ArticleDrug metabolism and disposition: the biological fate of chemicals2010
Monoclonal antibody-glial-derived neurotrophic factor fusion protein penetrates the blood-brain barrier in the mouse.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 46 citations in OpenAlex.
- Antibody-Based Biologics for CNS Disorders.Antibodies (Basel, Switzerland) · 2026Review
- Article
- Bispecific antibody shuttles targeting CD98hc mediate efficient and long-lived brain delivery of IgGs.Cell chemical biology · 2024Article
- Treatment of Parkinson's disease with biologics that penetrate the blood-brain barrier via receptor-mediated transport.Frontiers in aging neuroscience · 2023Review
- IgG Fusion Proteins for Brain Delivery of Biologics via Blood-Brain Barrier Receptor-Mediated Transport.Pharmaceutics · 2022Review
- A Historical Review of Brain Drug Delivery.Pharmaceutics · 2022Review
- Tetravalent Bispecific Tandem Antibodies Improve Brain Exposure and Efficacy in an Amyloid Transgenic Mouse Model.Molecular therapy. Methods & clinical development · 2020Article
- A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity.Fluids and barriers of the CNS · 2020Review
- Aptamer-Based In Vivo Therapeutic Targeting of Glioblastoma.Molecules (Basel, Switzerland) · 2020Review
- Non-Invasive Delivery of Therapeutics into the Brain: The Potential of Aptamers for Targeted Delivery.Biomedicines · 2020Review
- Passive Immunotherapies for Central Nervous System Disorders: Current Delivery Challenges and New Approaches.Bioconjugate chemistry · 2018Review
- Next generation antibody drugs: pursuit of the 'high-hanging fruit'.Nature reviews. Drug discovery · 2018Review
- Agile delivery of protein therapeutics to CNS.Journal of controlled release : official journal of the Controlled Release Society · 2014Review
- Targeted delivery of nano-therapeutics for major disorders of the central nervous system.Pharmaceutical research · 2013Review
- Calcitriol imparts neuroprotection in vitro to midbrain dopaminergic neurons by upregulating GDNF expression.PloS one · 2013Article
- Drug transport across the blood-brain barrier.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2012Review
- Pharmacokinetics of recombinant bifunctional fusion proteins.Expert opinion on drug metabolism & toxicology · 2012Review
- Delivery of a peptide radiopharmaceutical to brain with an IgG-avidin fusion protein.Bioconjugate chemistry · 2011Article
- Chronic dosing of mice with a transferrin receptor monoclonal antibody-glial-derived neurotrophic factor fusion protein.Drug metabolism and disposition: the biological fate of chemicals · 2011Article
- Brain-penetrating tumor necrosis factor decoy receptor in the mouse.Drug metabolism and disposition: the biological fate of chemicals · 2011Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Glial-derived neurotrophic factor (GDNF) is a potent neuroprotective agent for multiple brain disorders, including Parkinson's disease. However, GDNF drug development is difficult because GDNF does not cross the blood-brain barrier (BBB). To enable future drug development of GDNF in mouse models, the neurotrophin was re-engineered as an IgG fusion protein to enable penetration through the BBB after intravenous administration. The 134-amino acid GDNF was fused to the heavy chain of a chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR) designated the cTfRMAb. This antibody undergoes receptor-mediated transport across the BBB and acts as a molecular Trojan horse to ferry the GDNF into mouse brain. The cTfRMAb-GDNF fusion protein was expressed by stably transfected Chinese hamster ovary cells, affinity-purified, and the biochemical identity was confirmed by mouse IgG and GDNF Western blotting. The cTfRMAb-GDNF fusion protein was bifunctional and bound with high affinity to both the GDNF receptor alpha1, ED(50) = 1.7 +/- 0.2 nM, and the mouse TfR, ED(50) = 3.2 +/- 0.3 nM. The cTfRMAb-GDNF fusion protein was rapidly taken up by brain, and the brain uptake was 3.1 +/- 0.2% injected dose/g brain at 60 min after intravenous injection of a 1-mg/kg dose of the fusion protein. Brain capillary depletion analysis showed the majority of the fusion protein was transcytosed across the BBB with penetration into brain parenchyma. The brain uptake results indicate it is possible to achieve therapeutic elevations of GDNF in mouse brain with intravenous administration of the cTfRMAb-GDNF fusion protein.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.