TDP-O A monoclonal antibody against misfolded TDP-43 for neurodegenerative diseases without perturbing native TDP-43
TDP-O 一種針對錯誤摺疊的 TDP-43 的單株抗體，用於治療神經退化性疾病，且不干擾天然 TDP-43
TDP-O antibody is a selective conformational antibody specific for misfolded TDP-43 oligomers to combat ALS and TDP-43 proteinopathies including frontal temporal dementia, and Alzheimer’s disease.
TDP-O 抗體是一種針對錯誤折疊的 TDP-43 寡聚體的選擇性構象抗體，用於對抗 ALS 和 TDP-43 蛋白質疾病，包括額顳失智症和阿茲海默症。
Targeted indication
• Amyotrophic lateral sclerosis (ALS)
•Frontal temporal dementia (FTD)
• Alzheimer’s disease (AD)
•Other TDP-43 proteinopathies
Status
pre-clinical
Key features
- A monoclonal antibody specific to misfolded TDP-43
- Rescue motor neurons and motor behaviors in mice
- Antibody humanization completed and successful
Market
- ALS is a motor neuron disease that leads to death in 3 to 5 years after disease onset without effective treatment.
- The compound annual growth rate (CAGR) is 5.8%. Based on rare disease drug price, the market should reach 2-6 billion annually.
- The number of patients with dementia worldwide has reached >47 millions including FTD and AD that cover most of the clinical dementia cases.
MODE OF ACTION
TDP-O antibody is a selective conformational antibody specific for misfolded TDP-43 oligomers to combat ALS and TDP-43 proteinopathies.
TDP-43 proteinopathies were found in several severe neurodegenerative diseases including > 95% of ALS, ~50% of FTD, and ~30-60% of AD patients. The inclusions are composed of TDP-43 aggregates. TDP-43 aggregation plays a worthening role in AD.
EXPERIMENTAL RESULTS
TDP-O specifically targets misfolded TDP-43 with high affinity but not native TDP-43.
- The efficacy of the antibody in vivo was proven by intravenous (i.v.) delivery of TDP-O antibody in two ALS mouse models. The administration significantlyincreased motor neuron survival, induced reinnervation in neuromuscular junction, improved motor behaviors, reduced TDP-43 oligomer level, and reduced inflammation.
- The i.v. administration of TDP-O9 antibody penetrates BBB about 0.2% similar to the FDA approved anti-amyloid-β antibody drugs (Aducanumab/Lecanumab) and were found in the cytoplasm of neurons.
- Treatment of TDP-O antibody to iPSC-derived motor neurons (iPSC-MN) from C9ORF72 patient increases neurite length for ~2 fold and reduces misfolded TDP-43 oligomers in ALS iPSC-MN.
- Humanization of TDP-O antibody is completed and successful.
- TDP-O antibody detects TDP-43 oligomer in plasma of ALS, where ALS patients have significant elevated TDP-43 oligomers in plasma.
- TDP-O antibody identifies and facilitates neuropathology characterization in post mortem tissues of ALS, FTD, and AD
NA
INTELLECTUAL PROPERTY
SELECTED PUBLICATIONS
1.Nature Communications, 5:4824 (2014) doi: 10.1038/ncomms5824.
2. Annals of Neurology, 78(2):211-21. (2015) doi: 10.1002/ana.24431.
3. Nature Communications. 11: 5950 (2020) doi: 10.1038/s41467-020-19786-7.
4. TDP-43-oligomer specific monoclonal antibodies identify TDP-43 oligomers in ALS patients and rescue abnormality in ALS mouse models (In preparation).
BUSINESS OPPORTUNITY
Investment/Partnership/Out-licensing
CONTACT
Prof. Dr. Yun-Ru (Ruby) Chen 陳韻如. Genomics Research Center, Academia Sinica, Taiwan.
Email: yrchen@as.edu.tw