Tariq Afroz, Switzerland

AC Immune SA Research
Dr. Afroz’s research focuses on understanding molecular mechanisms of neurodegeneration and pathways for therapeutic interventions in various CNS indications. At AC Immune, Dr. Afroz serves as senior scientist and project leader for TDP-43 antibody therapeutic program. Prior to joining AC Immune in 2017, Dr. Afroz was a post-doctoral scientist in the lab of Prof. Polymenidou at the University of Zürich where he investigated the pathways that trigger aggregation of ALS/FTD-linked proteins, the mechanisms of neurotoxicity and underlying molecular basis of disease heterogeneity. Dr. Afroz obtained his Master’s degree in Biotechnology at the Indian Institute of Technology in Mumbai, India. 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 2 Presentations

 Conference Calendar

LIVE DISCUSSION

Session Name
LIVE DISCUSSION - TDP-43 IN ALS AND FTD
Session Type
LIVE SYMPOSIUM DISCUSSION
Date
11.03.2021, Thursday
Session Time
16:30 - 17:00
Room
Live Symposia Discussion C
Lecture Time
16:30 - 17:00
Presenter
Session Icon
Live

TDP-43 ANTIBODY DIRECTED MICROGLIAL CLEARANCE AND INHIBITION OF SEEDED AGGREGATION MITIGATES NEUROPATHOLOGY IN MODELS OF TDP-43 PROTEINOPATHY

Session Name
TDP-43 IN ALS AND FTD
Session Type
SYMPOSIUM
Date
11.03.2021, Thursday
Session Time
10:00 - 11:45
Room
On Demand Symposia C
Lecture Time
11:15 - 11:30
Presenter
Session Icon
On-Demand

Abstract

Aims

Accumulation of TDP-43 into intracellular inclusions is the hallmark of frontotemporal lobar degeneration-TDP (FTLD-TDP), amyotrophic lateral sclerosis (ALS) and limbic-predominant age-related TDP-43 encephalopathy (LATE) and present as co-pathologies in other neurodegenerative diseases. However, no therapeutic interventions targeting TDP-43 pathology are available. Antibody-mediated clearance of misfolded TDP-43 by microglia and inhibition of cell-to-cell protein spreading represents an attractive strategy for therapeutic intervention.

Methods

Monoclonal antibodies (mAbs) were generated against various regions of TDP-43 using our proprietary SupraAntigenTM platform and selected for evaluation in cell-based and transgenic Tg(rNLS8) models of TDP-43 proteinopathies.

Results

High-affinity mAbs targeting different regions of TDP-43 displayed conformational selectivity to misfolded TDP-43 or all TDP-43 isoforms. One mAb, ACI-5891, binding to the C-terminal domain of TDP-43, demonstrated inhibition in vitro of de novo and seeded TDP-43 aggregation using recombinant and FTD brain-derived TDP-43 extracts, respectively. Furthermore, using mouse primary microglial cultures, ACI-5891 efficiently increased the capacity for cellular uptake of TDP-43 aggregates. When tested in the Tg(rNLS8) mouse model of ALS/FTLD-TDP, ACI-5891 significantly reduced the levels of phosphorylated TDP-43 and insoluble TDP-43 in the brain with a concomitant increase in the size of hypertrophic microglia.

Conclusions

From a panel of high-affinity, conformation-specific and pan antibodies, ACI-5891 was identified with unique properties for effectively inhibiting TDP-43 seeding and spreading in cellular assays and efficiently promoting microglia activity in vitro and in vivo. These characteristics demonstrated for the first time that an antibody targeting TDP-43 ameliorates TDP-43-mediated pathology in vivo providing validation for further development to target TDP-43-mediated neuropathology.

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