁹ Department of Pathology, New York University School of Medicine, New York, NY, United States.

Abstract

Different strategies for treatment and prevention of Alzheimer's disease (AD) are currently under investigation, including passive immunization with anti-amyloid β (anti-Aβ) monoclonal antibodies (mAbs). Here, we investigate the therapeutic potential of a novel type of Aβ-targeting agent based on an affibody molecule with fundamentally different properties to mAbs. We generated a therapeutic candidate, denoted Z_SYM73-albumin-binding domain (ABD; 16.8 kDa), by genetic linkage of the dimeric Z_SYM73 affibody for sequestering of monomeric Aβ-peptides and an ABD for extension of its in vivo half-life. Amyloid precursor protein (APP)/PS1 transgenic AD mice were administered with Z_SYM73-ABD, followed by behavioral examination and immunohistochemistry. Results demonstrated rescued cognitive functions and significantly lower amyloid burden in the treated animals compared to controls. No toxicological symptoms or immunology-related side-effects were observed. To our knowledge, this is the first reported in vivo investigation of a systemically delivered scaffold protein against monomeric Aβ, demonstrating a therapeutic potential for prevention of AD.

Keywords: Alzheimer’s disease; affibody molecule; amyloid beta (Aβ); behavior; histology; immunotherapy; transgenic mice.

Abstract

Grants and funding