Oskar Adolfsson, Switzerland
AC Immune SA ResearchAuthor Of 1 Presentation
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.