Tariq Afroz (Switzerland)
AC Immune
Research
Dr. Afroz’s research has focused on understanding molecular mechanisms of neurodegeneration and pathways for therapeutic interventions in various CNS indications. At AC Immune, Dr. Afroz serves as Team and project leader for TDP-43 therapeutic antibody program. Prior to joining AC Immune in 2017, Dr. Afroz was a post-doctoral scientist at the University of Zürich where he investigated the pathways that trigger aggregation of ALS/FTD-linked proteins, the mechanisms of neurotoxicity and the molecular basis of disease heterogeneity. Dr. Afroz obtained his master’s degree in Biotechnology at the Indian Institute of Technology in Mumbai. In 2013, he obtained his Ph.D. in Molecular Biology and Biophysics at ETH Zürich where he studied the role of sequence-specific protein-RNA interactions in RNA processing and metabolism.

Presenter of 1 Presentation

 Conference Calendar

DEVELOPMENT OF TDP-43 IMMUNOTHERAPY BLOCKING TRANSMISSION OF SEEDING-COMPETENT SPECIES FROM ALS/FTD

Session Name
3720 - SYMPOSIUM: FTD, ALS: C9ORF72, TDP-43 (ID 70)
Session Type
SYMPOSIUM
Date
Thu, 30.03.2023
Session Time
16:20 - 18:20
Room
ONSITE - HALL G3
Presenter
Lecture Time
18:05 - 18:20

Abstract

Aims

Accumulation of pathological transactive response DNA binding protein 43 (TDP-43) into intracellular inclusions underlies frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). Multiple mechanisms contribute to spreading of TDP-43 pathology including transmission across synaptic terminals, exosomes and release of misfolded TDP-43 from dying neurons. Cerebrospinal fluid (CSF) obtained from ALS/FTD-TDP patients contains seeding competent TDP-43 species, explaining the spread of pathology including the non-contiguous pattern of clinical manifestations observed in ALS. Therefore, antibody-mediated clearance of pathological TDP-43 represents an attractive therapeutic strategy.

Methods

High affinity antibodies were generated against various regions of TDP-43 using AC Immune’s proprietary SupraAntigen® platform and evaluated in mechanistic assays in vitro and in mouse models of TDP-43 proteinopathies. The effect on pathological TDP-43 in CSF was evaluated using the real-time quaking-induced conversion assay. Humanized antibody was further evaluated for PK/PD and safety.

Results

Targeting the C-terminal domain of TDP-43 but not the RNA recognition motifs reduced TDP-43 pathology and prevented neuronal loss in vivo. This rescue was dependent on Fc receptor-mediated immune complex uptake by microglia. The latter also promoted phagocytic capacity of ALS patient-derived microglia. Antibody-mediated depletion of seeding-competent brain and CSF species will be presented. Modelling from non-clinical PK studies for humanized antibody predicts a half-life supporting target saturation in humans.

Conclusions

Our findings confirm the presence of extracellular seeding-competent species in ALS/FTD patients and that an antibody targeting the C-terminal domain rescues multiple patho-mechanisms involved in the disease progression, supporting an immunotherapy approach.

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