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ItemAnti-A beta antibody target engagement: a response to Siemers et al.Watt, AD ; Crespi, GAN ; Down, RA ; Ascher, DB ; Gunn, A ; Perez, KA ; McLean, CA ; Villemagne, VL ; Parker, MW ; Barnham, KJ ; Miles, LA (SPRINGER, 2014-10-01)
ItemDo current therapeutic anti-A beta antibodies for Alzheimer's disease engage the target?Watt, AD ; Crespi, GAN ; Down, RA ; Ascher, DB ; Gunn, A ; Perez, KA ; McLean, CA ; Villemagne, VL ; Parker, MW ; Barnham, KJ ; Miles, LA (SPRINGER, 2014-06-01)Reducing amyloid-β peptide (Aβ) burden at the pre-symptomatic stages of Alzheimer's disease (AD) is currently the advocated clinical strategy for treating this disease. The most developed method for targeting Aβ is the use of monoclonal antibodies including bapineuzumab, solanezumab and crenezumab. We have synthesized these antibodies and used surface plasmon resonance (SPR) and mass spectrometry to characterize and compare the ability of these antibodies to target Aβ in transgenic mouse tissue as well as human AD tissue. SPR analysis showed that the antibodies were able to bind Aβ with high affinity. All of the antibodies were able to bind Aβ in mouse tissue. However, significant differences were observed in human brain tissue. While bapineuzumab was able to capture a variety of N-terminally truncated Aβ species, the Aβ detected using solanezumab was barely above detection limits while crenezumab did not detect any Aβ. None of the antibodies were able to detect any Aβ species in human blood. Immunoprecipitation experiments using plasma from AD subjects showed that both solanezumab and crenezumab have extensive cross-reactivity with non-Aβ related proteins. Bapineuzumab demonstrated target engagement with brain Aβ, consistent with published clinical data. Solanezumab and crenezumab did not, most likely as a result of a lack of specificity due to cross-reactivity with other proteins containing epitope overlap. This lack of target engagement raises questions as to whether solanezumab and crenezumab are suitable drug candidates for the preventative clinical trials for AD.
ItemPeripheral alpha-Defensins 1 and 2 are Elevated in Alzheimer's DiseaseWatt, AD ; Perez, KA ; Ang, C-S ; O'Donnell, P ; Rembach, A ; Pertile, KK ; Rumble, RL ; Trounson, BO ; Fowler, CJ ; Faux, NG ; Masters, CL ; Villemagne, VL ; Barnham, KJ (IOS PRESS, 2015-01-01)Biomarkers enabling the preclinical identification of Alzheimer's disease (AD) remain one of the major unmet challenges in the field. The blood cellular fractions offer a viable alternative to current cerebrospinal fluid and neuroimaging modalities. The current study aimed to replicate our earlier reports of altered binding within the AD-affected blood cellular fraction to copper-loaded immobilized metal affinity capture (IMAC) arrays. IMAC and anti-amyloid-β (Aβ) antibody arrays coupled with mass spectrometry were used to analyze blood samples collected from 218 participants from within the AIBL Study of Aging. Peripheral Aβ was fragile and prone to degradation in the AIBL samples, even when stored at -80°C. IMAC analysis of the AIBL samples lead to the isolation and identification of alpha-defensins 1 and 2 at elevated levels in the AD periphery, validating earlier findings. Alpha-defensins 1 and 2 were elevated in AD patients indicating that an inflammatory phenotype is present in the AD periphery; however, peripheral Aβ levels are required to supplement their prognostic power.