Targeting tau only extracellularly is likely to be less efficacious than targeting it both intra- and extracellularly

Congdon, Erin E.; Jiang, Yixiang; Sigurdsson, Einar M.

doi:10.1016/j.semcdb.2021.12.002

Cited by 19 publications

(24 citation statements)

References 280 publications

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“…In the last 15 years, tau immunotherapies have advanced from proof-of-concept studies to over a dozen clinical trials (for recent reviews see 1 , 2 , 3 , 4 , 5 , 6 ). Some of those trials have failed and there are some likely reasons for that.…”

Section: Introductionmentioning

confidence: 99%

Single domain antibodies targeting pathological tau protein: Influence of four IgG subclasses on efficacy and toxicity

et al. 2022

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Section: Introductionmentioning

confidence: 99%

Single domain antibodies targeting pathological tau protein: Influence of four IgG subclasses on efficacy and toxicity

et al. 2022

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“…Although not quantitatively documented, similar concerns have recently been raised in the literature [50].…”

Section: Discussionmentioning

confidence: 59%

Clinical failure of anti-tau and anti-synuclein antibodies in neurodegeneration: a quantitative systems pharmacology model analysis

Geerts

Bergeler

Walker³

et al. 2023

Preprint

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Misfolded proteins in Alzheimer’s disease (AD) and Parkinson’s disease (PD) follow a well-defined connectomics-based spatial progression. Several anti-tau and anti-alpha synuclein (aSyn) antibodies have failed to provide clinical benefit in clinical trials despite substantial target engagement in the experimentally accessible cerebrospinal fluid (CSF). The proposed mechanism of action is reducing neuronal uptake of seed-competent protein from the synaptic cleft. We built a quantitative systems pharmacology (QSP) model to quantitatively simulate intrasynaptic secretion, diffusion and antibody capture in the synaptic cleft, postsynaptic membrane binding and internalization of monomeric and seed-competent tau and aSyn proteins. Integration with a physiologically based pharmacokinetic (PBPK) model allowed us to simulate clinical trials of anti-tau antibodies gosuranemab, tilavonemab, semorinemab, and anti-aSyn antibodies cinpanemab and prasineuzumab. Maximal target engagement for monomeric tau was simulated as 45% (semorinemab) to 99% (gosuranemab) in CSF, 30% to 99% in ISF but only 1% to 3% in the synaptic cleft, leading to a reduction of less than 1% in uptake of seed-competent tau. Simulations for prasineuzumab and cinpanemab suggest target engagement of free monomeric aSyn of only 6-8% in CSF, 4-6% and 1-2% in the ISF and synaptic cleft, while maximal target engagement of aggregated aSyn was predicted to reach 99% and 80% in the synaptic cleft with similar effects on neuronal uptake. The study generates optimal values of selectivity, sensitivity and PK profiles for antibodies. The study identifies a gradient of decreasing target engagement from CSF to the synaptic cleft as a key driver of efficacy, quantitatively identifies various improvements for drug design and emphasizes the need for QSP modelling to support the development of tau and aSyn antibodies. Trial registration : N/A

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“…Notably, no major side effects have been observed in these trials alleviating the potential drawbacks noted above. To improve efficacy, one strategy is to use smaller antibody fragments, such as single-chain variable fragments (scFv, 25 kDa) or single-domain antibodies (sdAbs or VHHs, ∼15 kDa), which have greater brain uptake albeit shorter half-life than whole antibodies ( 27, 28 ).…”

Section: Introductionmentioning

confidence: 99%

Single-Domain Antibody-Based Protein Degrader for Synucleinopathies

Jiang,

Lin,

Tetlow

et al. 2024

Preprint

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Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein (α-syn) in the brain, leading to motor and neuropsychiatric symptoms. Currently, there are no known cures for synucleinopathies, and treatments mainly focus on symptom management. In this study, we developed a single-domain antibody (sdAb)-based protein degrader with features designed to enhance proteasomal degradation of α-syn. This sdAb derivative targets both α-syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4CRBN, and thereby induces α-syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic ligand enhances proteasomal degradation of α-syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of α-syn, we improved clearance of α-syn in primary culture and mouse models of synucleinopathy. These findings indicate that our sdAb-based protein degrader is a promising therapeutic for synucleinopathies. Considering that only a small percentage of antibodies enter the brain, more potent sdAbs with greater brain entry than whole antibodies could enhance clinical benefits of antibody-based therapies.

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Targeting tau only extracellularly is likely to be less efficacious than targeting it both intra- and extracellularly

Cited by 19 publications

References 280 publications

Single domain antibodies targeting pathological tau protein: Influence of four IgG subclasses on efficacy and toxicity

Single domain antibodies targeting pathological tau protein: Influence of four IgG subclasses on efficacy and toxicity

Clinical failure of anti-tau and anti-synuclein antibodies in neurodegeneration: a quantitative systems pharmacology model analysis

Single-Domain Antibody-Based Protein Degrader for Synucleinopathies

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