A monoclonal antibody targeting amyloid β (Aβ) restores complement factor I bioactivity: Potential implications in age-related macular degeneration and Alzheimer's disease

PloS One
Kameran LashkariFrancisco J López

Abstract

Activation of the alternative complement cascade has been implicated in the pathogenesis of age related macular degeneration (AMD) and Alzheimer's disease (AD). Amyloid β (Aβ), a component of drusen, may promote complement activation by inhibiting CFI bioactivity. We determined whether Aβ reduced CFI bioactivity and whether antibodies against Aβ including a monoclonal antibody, GSK933776 could restore CFI bioactivity. We also measured CFI bioactivity in plasma of subjects with AMD and AD. In support of the GSK933776 development program in AMD (geographic atrophy), we developed a quantitative assay to measure CFI bioactivity based on its ability to cleave C3b to iC3b, and repeated it in presence or absence of Aβ and anti-Aβ antibodies. Using this assay, we measured CFI bioactivity in plasma of 194 subjects with AMD, and in samples from subjects with AD that had been treated with GSK933776 as part of the GSK933776 development program in AD. Aβ reduced the CFI bioactivity by 5-fold and pre-incubation with GSK933776 restored CFI bioactivity. In subjects with AMD, plasma CFI levels and bioactivity were not significantly different from non-AMD controls. However, we detected a positive linear trend, suggesting increasing activity with...Continue Reading

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Citations

Nov 30, 2019·Frontiers in Neuroscience·Virginie DinetJerome Badaut
Mar 4, 2021·International Journal of Molecular Sciences·Liang Wang, Xiaobo Mao
Feb 22, 2021·Progress in Retinal and Eye Research·Sarah de JongAnneke I den Hollander
Apr 4, 2021·International Journal of Molecular Sciences·Chiara MelePaolo Marzullo
Jun 24, 2020·Neuro-ophthalmology·Alvin TanKenneth Ooi

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Methods Mentioned

BETA
ELISA

Clinical Trials Mentioned

NCT00459550
NCT01342926

Software Mentioned

R
Gen 5 TM

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