ArticleScientific reports2023
Analysis of clinical failure of anti-tau and anti-synuclein antibodies in neurodegeneration using a quantitative systems pharmacology model.
Article in Scientific reports, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 23 citations in OpenAlex.
- Phase 1, randomized trials of MEDI1341: cerebrospinal fluid free α-synuclein lowered by >50.Brain communications · 2025Trial
- Intranasal drug delivery to the brain for neurodegenerative diseases: Current efforts and challenges in delivery platforms and modeling.Advanced drug delivery reviews · 2026Review
- Cross-disease protein aggregate interactions in neurodegeneration: from molecular mechanisms to therapeutic strategies.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026Review
- A third-generation, high-affinity biparatopic anti-tau antibody inhibits intracellular tau aggregation seeded by Alzheimer's brain extracts.Alzheimer's research & therapy · 2026Article
- Patient-derived tau-seeded human neuronal chimeras recapitulate mature Alzheimer's tau pathology and uncover human-specific neuronal vulnerability.bioRxiv : the preprint server for biology · 2026Article
- The expanding role of protease therapeutics (2012-2026): from replacement therapies to immune system modulation and beyond.The Biochemical journal · 2026Review
- The neuroimmune system and cognition.Nature immunology · 2026Review
- Review
- Unmasking the hidden catalyst: How infections trigger Alzheimer's disease.Journal of Alzheimer's disease : JAD · 2026Review
- From seeds to symptoms: the molecular landscape of tau seeding in Alzheimer's disease.Frontiers in neuroscience · 2026Review
- Mechanistic modeling of amyloid dynamics relating to Alzheimer's disease progression.Frontiers in aging neuroscience · 2026Article
- The role for artificial intelligence in identifying combination therapies for Alzheimer's disease.The journal of prevention of Alzheimer's disease · 2025Review
- Fc-Modified IVIG with Enhanced Blood-Brain Barrier Penetration Ameliorates Cognitive Deficits and Neuropathology in A53T α-Synuclein Transgenic Mice.Cellular and molecular neurobiology · 2025Article
- DDOX expands the repertoire of tetracyclines for Parkinson's disease by preventing the cellular uptake and intracellular impact of α-synuclein preformed fibrils.Scientific reports · 2025Article
- Tau-Targeted Therapeutic Strategies: Mechanistic Targets, Clinical Pipelines, and Analysis of Failures.Cells · 2025Review
- Pathological mechanisms and treatment progression of Alzheimer's disease.European journal of medical research · 2025Review
- Interactions of Therapeutic Antibodies With Presynaptically-Released Misfolded Proteins in Neurodegenerative Diseases. A Spatial Monte-Carlo Simulation Study.CPT: pharmacometrics & systems pharmacology · 2025Article
- Immunization targeting diseased proteins in synucleinopathy and tauopathy: insights from clinical trials.Translational neurodegeneration · 2025Review
- A mechanistic model of pure and lipidic α-synuclein aggregation for advancing Parkinson's therapies.Communications chemistry · 2025Article
- Rational selection of the monoclonal α-synuclein antibody amlenetug (Lu AF82422) for the treatment of α-synucleinopathies.NPJ Parkinson's disease · 2025Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Misfolded proteins in Alzheimer's disease and Parkinson's disease follow a well-defined connectomics-based spatial progression. Several anti-tau and anti-alpha synuclein (aSyn) antibodies have failed to provide clinical benefit in clinical trials despite substantial target engagement in the experimentally accessible cerebrospinal fluid (CSF). The proposed mechanism of action is reducing neuronal uptake of oligomeric protein from the synaptic cleft. We built a quantitative systems pharmacology (QSP) model to quantitatively simulate intrasynaptic secretion, diffusion and antibody capture in the synaptic cleft, postsynaptic membrane binding and internalization of monomeric and oligomeric tau and aSyn proteins. Integration with a physiologically based pharmacokinetic (PBPK) model allowed us to simulate clinical trials of anti-tau antibodies gosuranemab, tilavonemab, semorinemab, and anti-aSyn antibodies cinpanemab and prasineuzumab. Maximal target engagement for monomeric tau was simulated as 45% (semorinemab) to 99% (gosuranemab) in CSF, 30% to 99% in ISF but only 1% to 3% in the synaptic cleft, leading to a reduction of less than 1% in uptake of oligomeric tau. Simulations for prasineuzumab and cinpanemab suggest target engagement of free monomeric aSyn of only 6-8% in CSF, 4-6% and 1-2% in the ISF and synaptic cleft, while maximal target engagement of aggregated aSyn was predicted to reach 99% and 80% in the synaptic cleft with similar effects on neuronal uptake. The study generates optimal values of selectivity, sensitivity and PK profiles for antibodies. The study identifies a gradient of decreasing target engagement from CSF to the synaptic cleft as a key driver of efficacy, quantitatively identifies various improvements for drug design and emphasizes the need for QSP modelling to support the development of tau and aSyn antibodies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.