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

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

doi:10.3389/fnagi.2019.00064

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 ZSYM73-albumin-binding domain (ABD; 16.8 kDa), by genetic linkage of the dimeric ZSYM73 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 ZSYM73-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.

Highlights

Alzheimer’s disease (AD) is the most common cause of dementia and is defined by a gradual onset and progression of deficits in several areas of cognition
The therapeutic candidate was designed as a bispecific fusion protein, consisting of a genetic linkage between the high-affinity amyloid β (Aβ)-capturing ZSYM73 affibody molecule and an albuminbinding domain (ABD) (Figure 1; Lindberg et al, 2015)
We present a novel approach to prevent the development of Aβ-related pathology, using the Aβ-sequestering affibody molecule ZSYM73

Summary

Introduction

Alzheimer’s disease (AD) is the most common cause of dementia and is defined by a gradual onset and progression of deficits in several areas of cognition. Active and passive immunotherapeutic approaches have been suggested to improve clinical progression and cognitive impairment through different mechanisms: (i) inhibition of Aβ production; (ii) interference with the formation of toxic aggregation intermediates; and (iii) accelerated clearance of Aβ from the CNS into the periphery (Citron, 2010; Karran et al, 2011). Several anti-Aβ antibodies have demonstrated effective clearance of Aβ together with cognitive improvements in transgenic animal models (Bard et al, 2000; DeMattos et al, 2001; Wilcock et al, 2004) and progressed to clinical trials (Sevigny et al, 2016; Siemers et al, 2016; Herline et al, 2018b). The monoclonal antibody (mAb) Solanezumab, that binds monomeric Aβ, was extensively evaluated in a phase III prevention trial in patients with mild AD. A recent phase Ib trial with the protofibrilbinding mAb Aducanumab has demonstrated promising results, which has motivated an on-going phase III trial (Sevigny et al, 2016)

Methods

Results

Conclusion