Iduronate-2-Sulfatase with Anti-human Transferrin Receptor Antibody for Neuropathic Mucopolysaccharidosis II: A Phase 1/2 Trial

• Published in: Molecular therapy Vol. 27; no. 2; pp. 456 - 464
• Main Authors: Okuyama, Torayuki, Eto, Yoshikatsu, Sakai, Norio, Minami, Kohtaro, Yamamoto, Tatsuyoshi, Sonoda, Hiroyuki, Yamaoka, Mariko, Tachibana, Katsuhiko, Hirato, Tohru, Sato, Yuji
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.02.2019; Elsevier Limited; American Society of Gene & Cell Therapy
• Subjects: Adolescent; Adult; Airway management; Animal models; Animals; anti-human transferrin receptor antibody; Antibodies - therapeutic use; Biomarkers; Blood-Brain Barrier; Brain; Cerebrospinal fluid; Child; clinical trial; CNS; Cognition; Cognition - drug effects; cognitive impairment; Delirium; dermatan sulfate; Disease Models, Animal; Drug dosages; Enzyme Replacement Therapy; Enzymes; Female; Genetic disorders; Glycosaminoglycans; Heparan sulfate; Humans; Hunter syndrome; Iduronate Sulfatase - genetics; Iduronate Sulfatase - metabolism; iduronate-2-sulfatase; Male; Metabolic disorders; Middle Aged; Mucopolysaccharidosis; mucopolysaccharidosis II; Mucopolysaccharidosis II - drug therapy; Mutation; Neurodegeneration; Original; Patients; Pharmacokinetics; Receptors, Transferrin - antagonists & inhibitors; Transferrins; Urine; Young Adult; blood brain barrier; clinical trial; Hunter syndrome; dermatan sulfate; iduronate-2-sulfatase; heparan sulfate; mucopolysaccharidosis II; CNS; cognitive impairment; anti-human transferrin receptor antibody; enzyme-replacement therapy
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2018.12.005

Hunter syndrome (mucopolysaccharidosis II [MPS II]), a deficiency of iduronate-2-sulfatase (IDS), causes an accumulation of glycosaminoglycans, giving rise to multiple systemic and CNS symptoms. The currently available therapies, idursulfase and idursulfase beta, are ineffective against the CNS symptoms because they cannot pass the blood-brain barrier (BBB). A novel IDS fused with anti-human transferrin receptor antibody (JR-141) has been shown to penetrate the BBB and ameliorate learning deficits in model mice. This first-in-human study evaluated the pharmacokinetics, safety, and potential efficacy of JR-141 in 14 patients with MPS II. In a dose-escalation study performed in two patients, JR-141 plasma concentrations were dose dependent and peaked at 3 hr after initiation of each infusion, and no or only mild adverse reactions were exhibited. In a subsequent 4-week evaluation at two dose levels, the plasma concentration profiles were similar between the first and final administration, indicating no drug accumulation. Levels of heparan sulfate (HS) and dermatan sulfate (DS) were suppressed in both plasma and urine and HS levels were significantly decreased in cerebrospinal fluid. Two patients experienced some amelioration of neurocognitive and motor symptoms. These results suggest that the drug successfully penetrates the BBB and could have CNS efficacy. Okuyama et al. report on a first-in-human study of iduronate-2-sulfatase fused with anti-human transferrin receptor antibody (JR-141) in 14 patients with mucopolysaccharidosis II to evaluate its pharmacokinetics, safety, and potential efficacy. The results show successful penetration of the compound across the blood-brain barrier, suggestive of its effect for neurodegeneration.