Neurobiology of Disease (Dec 2019)

Preclinical development of a high affinity α-synuclein antibody, MEDI1341, that can enter the brain, sequester extracellular α-synuclein and attenuate α-synuclein spreading in vivo

  • Darren J. Schofield,
  • Lorraine Irving,
  • Laura Calo,
  • Anna Bogstedt,
  • Gareth Rees,
  • Annalisa Nuccitelli,
  • Rajesh Narwal,
  • Marcella Petrone,
  • Jennifer Roberts,
  • Lee Brown,
  • Fiona Cusdin,
  • Bhupinder Dosanjh,
  • Christopher Lloyd,
  • Claire Dobson,
  • Ian Gurrell,
  • Graham Fraser,
  • Mary McFarlane,
  • Edward Rockenstein,
  • Brian Spencer,
  • Eliezer Masliah,
  • Maria Grazia Spillantini,
  • Keith Tan,
  • Andrew Billinton,
  • Tris Vaughan,
  • Iain Chessell,
  • Michael S. Perkinton

Journal volume & issue
Vol. 132

Abstract

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There are no approved drug therapies that can prevent or slow the progression of Parkinson's disease (PD). Accumulation and aggregation of α-synuclein protein is observed throughout the nervous system in PD. α-Synuclein is a core component of Lewy bodies and neurites that neuropathologically define PD, suggesting that α-synuclein may be a key causative agent in PD. Recent experimental data suggest that PD progression may arise due to spreading of pathological forms of extracellular α-synuclein throughout the brain via a cellular release, uptake and seeding mechanism. We have developed a high affinity α-synuclein antibody, MEDI1341, that can enter the brain, sequester extracellular α-synuclein and attenuate α-synuclein spreading in vivo. MEDI1341 binds both monomeric and aggregated forms of α-synuclein. In vitro, MEDI1341 blocks cell-to-cell transmission of pathologically relevant α-synuclein preformed fibrils (pffs). After intravenous injection into rats and cynomolgus monkeys, MEDI1341 rapidly enters the central nervous system and lowers free extracellular α-synuclein levels in the interstitial fluid (ISF) and cerebrospinal fluid (CSF) compartments. Using a novel lentiviral-based in vivo mouse model of α-synuclein spreading in the brain, we show that treatment with MEDI1341 significantly reduces α-synuclein accumulation and propagation along axons. In this same model, we demonstrate that an effector-null version of the antibody was equally as effective as one with effector function. MEDI1341 is now in Phase 1 human clinical trial testing as a novel treatment for α-synucleinopathies including PD with the aim to slow or halt disease progression.

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