Pharmacological property, mechanism of action and clinical study results of Pabinafusp Alfa (Genetical Recombination) (IZCARGO&lt;sup&gt;®&lt;/sup&gt; I.V. Infusion 10 mg) as the therapeutic for Mucopolysaccharidosis type-II (Hunter syndrome)

Yamamoto, Ryûji; Kawashima, Seiichiro

doi:10.1254/fpj.21080

Cited by 13 publications

(9 citation statements)

References 20 publications

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“…The positive effect of the fusion protein in the peripheral end points, i.e., serum HS and liver and spleen volumes, was comparable to that of the IDS enzyme replacement therapy [ 71 ]. Based on this trial, pabinafusp alfa was approved by the Ministry of Health, Labour and Welfare (MHLW) in Japan for the treatment of Hunter MPSII syndrome [ 72 ].…”

Section: Enzyme-igg Fusion Proteinsmentioning

confidence: 99%

IgG Fusion Proteins for Brain Delivery of Biologics via Blood–Brain Barrier Receptor-Mediated Transport

Boado

2022

Pharmaceutics

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The treatment of neurological disorders with large-molecule biotherapeutics requires that the therapeutic drug be transported across the blood–brain barrier (BBB). However, recombinant biotherapeutics, such as neurotrophins, enzymes, decoy receptors, and monoclonal antibodies (MAb), do not cross the BBB. These biotherapeutics can be re-engineered as brain-penetrating bifunctional IgG fusion proteins. These recombinant proteins comprise two domains, the transport domain and the therapeutic domain, respectively. The transport domain is an MAb that acts as a molecular Trojan horse by targeting a BBB-specific endogenous receptor that induces receptor-mediated transcytosis into the brain, such as the human insulin receptor (HIR) or the transferrin receptor (TfR). The therapeutic domain of the IgG fusion protein exerts its pharmacological effect in the brain once across the BBB. A generation of bifunctional IgG fusion proteins has been engineered using genetically engineered MAbs directed to either the BBB HIR or TfR as the transport domain. These IgG fusion proteins were validated in animal models of lysosomal storage disorders; acute brain conditions, such as stroke; or chronic neurodegeneration, such as Parkinson’s disease and Alzheimer’s disease. Human phase I–III clinical trials were also completed for Hurler MPSI and Hunter MPSII using brain-penetrating IgG-iduronidase and -iduronate-2-sulfatase fusion protein, respectively.

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Section: Enzyme-igg Fusion Proteinsmentioning

confidence: 99%

IgG Fusion Proteins for Brain Delivery of Biologics via Blood–Brain Barrier Receptor-Mediated Transport

Boado

2022

Pharmaceutics

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“…Figure 1 illustrates the mechanism of transcytosis mediated by TfRs [46]. Transferrin binds to the TfRs located on the luminal side of the microvascular endothelial cells in the brain and is absorbed into the endothelial cells (endocytosis), in which it is then transported towards the abluminal side of the cells facing the brain, and subsequently released from the receptors to reach the brain parenchyma (exocytosis).…”

Section: Application Of Receptor-mediated Transcytosis For Brain Drug...mentioning

confidence: 99%

Treatment of Neuronopathic Mucopolysaccharidoses with Blood–Brain Barrier-Crossing Enzymes: Clinical Application of Receptor-Mediated Transcytosis

et al. 2022

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Enzyme replacement therapy (ERT) has paved the way for treating the somatic symptoms of lysosomal storage diseases (LSDs), but the inability of intravenously administered enzymes to cross the blood–brain barrier (BBB) has left the central nervous system (CNS)-related symptoms of LSDs largely impervious to the therapeutic benefits of ERT, although ERT via intrathecal and intracerebroventricular routes can be used for some neuronopathic LSDs (in particular, mucopolysaccharidoses). However, the considerable practical issues involved make these routes unsuitable for long-term treatment. Efforts have been made to modify enzymes (e.g., by fusing them with antibodies against innate receptors on the cerebrovascular endothelium) so that they can cross the BBB via receptor-mediated transcytosis (RMT) and address neuronopathy in the CNS. This review summarizes the various scientific and technological challenges of applying RMT to the development of safe and effective enzyme therapeutics for neuronopathic mucopolysaccharidoses; it then discusses the translational and methodological issues surrounding preclinical and clinical evaluation to establish RMT-applied ERT.

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“…The results of a phase II study in Brazil also showed decreased CSF HS levels after treatment with pabinafusp alfa along with positive neurocognitive changes despite a short study period of 26 weeks [ 111 ]. Idursulfase, a recombinant IDS that does not cross the BBB, failed to decrease CSF HS concentrations and provided no neurocognitive benefits in patients with MPS II [ 144 , 145 ]. Intriguingly, CSF HS levels in the patients that participated in the clinical study increased after switching from pabinafusp alfa treatment to idursulfase treatment as standard therapy in the interim period but decreased again with the resumption of pabinafusp alfa in the next trial ( Figure 6 ) [ 145 ].…”

Section: Hs As a Biomarker For Mpssmentioning

confidence: 99%

“…Idursulfase, a recombinant IDS that does not cross the BBB, failed to decrease CSF HS concentrations and provided no neurocognitive benefits in patients with MPS II [ 144 , 145 ]. Intriguingly, CSF HS levels in the patients that participated in the clinical study increased after switching from pabinafusp alfa treatment to idursulfase treatment as standard therapy in the interim period but decreased again with the resumption of pabinafusp alfa in the next trial ( Figure 6 ) [ 145 ]. The results demonstrate the capacity of pabinafusp alfa to reduce CSF HS concentrations via drug delivery through the BBB into the brain.…”

Section: Hs As a Biomarker For Mpssmentioning

confidence: 99%

Pathogenic Roles of Heparan Sulfate and Its Use as a Biomarker in Mucopolysaccharidoses

Minami

Morimoto

Morioka

et al. 2022

IJMS

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Heparan sulfate (HS) is an essential glycosaminoglycan (GAG) as a component of proteoglycans, which are present on the cell surface and in the extracellular matrix. HS-containing proteoglycans not only function as structural constituents of the basal lamina but also play versatile roles in various physiological processes, including cell signaling and organ development. Thus, inherited mutations of genes associated with the biosynthesis or degradation of HS can cause various diseases, particularly those involving the bones and central nervous system (CNS). Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders involving GAG accumulation throughout the body caused by a deficiency of GAG-degrading enzymes. GAGs are stored differently in different types of MPSs. Particularly, HS deposition is observed in patients with MPS types I, II, III, and VII, all which involve progressive neuropathy with multiple CNS system symptoms. While therapies are available for certain symptoms in some types of MPSs, significant unmet medical needs remain, such as neurocognitive impairment. This review presents recent knowledge on the pathophysiological roles of HS focusing on the pathogenesis of MPSs. We also discuss the possible use and significance of HS as a biomarker for disease severity and therapeutic response in MPSs.

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Pharmacological property, mechanism of action and clinical study results of Pabinafusp Alfa (Genetical Recombination) (IZCARGO<sup>®</sup> I.V. Infusion 10 mg) as the therapeutic for Mucopolysaccharidosis type-II (Hunter syndrome)

Cited by 13 publications

References 20 publications

IgG Fusion Proteins for Brain Delivery of Biologics via Blood–Brain Barrier Receptor-Mediated Transport

IgG Fusion Proteins for Brain Delivery of Biologics via Blood–Brain Barrier Receptor-Mediated Transport

Treatment of Neuronopathic Mucopolysaccharidoses with Blood–Brain Barrier-Crossing Enzymes: Clinical Application of Receptor-Mediated Transcytosis

Pathogenic Roles of Heparan Sulfate and Its Use as a Biomarker in Mucopolysaccharidoses

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