Tariq Afroz, Switzerland
AC Immune SA ResearchAuthor Of 3 Presentations
TDP-43 ANTIBODY DIRECTED MICROGLIAL CLEARANCE AND INHIBITION OF SEEDED AGGREGATION MITIGATES NEUROPATHOLOGY IN MODELS OF TDP-43 PROTEINOPATHY
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.
DISCOVERY OF PET TRACERS FOR TDP-43 PROTEINOPATHIES
Abstract
Aims
Intracellular aggregation of TDP-43 is found in most patients with amyotrophic lateral sclerosis (ALS), 45% of patients with frontotemporal dementia (FTD) as well as patients with limbic-predominant age-related TDP-43 encephalopathy (LATE). Having better tools to aid in more accurate and earlier diagnosis would substantially improve patient care. Thus, our aim is to provide the first tracer for the detection of TDP-43 aggregates by positron emission tomography (PET) to enhance diagnosis, staging, longitudinal measurement of disease progression and assessment of therapeutic efficacy in clinical trials.
Methods
Various methods including radiobinding and autoradiography were established to screen small molecules from our proprietary MorphomerTM library. Both recombinant and TDP-43 aggregates obtained from brain tissue of patients with TDP-43 proteinopathies were used. For selected compounds, the physico-chemical properties, ADME and pharmacokinetic profiles were evaluated.
Results
Screening of the MorphomerTM library led to identifying compounds binding to recombinant TDP-43 aggregates with Ki < 20 nM and confirmed on pathological TDP-43 derived from FTLD-TDP samples. Selectivity over other aggregation-prone proteins (amyloid beta, alpha-synuclein and Tau) was established. Target engagement on FTLD-TDP brain sections was demonstrated for selected compounds by autoradiography. Compounds with favorable CNS properties were profiled in pharmacokinetic studies.
Conclusions
Medicinal chemistry compound optimization and iterative design allowed the identification of compounds that bind to pathological TDP-43 with low nanomolar affinity. Compounds displaying suitable CNS pharmacokinetic profiles of a quick uptake with a fast and complete washout are being investigated to select a PET tracer for further development.
LIVE DISCUSSION
Presenter of 2 Presentations
TDP-43 ANTIBODY DIRECTED MICROGLIAL CLEARANCE AND INHIBITION OF SEEDED AGGREGATION MITIGATES NEUROPATHOLOGY IN MODELS OF TDP-43 PROTEINOPATHY
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.
LIVE DISCUSSION