ArticleDrug metabolism and disposition: the biological fate of chemicals2012
Glycemic control and chronic dosing of rhesus monkeys with a fusion protein of iduronidase and a monoclonal antibody against the human insulin receptor.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
27 citing papers in PubMed, 57 citations in OpenAlex.
- Neurocognitive and somatic stabilization in pediatric patients with severe Mucopolysaccharidosis Type I after 52 weeks of intravenous brain-penetrating insulin receptor antibody-iduronidase fusion protein (valanafusp alpha): an open label phase 1-2 trial.Orphanet journal of rare diseases · 2018Trial
- Strategies to Screen and Evaluate Brain Targeting Antibodies Using an iPSC-Derived Blood-Brain Barrier Model.Antibodies (Basel, Switzerland) · 2025Article
- Targeting the central nervous system in lysosomal storage diseases: Strategies to deliver therapeutics across the blood-brain barrier.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Review
- Drug delivery for neuronopathic lysosomal storage diseases: evolving roles of the blood brain barrier and cerebrospinal fluid.Metabolic brain disease · 2022Review
- IgG Fusion Proteins for Brain Delivery of Biologics via Blood-Brain Barrier Receptor-Mediated Transport.Pharmaceutics · 2022Review
- Treatment of Neuronopathic Mucopolysaccharidoses with Blood-Brain Barrier-Crossing Enzymes: Clinical Application of Receptor-Mediated Transcytosis.Pharmaceutics · 2022Review
- Exploring ITM2A as a new potential target for brain delivery.Fluids and barriers of the CNS · 2022Article
- Article
- Low-Level Endothelial TRAIL-Receptor Expression Obstructs the CNS-Delivery of Angiopep-2 Functionalised TRAIL-Receptor Agonists for the Treatment of Glioblastoma.Molecules (Basel, Switzerland) · 2021Article
- Novel Ion Channel Targets and Drug Delivery Tools for Controlling Glioblastoma Cell Invasiveness.International journal of molecular sciences · 2021Review
- Highly Specific Blood-Brain Barrier Transmigrating Single-Domain Antibodies Selected by an In Vivo Phage Display Screening.Pharmaceutics · 2021Article
- Investigating receptor-mediated antibody transcytosis using blood-brain barrier organoid arrays.Fluids and barriers of the CNS · 2021Article
- Brain Disposition of Antibody-Based Therapeutics: Dogma, Approaches and Perspectives.International journal of molecular sciences · 2021Review
- Treatment of Alzheimer's Disease and Blood-Brain Barrier Drug Delivery.Pharmaceuticals (Basel, Switzerland) · 2020Review
- Allosteric inhibition of LRRK2, where are we now.Biochemical Society transactions · 2020Review
- GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies.International journal of molecular sciences · 2020Review
- The Challenge of Modulating Heparan Sulfate Turnover by Multitarget Heparin Derivatives.Molecules (Basel, Switzerland) · 2020Review
- A Blood-Brain-Barrier-Penetrating Anti-human Transferrin Receptor Antibody Fusion Protein for Neuronopathic Mucopolysaccharidosis II.Molecular therapy : the journal of the American Society of Gene Therapy · 2018Article
- Current progress in innovative engineered antibodies.Protein & cell · 2018Review
- Transcytosis to Cross the Blood Brain Barrier, New Advancements and Challenges.Frontiers in neuroscience · 2018Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Hurler's syndrome, or mucopolysaccharidosis type I, is a lysosomal storage disorder caused by mutations in the gene encoding the lysosomal enzyme iduronidase (IDUA). The disease affects both peripheral tissues and the central nervous system (CNS). Recombinant IDUA treatment does not affect the CNS, because IDUA does not cross the blood-brain barrier (BBB). To enable BBB penetration, human IDUA was re-engineered as an IgG-IDUA fusion protein, where the IgG domain is a genetically engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb penetrates the brain from the blood via transport on the endogenous BBB insulin receptor and acts as a molecular Trojan horse to deliver the fused IDUA to the brain. Before human testing, the HIRMAb-IDUA fusion protein was evaluated in a 6-month weekly dosing toxicology study at doses of 0, 3, 9, and 30 mg/kg/week of the fusion protein administered to 40 rhesus monkeys. The focus of the present study is the effect of chronic high dose administration of this fusion protein on plasma glucose and long-term glycemic control. The results show that the HIRMAb has weak insulin agonist activity and causes hypoglycemia at the high dose, 30 mg/kg, after intravenous infusion in normal saline. When dextrose is added to the saline infusion solution, no hypoglycemia is observed at any dose. An intravenous glucose tolerance test performed at the end of the 6 months of chronic treatment showed no change in glucose tolerance at any dose of the HIRMAb-IDUA fusion protein.
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Registered trials
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.