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

Mickael Audrain; Anne-Laure Egesipe; Noémie Tentillier; Laure Font; Monisha Ratnam; Lorene Mottier; Mathieu Clavel; Morgan Le Roux-Bourdieu; Alexis Fenyi; Romain Ollier; Elodie Chevalier; Florence Guilhot; Aline Fuchs; Kasia Piorkowska; Becky Carlyle; Steven E Arnold; James D Berry; Ruth Luthi-Carter; Oskar Adolfsson; Andrea Pfeifer; Marie Kosco-Vilbois; Tamara Seredenina; Tariq Afroz

doi:10.1093/braincomms/fcad306

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

Brain Commun. 2023 Nov 3;5(6):fcad306. doi: 10.1093/braincomms/fcad306. eCollection 2023.

Authors

Mickael Audrain¹, Anne-Laure Egesipe¹, Noémie Tentillier¹, Laure Font¹, Monisha Ratnam¹, Lorene Mottier¹, Mathieu Clavel¹, Morgan Le Roux-Bourdieu¹, Alexis Fenyi¹, Romain Ollier¹, Elodie Chevalier¹, Florence Guilhot¹, Aline Fuchs¹, Kasia Piorkowska¹, Becky Carlyle², Steven E Arnold³, James D Berry⁴, Ruth Luthi-Carter¹, Oskar Adolfsson¹, Andrea Pfeifer¹, Marie Kosco-Vilbois¹, Tamara Seredenina¹, Tariq Afroz¹

Affiliations

¹ Research, AC Immune SA, 1015 Lausanne, Switzerland.
² Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.
³ Department of Neurology and the Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
⁴ Sean M. Healey & AMG Center for ALS & the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

Abstract

In amyotrophic lateral sclerosis, a disease driven by abnormal transactive response DNA-binding protein of 43 kDa aggregation, CSF may contain pathological species of transactive response DNA-binding protein of 43 kDa contributing to the propagation of pathology and neuronal toxicity. These species, released in part by degenerating neurons, would act as a template for the aggregation of physiological protein contributing to the spread of pathology in the brain and spinal cord. In this study, a robust seed amplification assay was established to assess the presence of seeding-competent transactive response DNA-binding protein of 43 kDa species in CSF of apparently sporadic amyotrophic lateral sclerosis patients. These samples resulted in a significant acceleration of substrate aggregation differentiating the kinetics from healthy controls. In parallel, a second assay was developed to determine the level of target engagement that would be necessary to neutralize such species in human CSF by a therapeutic monoclonal antibody targeting transactive response DNA-binding protein of 43 kDa. For this, evaluation of the pharmacokinetic/pharmacodynamic effect for the monoclonal antibody, ACI-5891.9, in vivo and in vitro confirmed that a CSF concentration of ≍1100 ng/mL would be sufficient for sustained target saturation. Using this concentration in the seed amplification assay, ACI-5891.9 was able to neutralize the transactive response DNA-binding protein of 43 kDa pathogenic seeds derived from amyotrophic lateral sclerosis patient CSF. This translational work adds to the evidence of transmission of transactive response DNA-binding protein of 43 kDa pathology via CSF that could contribute to the non-contiguous pattern of clinical manifestations observed in amyotrophic lateral sclerosis and demonstrates the ability of a therapeutic monoclonal antibody to neutralize the toxic, extracellular seeding-competent transactive response DNA-binding protein of 43 kDa species in the CSF of apparently sporadic amyotrophic lateral sclerosis patients.

Keywords: ALS; RT-QuIC; TDP-43; biomarker; immunotherapy.