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Updated: Jul 9, 2025

Novel Atomic Force Microscopy Based Biopanning for Isolation of Morphology Specific Reagents against TDP-43 Variants in Amyotrophic Lateral Sclerosis

Novel Atomic Force Microscopy Based Biopanning for Isolation of Morphology Specific Reagents against TDP-43 Variants in Amyotrophic Lateral Sclerosis

Published on: February 12, 2015

Targeting amyotrophic lateral sclerosis by neutralizing seeding-competent TDP-43 in CSF.

Mickael Audrain¹, Anne-Laure Egesipe¹, Noémie Tentillier¹

¹Research, AC Immune SA, 1015 Lausanne, Switzerland.

Brain Communications

|November 29, 2023

Summary

Pathological transactive response DNA-binding protein of 43 kDa (TDP-43) species in cerebrospinal fluid (CSF) may drive amyotrophic lateral sclerosis (ALS) progression. A new assay detects these seeds, and a monoclonal antibody neutralizes them in ALS patient CSF.

Keywords:

ALS RT-QuIC TDP-43 biomarker immunotherapy

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Use of Capillary Electrophoresis Immunoassay to Search for Potential Biomarkers of Amyotrophic Lateral Sclerosis in Human Platelets

Published on: February 10, 2020

Area of Science:

Neuroscience
Biochemistry
Pathology

Background:

Amyotrophic lateral sclerosis (ALS) is characterized by abnormal transactive response DNA-binding protein of 43 kDa (TDP-43) aggregation.
Pathological TDP-43 species in cerebrospinal fluid (CSF) may contribute to disease propagation and neurotoxicity.
These species can act as seeds, templating aggregation of physiological TDP-43 and spreading pathology.

Purpose of the Study:

To establish a seed amplification assay (SAA) for detecting seeding-competent TDP-43 species in the CSF of sporadic ALS patients.
To develop an assay to determine the therapeutic antibody concentration needed for neutralizing these pathological TDP-43 species in human CSF.
To demonstrate the efficacy of a monoclonal antibody (ACI-5891.9) in neutralizing TDP-43 seeds in ALS patient CSF.

Main Methods:

Development of a robust seed amplification assay (SAA) to detect seeding-competent TDP-43 in patient CSF.
Creation of a second assay to measure target engagement for neutralizing TDP-43 species with a therapeutic monoclonal antibody.
Pharmacokinetic/pharmacodynamic evaluation of monoclonal antibody ACI-5891.9 in vivo and in vitro to establish effective CSF concentration.

Main Results:

The SAA detected significant acceleration of substrate aggregation in CSF from sporadic ALS patients compared to healthy controls.
A CSF concentration of approximately 1100 ng/mL of ACI-5891.9 was determined to be sufficient for sustained target saturation.
ACI-5891.9 effectively neutralized TDP-43 pathogenic seeds in the CSF of ALS patients within the SAA.

Conclusions:

Evidence supports the transmission of TDP-43 pathology via CSF, potentially explaining the non-contiguous clinical spread in ALS.
Therapeutic monoclonal antibody ACI-5891.9 demonstrates the ability to neutralize toxic, extracellular seeding-competent TDP-43 species in ALS patient CSF.
This translational research validates TDP-43 seeding in CSF as a potential biomarker and therapeutic target for ALS.