A monoclonal antibody targeting amyloid [beta] 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: Public Library of Science 21.05.2018
• Subjects: Alzheimer's disease; Amyloid beta-protein; Care and treatment; Complement (Immunology); Development and progression; Health aspects; Macular degeneration; Monoclonal antibodies; Physiological aspects
• 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 [beta] (A[beta]), a component of drusen, may promote complement activation by inhibiting CFI bioactivity. We determined whether A[beta] reduced CFI bioactivity and whether antibodies against A[beta] 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 A[beta] and anti-A[beta] 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. A[beta] 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 A[beta] and be altered in proinflammatory diseases such as AMD and AD, in which deposition of A[beta] and activation of the alternative complement cascade are believed to play a key role in the disease process.