Background
Accumulation of tau oligomers at the synapses in Alzheimer’s disease (AD) disrupts neuronal activities and leads to neurodegeneration. Tau immunotherapy has been actively pursued as a ...treatment for tauopathies in the past decade. Despite several failed Phase 2 trials of N‐terminus binding antibodies a variety of tau epitopes are being investigated at different stages of clinical trials. APNmAb005 is a humanized monoclonal antibody designed to block synaptic toxicity elicited by tau oligomers.
Method
APNmAb005 was selected as a clinical candidate from APRINOIA’s antibody discovery platform based on its unique binding properties to pathological tau in vitro immunoassays as well in vivo efficacy studies in rTg4510 mice. Humanized APNmAb005 is in IgG4 backbone and the production was scaled up successfully with good stability and solubility to support preclinical and clinical development. GLP safety study was conducted in cynomolgus monkeys. A Phase 1a randomized, double‐blind, placebo‐controlled study of APNmAb005 in healthy subjects is underway.
Result
Epitope‐mapping study reveals that APNmAb005 binds to a conformation‐dependent epitope in the mid‐region, which results in a preferable recognition of pathological tau in early Braak stage (III‐IV) AD brains as well as tau aggregates in astrocytes and oligodendrocytes in brains from progressive supranuclear palsy (PSP) patients but not monomeric tau in normal brains. APNmAb005 blocks in vitro tau seeding at nanomolar concentrations and rescues neuronal loss in rTG4510 mice. Four‐week repeat dosing toxicology study shows no observed adverse effects.
Conclusion
APNmAb005 is a conformation selective antibody that binds to tau oligomers and aggregates preferentiually in synapses in pathological brain tissues and inhibits tau spreading. The mid‐region conformation dependent epitope is distinct from all other tau antibodies currently in clinical development. APNmAb005 offers a unique tau immunotherapy for neurodegenerative disorders and is currently in Phase 1 to evaluate its safety and tolerability.
Background
The need for a light stable 4R tau PET tracer for use in diverse tauopathies is widely appreciated. We aimed to assess the initial human imaging profile of 18FAPN‐1701 as such a tracer and ...to compare its imaging profile to the well‐established but light‐sensitive tracer 18F‐APN‐1607 that can detect 4R aggregates as well as 3R and mixed 3R/4R aggregates. 18FAPN‐1607 has progressed to a multicenter Phase 2 clinical trial for Alzheimer’s disease (AD); therefore, prior imaging data with it was considered valuable for comparison.
Method
One cognitively normal (CN) subject (male, 73yo) and one AD subject (female, 58 yo), who had undergone prior amyloid profiling using 18Fflorbetapir PET and subsequent imaging with 18FAPN‐1607 in a proof‐of‐concept study and a test‐retest study, respectively, participated in the current study. Dynamic imaging with 18FAPN‐1701 was performed over 180 min to obtain kinetic data.
Result
Overall, for both subjects 18FAPN‐1701 generally matched 18FAPN‐1607 findings, i.e., peak SUV values reached similar levels. The CN subject, who was amyloid negative, had slight, uniform cortical 18F‐APN‐1701 uptake and more substantial uptake in the pallidum, pons and midbrain. SUVr images for the AD subject showed retention in similar brain regions for both tau tracers with the same rank order of regional SUV/SUVr. Notably, for this subject 18FAPN‐1701 continued to accumulate up to the end of image acquisition.
Conclusion
18FAPN‐1701 demonstrates cortical uptake generally similar to 18FAPN‐1607 but its slow kinetics are unfavorable for further development.
PROGRESS TOWARDS AN A‐SYNUCLEIN PET TRACER Tempest, Paul; Tai, Chin‐Yin; Ono, Maiko ...
Alzheimer's & dementia,
December 2022, 2022-12-00, Volume:
18, Issue:
S6
Journal Article
Peer reviewed
Background
The high value for Parkinson’s disease and related disorders of the availability of a potent, selective, brain penetrant α‐synuclein (α‐Syn) PET tracer is widely acknowledged. We aimed to ...develop such an agent by applying an established radiotracer development strategy that has been successfully used with another misfolded CNS protein target.
Method
We used a proprietary collection of CNS‐focused aggregated protein binding agents that APRINOIA had previously created to map the structure‐activity relationship of its tau PET tracer programs, including 18FAPN‐1607. This tracer has a unique binding site on aggregated tau and has recently been characterized by cryo‐EM.
The collection was first screened for selective binding of α‐Syn aggregates vs. tau aggregates using recombinant fibrils. This was followed by fluorescence‐based binding to DLB and MSA tissues. These assays identified 16 promising compounds for progression into autoradiography and homogenate binding assays.
Result
Tritiation was successful for 13 of the hits. Self‐blocking studies confirmed specific binding in human brain tissue sections and homogenates. A lead compound was selected, and preliminary PK experiments in wild type mice indicated that brain uptake and clearance properties were compatible with a desirable PET tracer profile in a non‐diseased state. Further studies to evaluate the binding properties in the diseased state and optimize the lead are ongoing.
Conclusion
The compound collection and tracer development strategy have led to the development of an advanced lead or potentially a viable α‐synuclein PET tracer.
Background
In Alzheimer’s Disease (AD) brains, pathological tau species accumulate at the synapses where the cell‐to‐cell transmission of tau has been experimentally demonstrated.
Method
A series of ...assays including: dot‐blot assay of synaptic versus cytosolic fractions, brain immunohistochemistry (IHC), HEK cell‐based tau seeding assay, mass spectrometry‐based epitope mapping and in vivo rTg4510 animal efficacy study were used to identify anti‐tau antibodies for therapeutic purposes.
Result
APRINOIA has characterized 12 anti‐tau antibodies bind to synaptic tau species isolated from AD brain tissues. These synaptic preferred anti‐tau antibodies were not only highly specific to pathological tau species in AD brains, but also exhibited diverse subcellular localization in rTg4510 tau transgenic mouse brains. Among them, we focused on 2 antibodies, APNmAb005 and 037. For 005, it localized at axodendritic compartments in the hippocampi of 3‐mo rTg4510 brains and was found to bind conformational epitopes in the mid‐region of tau protein. On the other hand, 037 localized in the somatic compartments with a conformational epitope in the repeat domain of tau. Moreover, both antibodies could block tau seeding from the rTg4510 mouse brain lysates or from the secreted tau of rTg4510 synaptoneurosomes. A 3‐month efficacy study was performed in rTg4510 animals for 005 and significant reduction of neuronal loss was observed.
Conclusion
The therapeutic potentials of anti‐tau antibodies are not judged by the location of epitopes or sub‐cellular localization, but by their abilities to recognize synaptically localized tau in AD brains.
Abstract
Background
Tauopathies are neurodegenerative characterized by the accumulation of abnormal phosphorylated and aggregated forms of Tau protein in the brain. rTg4510 (MAPT*P301L) mouse model ...is a widely used tauopathy model for studying therapeutic intervention that target neurodegeneration and tau pathology.
Method
In this study rTg4510 mice (n=13‐15/group) were treated with RAA7 (10 mg/kg and 50 mg/kg) or vehicle (PBS). At 7 months of age tau pathology and neurodegeneration was characterized using cresyl fast violet staining (CFV) and NeuN for neurodegeneration, total human Tau (HT7) and phosphorylated human Tau (AT8). Sections were analyzed as % of area of positive signal. Four regions of interest were examined: cortex, CA1 and dentate gyrus regions and whole hippocampus.
Result
Our results showed that RAA7 treatment diminish neurodegeneration and affect tau pathology. In CFV and NeuN staining, RAA7 10 mg/kg increased % of stained area in all analyzed brain regions, whereas RAA7 50 mg/kg in the CA1 region when compared to PBS group. In addition, high dose treatment showed neuroprotective effect in the DG regions of hippocampus as well. NeuN/CFV ratio was decreased by RAA7 10 mg/kg treatment in all analyzed areas. Assessment of tau expression revealed that RAA7 10 mg/kg decreased level of total Tau in CA1 region and phosphorylated Tau in cortex when compared to PBS group. Unexpectedly, RAA7 50 mg/kg showed significantly higher total tau level in the whole hippocampus when compared to PBS group, and no effect on the tau phosphorylation level.
Conclusion
In conclusion, RAA7 treatment showed neuroprotective in Tg4510 mice demonstrated by reduced Tau accumulation and phosphorylation driven inhibition of neuronal cell death.
Abstract
Background
In Alzheimer’s Disease (AD) brains, pathological tau species accumulate at the synapses where the cell‐to‐cell transmission of tau has been experimentally demonstrated.
Method
A ...series of assays including: dot‐blot assay of synaptic versus cytosolic fractions, brain immunohistochemistry (IHC), HEK cell‐based tau seeding assay, mass spectrometry‐based epitope mapping and in vivo rTg4510 animal efficacy study were used to identify anti‐tau antibodies for therapeutic purposes.
Result
APRINOIA has characterized 12 anti‐tau antibodies bind to synaptic tau species isolated from AD brain tissues. These synaptic preferred anti‐tau antibodies were not only highly specific to pathological tau species in AD brains, but also exhibited diverse subcellular localization in rTg4510 tau transgenic mouse brains. Among them, we focused on 2 antibodies, APNmAb005 and 037. For 005, it localized at axodendritic compartments in the hippocampi of 3‐mo rTg4510 brains and was found to bind conformational epitopes in the mid‐region of tau protein. On the other hand, 037 localized in the somatic compartments with a conformational epitope in the repeat domain of tau. Moreover, both antibodies could block tau seeding from the rTg4510 mouse brain lysates or from the secreted tau of rTg4510 synaptoneurosomes. A 3‐month efficacy study was performed in rTg4510 animals for 005 and significant reduction of neuronal loss was observed.
Conclusion
The therapeutic potentials of anti‐tau antibodies are not judged by the location of epitopes or sub‐cellular localization, but by their abilities to recognize synaptically localized tau in AD brains.
Background
Tauopathies are neurodegenerative characterized by the accumulation of abnormal phosphorylated and aggregated forms of Tau protein in the brain. rTg4510 (MAPT*P301L) mouse model is a ...widely used tauopathy model for studying therapeutic intervention that target neurodegeneration and tau pathology.
Method
In this study rTg4510 mice (n=13‐15/group) were treated with RAA7 (10 mg/kg and 50 mg/kg) or vehicle (PBS). At 7 months of age tau pathology and neurodegeneration was characterized using cresyl fast violet staining (CFV) and NeuN for neurodegeneration, total human Tau (HT7) and phosphorylated human Tau (AT8). Sections were analyzed as % of area of positive signal. Four regions of interest were examined: cortex, CA1 and dentate gyrus regions and whole hippocampus.
Result
Our results showed that RAA7 treatment diminish neurodegeneration and affect tau pathology. In CFV and NeuN staining, RAA7 10 mg/kg increased % of stained area in all analyzed brain regions, whereas RAA7 50 mg/kg in the CA1 region when compared to PBS group. In addition, high dose treatment showed neuroprotective effect in the DG regions of hippocampus as well. NeuN/CFV ratio was decreased by RAA7 10 mg/kg treatment in all analyzed areas. Assessment of tau expression revealed that RAA7 10 mg/kg decreased level of total Tau in CA1 region and phosphorylated Tau in cortex when compared to PBS group. Unexpectedly, RAA7 50 mg/kg showed significantly higher total tau level in the whole hippocampus when compared to PBS group, and no effect on the tau phosphorylation level.
Conclusion
In conclusion, RAA7 treatment showed neuroprotective in Tg4510 mice demonstrated by reduced Tau accumulation and phosphorylation driven inhibition of neuronal cell death.
N-methyl D-aspartate (NMDA) receptors (NMDARs) mediate fast excitatory synaptic transmission and play a critical role in synaptic plasticity associated with learning and memory. NMDAR hypoactivity ...has been implicated in the pathophysiology of schizophrenia, and clinical studies have revealed reduced negative symptoms of schizophrenia with a dose of pregnenolone that elevates serum levels of the neuroactive steroid pregnenolone sulfate (PregS). This report describes a novel process of delayed-onset potentiation whereby PregS approximately doubles the cell's response to NMDA via a mechanism that is pharmacologically and kinetically distinct from rapid positive allosteric modulation by PregS. The number of functional cell-surface NMDARs in cortical neurons increases 60-100% within 10 minutes of exposure to PregS, as shown by surface biotinylation and affinity purification. Delayed-onset potentiation is reversible and selective for expressed receptors containing the NMDAR subunit subtype 2A (NR2A) or NR2B, but not the NR2C or NR2D, subunits. Moreover, substitution of NR2B J/K helices and M4 domain with the corresponding region of NR2D ablates rapid allosteric potentiation of the NMDA response by PregS but not delayed-onset potentiation. This demonstrates that the initial phase of rapid positive allosteric modulation is not a first step in NMDAR upregulation. Delayed-onset potentiation by PregS occurs via a noncanonical, pertussis toxin-sensitive, G protein-coupled, and Ca(2+)-dependent mechanism that is independent of NMDAR ion channel activation. Further investigation into the sequelae for PregS-stimulated trafficking of NMDARs to the neuronal cell surface may uncover a new target for the pharmacological treatment of disorders in which NMDAR hypofunction has been implicated.
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