While clearing out amyloid-β from the brain has so far proven to be a matter of too little, too late in late stage Alzheimer's disease patients, there is still a strong basis of evidence for the merits of removing amyloid-β. It is reasonable to say that it causes meaningful pathology; if people did not accumulate amyloid-β deposits, then there would be no consequent disarray in the function of neurons and immune cells in the brain. This particular foundation of the development of dementia would be removed. Even if the mechanisms of the later stages of Alzheimer's, the chronic inflammation and tau protein aggregation, for example, were blocked, then amyloid-β accumulation would still cause at least mild cognitive impairment on its own. Thus despite the continued failure of clinical trials, even those in which amyloid-β was in fact cleared to a fair degree from the brains of Alzheimer's patients, we should still be encouraged by new approaches and other signs of progress in this area of the field.
Present therapies for Alzheimer's disease (AD) have either no or minimal disease-modifying effect, and thus, there is an urgent need for new effective treatments. Numerous therapeutic strategies are under investigation to delay the onset or slow progression of the disease. Active and passive immunotherapeutic approaches have been suggested to improve clinical progression and cognitive impairment through different mechanisms: (i) inhibition of amyloid-β (Aβ) production; (ii) interference with the formation of toxic aggregation intermediates; and (iii) accelerated clearance of Aβ from the central nervous system into the periphery.
Several anti-Aβ antibodies have demonstrated effective clearance of Aβ together with cognitive improvements in transgenic animal models and consequently progressed to clinical trials. However, translation to safe and efficacious therapies for humans has been challenging as AD clinical trials have failed to show sufficient clinical benefits. Recently, the monoclonal antibody (mAb) Solanezumab, that binds monomeric Aβ, was extensively evaluated in a phase III prevention trial in patients with mild AD. The study was however terminated due to failure in showing cognitive improvements.
It has been proposed that challenges related to the failure in showing overall clinical improvement or clear disease-modifying results of these mAbs could be addressed to some of the inherent properties of antibodies. Thus, new approaches based on engineered antibody domains or alternative scaffold-proteins that generally lack immunoglobulin-related effector functions are now investigated and moving into clinical development, as they might provide safer and more effective treatments. Antibody derivatives and non-immunoglobulin affinity proteins are in general smaller than full-length antibodies. Their smaller size could potentially result in a different in vivo biodistribution profile as well as simplified administration routes, which could be important in the treatment of e.g., AD.
Affibody molecules represent a class of promising alternative scaffold proteins that have been investigated for various applications. We have previously reported on the generation of an affibody molecule (denoted ZAb3) that binds to monomeric Aβ. This Aβ-sequestering affibody molecule has demonstrated efficient inhibition of formation of Aβ aggregates in an in vivo Drosophila AD model, and abolished the neurotoxic effects as well as restored the life span of the flies. The affibody molecule was further engineered into a truncated genetic dimer, ZSYM73-ABD.
Encouraged by these positive results, we here investigate the efficacy of ZSYM73-ABD as a therapeutic candidate to prevent the development of AD-related pathology in transgenic AD mice. The animals received three weekly injections of 100 μg therapeutic protein or negative control protein during 13 weeks, starting at the expected onset of pathology development. Extensive behavioral assessment together with histological evaluation demonstrated a significantly lower amyloid burden in both cortex and hippocampus, as well as rescued cognitive functions of the ZSYM73-ABD treated mice relative to controls.