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- W2896446868 abstract "Advances in the understanding of Alzheimer's disease (AD) pathogenesis suggest that progressive neurodegeneration is not caused by plaque burden but rather by low molecular weight (LMW) soluble toxic amyloid-beta oligomers (AßO). Binding of Aß monomers and/or fibrils by therapeutic antibodies has been associated with suboptimal efficacy and adverse events in clinical trials. To achieve improved efficacy and safety, mouse monoclonal antibody PMN310 was raised against a conformational epitope predicted by computational algorithms to be exposed in toxic AßO but not on monomers or fibrils. Previous in vitro and in vivo testing showed that muPMN310 selectively binds synthetic AßO and neutralizes their toxicity (AAIC 2017, abstract 14543). Here, key validation studies with material from AD patients were conducted to assess the ability of PMN310 to achieve greater therapeutic potency vs other Aß-directed antibodies. Frozen human AD brain sections were stained with PMN310 and other Aß-directed antibodies to evaluate the degree of binding to parenchymal Aß plaque and vascular Aß deposits. Soluble human AD brain extracts were separated into LMW (<70kDa) and high molecular (HMW; >70kDa) fractions by size-exclusion chromatography (SEC). Antibody binding to SEC fractions was assessed by surface plasmon resonance (SPR). Clear binding of parenchymal and vascular Aß in AD brain was observed with aducanumab and bapineuzumab, consistent with the clinical occurrence of ARIA associated with these antibodies. By comparison, no immunoreactivity of Aß deposits was observed with PMN310. SEC fractionation of soluble human AD brain extracts gave rise to a reproducible pattern with LMW peaks consistent with the presence of reportedly toxic dimers, tetramers and dodecamers. SPR analysis showed preferential binding of PMN310 to the toxic oligomer-enriched LMW fraction compared to aducanumab and bapineuzumab. The binding response of humanized PMN310 for the LMW fraction was ∼1.5-2 fold greater than that obtained with aducanumab. Results obtained with AD patient material suggest that PMN310 is likely to achieve greater therapeutic potency compared to other Aß-directed antibodies due to: 1) Selective targeting of soluble toxic LMW oligomers, and 2) Reduced risk of ARIA allowing for safe administration of higher doses of antibody. Humanized PMN310 is currently in preclinical development." @default.
- W2896446868 created "2018-10-26" @default.
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- W2896446868 date "2018-07-01" @default.
- W2896446868 modified "2023-10-16" @default.
- W2896446868 title "P2‐048: HUMANIZED PMN310 SHOWS ENHANCED THERAPEUTIC POTENTIAL BY BINDING TOXIC LOW MOLECULAR WEIGHT Aβ OLIGOMERS WHILE AVOIDING ARIA‐RELATED BINDING TO Aβ DEPOSITS IN AD PATIENT BRAINS" @default.
- W2896446868 doi "https://doi.org/10.1016/j.jalz.2018.06.732" @default.
- W2896446868 hasPublicationYear "2018" @default.
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