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Characterization of a HIR-Fab-IDS, Novel Iduronate 2-Sulfatase Fusion Protein for the Treatment of Neuropathic Mucopolysaccharidosis Type II (Hunter Syndrome)

Background Mucopolysaccharidosis type II is a severe lysosomal storage disease caused by deficient activity of the enzyme iduronate-2-sulfatase. The only medicinal product approved by the US Food and Drug Administration for enzyme replacement therapy, recombinant iduronate-2-sulfatase (idursulfase,...

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Published in:BioDrugs : clinical immunotherapeutics, biopharmaceuticals, and gene therapy biopharmaceuticals, and gene therapy, 2023-05, Vol.37 (3), p.375-395
Main Authors: Gusarova, Valentina D., Smolov, Maxim A., Lyagoskin, Ivan V., Degterev, Maksim B., Rechetnik, Elizaveta V., Rodionov, Alexander V., Pantyushenko, Marina S., Shukurov, Rahim R.
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container_title BioDrugs : clinical immunotherapeutics, biopharmaceuticals, and gene therapy
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creator Gusarova, Valentina D.
Smolov, Maxim A.
Lyagoskin, Ivan V.
Degterev, Maksim B.
Rechetnik, Elizaveta V.
Rodionov, Alexander V.
Pantyushenko, Marina S.
Shukurov, Rahim R.
description Background Mucopolysaccharidosis type II is a severe lysosomal storage disease caused by deficient activity of the enzyme iduronate-2-sulfatase. The only medicinal product approved by the US Food and Drug Administration for enzyme replacement therapy, recombinant iduronate-2-sulfatase (idursulfase, Elaprase ® ), is a large molecule that is not able to cross the blood–brain barrier and neutralize progressive damage of the central nervous system caused by the accumulation of glycosaminoglycans. Novel chimeric protein HIR-Fab-IDS is an anti-human insulin receptor Fab fragment fused to recombinant modified iduronate-2-sulfatase. This modification provides a highly selective interaction with the human insulin receptor, which leads to the HIR-Fab-IDS crossing the blood–brain barrier owing to internalization of the hybrid molecule by transcytosis into endothelial cells adjacent to the nervous system by the principle of a ‘molecular Trojan horse’. Objectives In this work, the physicochemical and biological characterization of a blood–brain barrier-penetrating fusion protein, HIR-Fab-IDS, is carried out. HIR-Fab-IDS consists of an anti-human insulin receptor Fab fragment fused to recombinant iduronate-2-sulfatase. Methods Comprehensive analytical characterization utilizing modern techniques (including surface plasmon resonance and mass spectrometry) was performed using preclinical and clinical batches of HIR-Fab-IDS. Critical quality parameters that determine the therapeutic effect of iduronate-2-sulfatase, as well as IDS enzymatic activity and in vitro cell uptake activity were evaluated in comparison with the marketed IDS product Elaprase ® (IDS RP). In vivo efficiency of HIR-Fab-IDS in reversing mucopolysaccharidosis type II pathology in IDS-deficient mice was also investigated. The affinity of the chimeric molecule for the INSR was also determined by both an enzyme-linked immunosorbent assay and surface plasmon resonance. We also compared the distribution of 125 I-radiolabeled HIR-Fab-IDS and IDS RP in the tissues and brain of cynomolgus monkeys after intravenous administration. Results The HIR-Fab-IDS primary structure investigation showed no significant post-translational modifications that could affect IDS activity, except for the formylglycine content, which was significantly higher for HIR-Fab-IDS compared with that for IDS RP (~ 76.5 vs ~ 67.7%). Because of this fact, the specific enzyme activity of HIR-Fab-IDS was slightly higher than that of IDS RP (~ 2
doi_str_mv 10.1007/s40259-023-00590-w
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The only medicinal product approved by the US Food and Drug Administration for enzyme replacement therapy, recombinant iduronate-2-sulfatase (idursulfase, Elaprase ® ), is a large molecule that is not able to cross the blood–brain barrier and neutralize progressive damage of the central nervous system caused by the accumulation of glycosaminoglycans. Novel chimeric protein HIR-Fab-IDS is an anti-human insulin receptor Fab fragment fused to recombinant modified iduronate-2-sulfatase. This modification provides a highly selective interaction with the human insulin receptor, which leads to the HIR-Fab-IDS crossing the blood–brain barrier owing to internalization of the hybrid molecule by transcytosis into endothelial cells adjacent to the nervous system by the principle of a ‘molecular Trojan horse’. Objectives In this work, the physicochemical and biological characterization of a blood–brain barrier-penetrating fusion protein, HIR-Fab-IDS, is carried out. HIR-Fab-IDS consists of an anti-human insulin receptor Fab fragment fused to recombinant iduronate-2-sulfatase. Methods Comprehensive analytical characterization utilizing modern techniques (including surface plasmon resonance and mass spectrometry) was performed using preclinical and clinical batches of HIR-Fab-IDS. Critical quality parameters that determine the therapeutic effect of iduronate-2-sulfatase, as well as IDS enzymatic activity and in vitro cell uptake activity were evaluated in comparison with the marketed IDS product Elaprase ® (IDS RP). In vivo efficiency of HIR-Fab-IDS in reversing mucopolysaccharidosis type II pathology in IDS-deficient mice was also investigated. The affinity of the chimeric molecule for the INSR was also determined by both an enzyme-linked immunosorbent assay and surface plasmon resonance. We also compared the distribution of 125 I-radiolabeled HIR-Fab-IDS and IDS RP in the tissues and brain of cynomolgus monkeys after intravenous administration. Results The HIR-Fab-IDS primary structure investigation showed no significant post-translational modifications that could affect IDS activity, except for the formylglycine content, which was significantly higher for HIR-Fab-IDS compared with that for IDS RP (~ 76.5 vs ~ 67.7%). Because of this fact, the specific enzyme activity of HIR-Fab-IDS was slightly higher than that of IDS RP (~ 2.73 × 10 6  U/μmol vs ~ 2.16 × 10 6  U/μmol). However, differences were found in the glycosylation patterns of the compared IDS products, causing a minor reduced in vitro cellular uptake of HIR-Fab-IDS by mucopolysaccharidosis type II fibroblasts compared with IDS RP (half-maximal effective concentration ~ 26.0 vs ~ 23.0 nM). The efficacy of HIR-Fab-IDS in IDS-deficient mice has demonstrated a statistically significant reduction in the level of glycosaminoglycans in the urine and tissues of the main organs to the level of healthy animals. The HIR-Fab-IDS has revealed high in vitro affinity for human and monkey insulin receptors, and the radioactively labeled product has been shown to penetrate to all parts of the brain and peripheral tissues after intravenous administration to cynomolgus monkeys. Conclusions These findings indicate that HIR-Fab-IDS, a novel iduronate-2-sulfatase fusion protein, is a promising candidate for the treatment of central nervous system manifestations in neurological mucopolysaccharidosis type II.</description><identifier>ISSN: 1173-8804</identifier><identifier>EISSN: 1179-190X</identifier><identifier>DOI: 10.1007/s40259-023-00590-w</identifier><identifier>PMID: 37014547</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Affinity ; Amino acid sequence ; Animals ; Antibodies ; Biomedical and Life Sciences ; Biomedicine ; Blood-brain barrier ; Cancer Research ; Central nervous system ; Disease ; Endothelial cells ; Endothelial Cells - metabolism ; Enzymatic activity ; Enzyme-linked immunosorbent assay ; Enzymes ; Fibroblasts ; Fusion protein ; Genetic disorders ; Glycosaminoglycans ; Glycosaminoglycans - metabolism ; Glycosaminoglycans - therapeutic use ; Glycosylation ; Humans ; Iduronic Acid ; Insulin ; Insulin receptors ; Internalization ; Intravenous administration ; Investigations ; Lysosomal storage diseases ; Macaca fascicularis - metabolism ; Mass spectrometry ; Mass spectroscopy ; Metabolic disorders ; Mice ; Molecular Medicine ; Monoclonal antibodies ; Mucopolysaccharidosis ; Mucopolysaccharidosis II - drug therapy ; Nervous system ; Original Research Article ; Peptides ; Pharmaceuticals ; Pharmacotherapy ; Post-translation ; Proteins ; Reagents ; Receptor, Insulin ; Recombinant Proteins - therapeutic use ; Scientific imaging ; Statistical analysis ; Surface plasmon resonance ; United States</subject><ispartof>BioDrugs : clinical immunotherapeutics, biopharmaceuticals, and gene therapy, 2023-05, Vol.37 (3), p.375-395</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Switzerland AG 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><rights>2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.</rights><rights>Copyright Springer Nature B.V. May 2023</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c326t-5383a9d3983a5c62cafa70264d33b4c81d06adc1d16a2e5df550077dadb406c23</cites><orcidid>0000-0001-7540-602X ; 0000-0002-6532-7835 ; 0000-0002-5541-5575 ; 0000-0002-9058-1106 ; 0000-0003-2935-7655</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27922,27923</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37014547$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gusarova, Valentina D.</creatorcontrib><creatorcontrib>Smolov, Maxim A.</creatorcontrib><creatorcontrib>Lyagoskin, Ivan V.</creatorcontrib><creatorcontrib>Degterev, Maksim B.</creatorcontrib><creatorcontrib>Rechetnik, Elizaveta V.</creatorcontrib><creatorcontrib>Rodionov, Alexander V.</creatorcontrib><creatorcontrib>Pantyushenko, Marina S.</creatorcontrib><creatorcontrib>Shukurov, Rahim R.</creatorcontrib><title>Characterization of a HIR-Fab-IDS, Novel Iduronate 2-Sulfatase Fusion Protein for the Treatment of Neuropathic Mucopolysaccharidosis Type II (Hunter Syndrome)</title><title>BioDrugs : clinical immunotherapeutics, biopharmaceuticals, and gene therapy</title><addtitle>BioDrugs</addtitle><addtitle>BioDrugs</addtitle><description>Background Mucopolysaccharidosis type II is a severe lysosomal storage disease caused by deficient activity of the enzyme iduronate-2-sulfatase. The only medicinal product approved by the US Food and Drug Administration for enzyme replacement therapy, recombinant iduronate-2-sulfatase (idursulfase, Elaprase ® ), is a large molecule that is not able to cross the blood–brain barrier and neutralize progressive damage of the central nervous system caused by the accumulation of glycosaminoglycans. Novel chimeric protein HIR-Fab-IDS is an anti-human insulin receptor Fab fragment fused to recombinant modified iduronate-2-sulfatase. This modification provides a highly selective interaction with the human insulin receptor, which leads to the HIR-Fab-IDS crossing the blood–brain barrier owing to internalization of the hybrid molecule by transcytosis into endothelial cells adjacent to the nervous system by the principle of a ‘molecular Trojan horse’. Objectives In this work, the physicochemical and biological characterization of a blood–brain barrier-penetrating fusion protein, HIR-Fab-IDS, is carried out. HIR-Fab-IDS consists of an anti-human insulin receptor Fab fragment fused to recombinant iduronate-2-sulfatase. Methods Comprehensive analytical characterization utilizing modern techniques (including surface plasmon resonance and mass spectrometry) was performed using preclinical and clinical batches of HIR-Fab-IDS. Critical quality parameters that determine the therapeutic effect of iduronate-2-sulfatase, as well as IDS enzymatic activity and in vitro cell uptake activity were evaluated in comparison with the marketed IDS product Elaprase ® (IDS RP). In vivo efficiency of HIR-Fab-IDS in reversing mucopolysaccharidosis type II pathology in IDS-deficient mice was also investigated. The affinity of the chimeric molecule for the INSR was also determined by both an enzyme-linked immunosorbent assay and surface plasmon resonance. We also compared the distribution of 125 I-radiolabeled HIR-Fab-IDS and IDS RP in the tissues and brain of cynomolgus monkeys after intravenous administration. Results The HIR-Fab-IDS primary structure investigation showed no significant post-translational modifications that could affect IDS activity, except for the formylglycine content, which was significantly higher for HIR-Fab-IDS compared with that for IDS RP (~ 76.5 vs ~ 67.7%). Because of this fact, the specific enzyme activity of HIR-Fab-IDS was slightly higher than that of IDS RP (~ 2.73 × 10 6  U/μmol vs ~ 2.16 × 10 6  U/μmol). However, differences were found in the glycosylation patterns of the compared IDS products, causing a minor reduced in vitro cellular uptake of HIR-Fab-IDS by mucopolysaccharidosis type II fibroblasts compared with IDS RP (half-maximal effective concentration ~ 26.0 vs ~ 23.0 nM). The efficacy of HIR-Fab-IDS in IDS-deficient mice has demonstrated a statistically significant reduction in the level of glycosaminoglycans in the urine and tissues of the main organs to the level of healthy animals. The HIR-Fab-IDS has revealed high in vitro affinity for human and monkey insulin receptors, and the radioactively labeled product has been shown to penetrate to all parts of the brain and peripheral tissues after intravenous administration to cynomolgus monkeys. Conclusions These findings indicate that HIR-Fab-IDS, a novel iduronate-2-sulfatase fusion protein, is a promising candidate for the treatment of central nervous system manifestations in neurological mucopolysaccharidosis type II.</description><subject>Affinity</subject><subject>Amino acid sequence</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Blood-brain barrier</subject><subject>Cancer Research</subject><subject>Central nervous system</subject><subject>Disease</subject><subject>Endothelial cells</subject><subject>Endothelial Cells - metabolism</subject><subject>Enzymatic activity</subject><subject>Enzyme-linked immunosorbent assay</subject><subject>Enzymes</subject><subject>Fibroblasts</subject><subject>Fusion protein</subject><subject>Genetic disorders</subject><subject>Glycosaminoglycans</subject><subject>Glycosaminoglycans - metabolism</subject><subject>Glycosaminoglycans - therapeutic use</subject><subject>Glycosylation</subject><subject>Humans</subject><subject>Iduronic Acid</subject><subject>Insulin</subject><subject>Insulin receptors</subject><subject>Internalization</subject><subject>Intravenous administration</subject><subject>Investigations</subject><subject>Lysosomal storage diseases</subject><subject>Macaca fascicularis - metabolism</subject><subject>Mass spectrometry</subject><subject>Mass spectroscopy</subject><subject>Metabolic disorders</subject><subject>Mice</subject><subject>Molecular Medicine</subject><subject>Monoclonal antibodies</subject><subject>Mucopolysaccharidosis</subject><subject>Mucopolysaccharidosis II - drug therapy</subject><subject>Nervous system</subject><subject>Original Research Article</subject><subject>Peptides</subject><subject>Pharmaceuticals</subject><subject>Pharmacotherapy</subject><subject>Post-translation</subject><subject>Proteins</subject><subject>Reagents</subject><subject>Receptor, Insulin</subject><subject>Recombinant Proteins - therapeutic use</subject><subject>Scientific imaging</subject><subject>Statistical analysis</subject><subject>Surface plasmon resonance</subject><subject>United States</subject><issn>1173-8804</issn><issn>1179-190X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNp9kd1u1DAQhSMEoqXwAlwgS9wUCYN_4vxcVgvLRioFsYvEnTVrT9hUSRxsh2p5GJ4Vb7eAxAVXM9J858xoTpY95ewVZ6x8HXImVE2ZkJQxVTN6cy875bysKa_Zl_u3vaRVxfKT7FEI14yxQtblw-xEloznKi9Ps5-LHXgwEX33A2LnRuJaAmTVfKJL2NLmzfoluXLfsSeNnb0bISIRdD33LUQISJZzOIg-ehexG0nrPIk7JBuPEAcc48HuCpNygrjrDHk_Gze5fh_AmLS5sy50gWz2E5KmIeereUynkPV-tN4N-OJx9qCFPuCTu3qWfV6-3SxW9PLDu2ZxcUmNFEWkSlYSaivrVJQphIEWSiaK3Eq5zU3FLSvAGm55AQKVbZVKDywt2G3OCiPkWXZ-9J28-zZjiHrogsG-hxHdHLQoayVVlSwT-vwf9NrNfkzXaVHxqi6UqA6UOFLGuxA8tnry3QB-rznTh_T0MT2d0tO36embJHp2Zz1vB7R_JL_jSoA8AiGNxq_o_-7-j-0v0K6mgA</recordid><startdate>20230501</startdate><enddate>20230501</enddate><creator>Gusarova, Valentina D.</creator><creator>Smolov, Maxim A.</creator><creator>Lyagoskin, Ivan V.</creator><creator>Degterev, Maksim B.</creator><creator>Rechetnik, Elizaveta V.</creator><creator>Rodionov, Alexander V.</creator><creator>Pantyushenko, Marina S.</creator><creator>Shukurov, Rahim R.</creator><general>Springer International Publishing</general><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>4T-</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-7540-602X</orcidid><orcidid>https://orcid.org/0000-0002-6532-7835</orcidid><orcidid>https://orcid.org/0000-0002-5541-5575</orcidid><orcidid>https://orcid.org/0000-0002-9058-1106</orcidid><orcidid>https://orcid.org/0000-0003-2935-7655</orcidid></search><sort><creationdate>20230501</creationdate><title>Characterization of a HIR-Fab-IDS, Novel Iduronate 2-Sulfatase Fusion Protein for the Treatment of Neuropathic Mucopolysaccharidosis Type II (Hunter Syndrome)</title><author>Gusarova, Valentina D. ; Smolov, Maxim A. ; Lyagoskin, Ivan V. ; Degterev, Maksim B. ; Rechetnik, Elizaveta V. ; Rodionov, Alexander V. ; Pantyushenko, Marina S. ; Shukurov, Rahim R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c326t-5383a9d3983a5c62cafa70264d33b4c81d06adc1d16a2e5df550077dadb406c23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Affinity</topic><topic>Amino acid sequence</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Blood-brain barrier</topic><topic>Cancer Research</topic><topic>Central nervous system</topic><topic>Disease</topic><topic>Endothelial cells</topic><topic>Endothelial Cells - metabolism</topic><topic>Enzymatic activity</topic><topic>Enzyme-linked immunosorbent assay</topic><topic>Enzymes</topic><topic>Fibroblasts</topic><topic>Fusion protein</topic><topic>Genetic disorders</topic><topic>Glycosaminoglycans</topic><topic>Glycosaminoglycans - metabolism</topic><topic>Glycosaminoglycans - therapeutic use</topic><topic>Glycosylation</topic><topic>Humans</topic><topic>Iduronic Acid</topic><topic>Insulin</topic><topic>Insulin receptors</topic><topic>Internalization</topic><topic>Intravenous administration</topic><topic>Investigations</topic><topic>Lysosomal storage diseases</topic><topic>Macaca fascicularis - metabolism</topic><topic>Mass spectrometry</topic><topic>Mass spectroscopy</topic><topic>Metabolic disorders</topic><topic>Mice</topic><topic>Molecular Medicine</topic><topic>Monoclonal antibodies</topic><topic>Mucopolysaccharidosis</topic><topic>Mucopolysaccharidosis II - drug therapy</topic><topic>Nervous system</topic><topic>Original Research Article</topic><topic>Peptides</topic><topic>Pharmaceuticals</topic><topic>Pharmacotherapy</topic><topic>Post-translation</topic><topic>Proteins</topic><topic>Reagents</topic><topic>Receptor, Insulin</topic><topic>Recombinant Proteins - therapeutic use</topic><topic>Scientific imaging</topic><topic>Statistical analysis</topic><topic>Surface plasmon resonance</topic><topic>United States</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gusarova, Valentina D.</creatorcontrib><creatorcontrib>Smolov, Maxim A.</creatorcontrib><creatorcontrib>Lyagoskin, Ivan V.</creatorcontrib><creatorcontrib>Degterev, Maksim B.</creatorcontrib><creatorcontrib>Rechetnik, Elizaveta V.</creatorcontrib><creatorcontrib>Rodionov, Alexander V.</creatorcontrib><creatorcontrib>Pantyushenko, Marina S.</creatorcontrib><creatorcontrib>Shukurov, Rahim R.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Docstoc</collection><collection>Immunology Abstracts</collection><collection>Health &amp; 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The only medicinal product approved by the US Food and Drug Administration for enzyme replacement therapy, recombinant iduronate-2-sulfatase (idursulfase, Elaprase ® ), is a large molecule that is not able to cross the blood–brain barrier and neutralize progressive damage of the central nervous system caused by the accumulation of glycosaminoglycans. Novel chimeric protein HIR-Fab-IDS is an anti-human insulin receptor Fab fragment fused to recombinant modified iduronate-2-sulfatase. This modification provides a highly selective interaction with the human insulin receptor, which leads to the HIR-Fab-IDS crossing the blood–brain barrier owing to internalization of the hybrid molecule by transcytosis into endothelial cells adjacent to the nervous system by the principle of a ‘molecular Trojan horse’. Objectives In this work, the physicochemical and biological characterization of a blood–brain barrier-penetrating fusion protein, HIR-Fab-IDS, is carried out. HIR-Fab-IDS consists of an anti-human insulin receptor Fab fragment fused to recombinant iduronate-2-sulfatase. Methods Comprehensive analytical characterization utilizing modern techniques (including surface plasmon resonance and mass spectrometry) was performed using preclinical and clinical batches of HIR-Fab-IDS. Critical quality parameters that determine the therapeutic effect of iduronate-2-sulfatase, as well as IDS enzymatic activity and in vitro cell uptake activity were evaluated in comparison with the marketed IDS product Elaprase ® (IDS RP). In vivo efficiency of HIR-Fab-IDS in reversing mucopolysaccharidosis type II pathology in IDS-deficient mice was also investigated. The affinity of the chimeric molecule for the INSR was also determined by both an enzyme-linked immunosorbent assay and surface plasmon resonance. We also compared the distribution of 125 I-radiolabeled HIR-Fab-IDS and IDS RP in the tissues and brain of cynomolgus monkeys after intravenous administration. Results The HIR-Fab-IDS primary structure investigation showed no significant post-translational modifications that could affect IDS activity, except for the formylglycine content, which was significantly higher for HIR-Fab-IDS compared with that for IDS RP (~ 76.5 vs ~ 67.7%). Because of this fact, the specific enzyme activity of HIR-Fab-IDS was slightly higher than that of IDS RP (~ 2.73 × 10 6  U/μmol vs ~ 2.16 × 10 6  U/μmol). However, differences were found in the glycosylation patterns of the compared IDS products, causing a minor reduced in vitro cellular uptake of HIR-Fab-IDS by mucopolysaccharidosis type II fibroblasts compared with IDS RP (half-maximal effective concentration ~ 26.0 vs ~ 23.0 nM). The efficacy of HIR-Fab-IDS in IDS-deficient mice has demonstrated a statistically significant reduction in the level of glycosaminoglycans in the urine and tissues of the main organs to the level of healthy animals. The HIR-Fab-IDS has revealed high in vitro affinity for human and monkey insulin receptors, and the radioactively labeled product has been shown to penetrate to all parts of the brain and peripheral tissues after intravenous administration to cynomolgus monkeys. Conclusions These findings indicate that HIR-Fab-IDS, a novel iduronate-2-sulfatase fusion protein, is a promising candidate for the treatment of central nervous system manifestations in neurological mucopolysaccharidosis type II.</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>37014547</pmid><doi>10.1007/s40259-023-00590-w</doi><tpages>21</tpages><orcidid>https://orcid.org/0000-0001-7540-602X</orcidid><orcidid>https://orcid.org/0000-0002-6532-7835</orcidid><orcidid>https://orcid.org/0000-0002-5541-5575</orcidid><orcidid>https://orcid.org/0000-0002-9058-1106</orcidid><orcidid>https://orcid.org/0000-0003-2935-7655</orcidid></addata></record>
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identifier ISSN: 1173-8804
ispartof BioDrugs : clinical immunotherapeutics, biopharmaceuticals, and gene therapy, 2023-05, Vol.37 (3), p.375-395
issn 1173-8804
1179-190X
language eng
recordid cdi_proquest_miscellaneous_2795358026
source Springer Nature
subjects Affinity
Amino acid sequence
Animals
Antibodies
Biomedical and Life Sciences
Biomedicine
Blood-brain barrier
Cancer Research
Central nervous system
Disease
Endothelial cells
Endothelial Cells - metabolism
Enzymatic activity
Enzyme-linked immunosorbent assay
Enzymes
Fibroblasts
Fusion protein
Genetic disorders
Glycosaminoglycans
Glycosaminoglycans - metabolism
Glycosaminoglycans - therapeutic use
Glycosylation
Humans
Iduronic Acid
Insulin
Insulin receptors
Internalization
Intravenous administration
Investigations
Lysosomal storage diseases
Macaca fascicularis - metabolism
Mass spectrometry
Mass spectroscopy
Metabolic disorders
Mice
Molecular Medicine
Monoclonal antibodies
Mucopolysaccharidosis
Mucopolysaccharidosis II - drug therapy
Nervous system
Original Research Article
Peptides
Pharmaceuticals
Pharmacotherapy
Post-translation
Proteins
Reagents
Receptor, Insulin
Recombinant Proteins - therapeutic use
Scientific imaging
Statistical analysis
Surface plasmon resonance
United States
title Characterization of a HIR-Fab-IDS, Novel Iduronate 2-Sulfatase Fusion Protein for the Treatment of Neuropathic Mucopolysaccharidosis Type II (Hunter Syndrome)
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