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

• Published in: PloS one Vol. 13; no. 5; p. e0195751
• Main Authors: Lashkari, Kameran, Teague, Gianna, Chen, Hong, Lin, Yong-Qing, Kumar, Sanjay, McLaughlin, Megan M., López, Francisco J.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.05.2018; Public Library of Science (PLoS)
• Subjects: Age; Age related diseases; Aged; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - immunology; Antibodies, Monoclonal - therapeutic use; Atrophy; Biological activity; Biology and Life Sciences; Biomarkers - blood; Case-Control Studies; Complement; Complement activation; Complement Activation - drug effects; Complement component C3b; Complement factor I; Complement Factor I - metabolism; Enzymatic activity; Female; Gene expression; Genomes; Humans; Inflammation; Macular degeneration; Macular Degeneration - drug therapy; Macular Degeneration - metabolism; Macular Degeneration - pathology; Male; Medicine and Health Sciences; Monoclonal antibodies; Pathogenesis; Peptides; Research and Analysis Methods; Vascular endothelial growth factor; United States > US; Massachusetts; Pennsylvania
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0195751

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 disease severity. In subjects with AD, we observed a 10% and 27% increase in overall CFI bioactivity after treatment with GSK933776 during the second and third dose. Our studies indicate that CFI enzymatic activity can be inhibited by Aβ and be altered in proinflammatory diseases such as AMD and AD, in which deposition of Aβ and activation of the alternative complement cascade are believed to play a key role in the disease process.