Evidence map›Paper›PMID 34709986›Full record

ArticlemAbs

Nonclinical safety evaluation, pharmacokinetics, and target engagement of Lu AF82422, a monoclonal IgG1 antibody against alpha-synuclein in development for treatment of synucleinopathies.

Lone Fjord-Larsen, Annemette Thougaard, Karen Malene Wegener, Joan Christiansen, Frank Larsen, Lise Maj Schrøder-Hansen, Marianne Kaarde, Dorte Kornerup Ditlevsen

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in mAbs. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.

0numbers the graph read from it
0cells of the map it votes in
21citing papers in PubMed
2.1field-weighted citation impact, top 11% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

21 citing papers in PubMed, 33 citations in OpenAlex.

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  11. Proteolytic therapeutic modalities for amyloidoses: Insights into immunotherapy, PROTAC, and photo-oxygenation.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025
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  20. Alpha-synuclein Immunization Strategies for Synucleinopathies in Clinical Studies: A Biological Perspective.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2022
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 1 institution in 1 country.

Lone Fjord-LarsenDepartment Regulatory Toxicology and Safety Assessment, H. Lundbeck A/S, Valby, Denmark.
Annemette ThougaardDepartment Exploratory Toxicology, H. Lundbeck A/S, Valby, Denmark.
Karen Malene WegenerDepartment Regulatory Toxicology and Safety Assessment, H. Lundbeck A/S, Valby, Denmark.
Joan ChristiansenDepartment Exploratory Toxicology, H. Lundbeck A/S, Valby, Denmark.
Frank LarsenDepartment PKPD Modelling and Simulation, H. Lundbeck A/S, Valby, Denmark.
Lise Maj Schrøder-HansenDepartment Regulatory Toxicology and Safety Assessment, H. Lundbeck A/S, Valby, Denmark.
Marianne KaardeDepartment Regulatory Toxicology and Safety Assessment, H. Lundbeck A/S, Valby, Denmark.
Dorte Kornerup DitlevsenDepartment Bioanalysis-Biologics, H. Lundbeck A/S, Valby, Denmark.
Lundbeck (Denmark) · DK

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Alpha-synuclein is a 15 kDa protein associated with neurodegenerative diseases such as Parkinson disease and multiple-system atrophy where pathological forms of alpha-synuclein aggregate and become neurotoxic. Here we describe the nonclinical program to support a first-in-human (FIH) single ascending dose (SAD) study for Lu AF82422, a human recombinant, anti-alpha-synuclein monoclonal antibody (mAb) in development for treatment of synucleinopathies. Alpha-synuclein is primarily expressed in brain, peripheral nerves and in blood cells. A tissue cross-reactivity assessment showed that Lu AF82422 binding was generally restricted to nervous tissues. Flow cytometry analysis did not show extracellular surface binding of Lu AF82422 to human platelets, erythrocytes, granulocytes, or lymphocytes, but to a low fraction of monocytes, without any functional consequences on activation or phagocytic capacity. A single dose pharmacokinetic (PK) study in cynomolgus monkeys with dose levels of 1-30 mg/kg confirmed PK properties in the expected range for a mAb with a soluble target, and target engagement was shown as a decrease in free alpha-synuclein in plasma. Four-week repeat-dose toxicity studies were conducted in rats and cynomolgus monkeys at doses up to 600 mg/kg administered intravenously every 10 days. Results showed no treatment-related adverse findings and the no-observed-adverse-effect-level was the highest dose tested. Target engagement was shown in plasma and cerebrospinal fluid. Taken together, the nonclinical data indicated no safety signal of concern and provided adequate safety margins between observed safe doses in animals and the planned dose levels in the FIH SAD study.

Indexed as

Parkinson DiseaseSynucleinopathiesalpha-SynucleinAnimalsAntibodies, MonoclonalImmunoglobulin GRatsalpha-SynucleinAntibodies, MonoclonalImmunoglobulin GAlpha-synucleincerebrospinal fluidcynomolgus monkeysmonoclonal antibodynonclinical safetypharmacokineticstarget engagement

Identifiers

PMID34709986
PMCPMC8555527
OpenAlexW3210864887

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC
Read underepoch 390

Registered trials

None linked

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 OpenQuestion graph.