Developing Therapeutic Antibodies for Neurodegenerative Disease

Abstract

The central nervous system has been considered off-limits to antibody therapeutics. However, recent advances in preclinical and clinical drug development suggest that antibodies can cross the blood-brain barrier in limited quantities and act centrally to mediate their effects. In particular, immunotherapy for Alzheimer's disease has shown that targeting beta amyloid with antibodies can reduce pathology in both mouse models and the human brain, with strong evidence supporting a central mechanism of action. These findings have fueled substantial efforts to raise antibodies against other central nervous system targets, particularly neurodegenerative targets, such as tau, beta-secretase, and alpha-synuclein. Nevertheless, it is also apparent that antibody penetration across the blood-brain barrier is limited, with an estimated 0.1-0.2 % of circulating antibodies found in brain at steady-state concentrations. Thus, technologies designed to improve antibody uptake in brain are receiving increased attention and are likely going to represent the future of antibody therapy for neurologic diseases, if proven safe and effective. Herein we review briefly the progress and limitations of traditional antibody drug development for neurodegenerative diseases, with a focus on passive immunotherapy. We also take a more in-depth look at new technologies for improved delivery of antibodies to the brain.

Antibody-conjugated, dual-modal, near-infrared fluorescent iron oxide nanoparticles for antiamyloidgenic activity and specific detection of amyloid-β fibrils

“…[21][22][23][24][25] Only a few studies have been reported on the inhibitory effect of nanoparticles on the Aβ fibrillation process. Very recently, Cabaleiro-Lago et al reported the inhibition of the Aβ 40 fibril formation by copolymer nanoparticles of variable hydrophobicity 32 and also demonstrated the dual effect of commercial polystyrene nanoparticles with amino modification toward the Aβ 40 and Aβ 42 fibril formation. 33 Yoo et al have shown the inhibition effect of CdTe quantum dots on Aβ 40 fibrillation.…”

“…Very recently, Cabaleiro-Lago et al reported the inhibition of the Aβ 40 fibril formation by copolymer nanoparticles of variable hydrophobicity 32 and also demonstrated the dual effect of commercial polystyrene nanoparticles with amino modification toward the Aβ 40 and Aβ 42 fibril formation. 33 Yoo et al have shown the inhibition effect of CdTe quantum dots on Aβ 40 fibrillation. 34 Fluorinated nanoparticles, 35 negatively charged gold nanoparticles, 36 and sulfonated and sulfated polystyrene nanoparticles also have been reported as potential candidates for the inhibition of Aβ fibril formation.…”

“…34 Fluorinated nanoparticles, 35 negatively charged gold nanoparticles, 36 and sulfonated and sulfated polystyrene nanoparticles also have been reported as potential candidates for the inhibition of Aβ fibril formation. 37 Our previous studies showed that the Leu-Pro-Phe-Phe-Asp peptide conjugated iron oxide nanoparticles 31 and the amino acid-based polymer nanoparticles containing hydrophobic dipeptides in the polymer side chains slightly inhibit the Aβ 40 fibrillation process. 38 Passive anti-Aβ immunotherapy has emerged as a promising and effective approach for the treatment of AD and has already advanced to ongoing clinical trials.…”

“…38 Passive anti-Aβ immunotherapy has emerged as a promising and effective approach for the treatment of AD and has already advanced to ongoing clinical trials. [39][40][41][42][43][44][45] This approach involves the direct intraperitoneal injection of anti-Aβ monoclonal antibodies (aAβmAbs) into the body to increase the rate of clearance and prevent aggregation of the Aβ peptide in the brain. [39][40][41][42][43][44][45] Specifically designed aAβmAbs have been reported to induce reduction in levels of soluble Aβ oligomers and plaques, restoration of neuritic architecture, and cognitive function in transgenic mouse models of AD.…”

“…[39][40][41][42][43][44][45] This approach involves the direct intraperitoneal injection of anti-Aβ monoclonal antibodies (aAβmAbs) into the body to increase the rate of clearance and prevent aggregation of the Aβ peptide in the brain. [39][40][41][42][43][44][45] Specifically designed aAβmAbs have been reported to induce reduction in levels of soluble Aβ oligomers and plaques, restoration of neuritic architecture, and cognitive function in transgenic mouse models of AD. 39,[46][47][48][49] For example, BAM10, a representative aAβmAb recognizing the N terminus of Aβ, significantly reduced Aβ plaque burden and reversed memory impairment in different transgenic mouse models of AD.…”