Relationship between MAN2B1 genotype/subcellular localization subgroups, antidrug antibody detection, and long‐term velmanase alfa treatment outcomes in patients with alpha‐mannosidosis
Alpha‐mannosidosis (AM), an autosomal recessive disorder caused by pathogenic biallelic variants in the MAN2B1 gene, leads to lysosomal alpha‐mannosidase deficiency and accumulation of mannose‐rich oligosaccharides. Velmanase alfa (VA), a recombinant human lysosomal alpha‐mannosidase, is the first e...
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| Published in | JIMD reports Vol. 64; no. 2; pp. 187 - 198 |
|---|---|
| Main Authors | , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Hoboken, USA
John Wiley & Sons, Inc
01.03.2023
Wiley |
| Subjects | |
| Online Access | Get full text |
| ISSN | 2192-8312 2192-8304 2192-8312 |
| DOI | 10.1002/jmd2.12349 |
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| Abstract | Alpha‐mannosidosis (AM), an autosomal recessive disorder caused by pathogenic biallelic variants in the MAN2B1 gene, leads to lysosomal alpha‐mannosidase deficiency and accumulation of mannose‐rich oligosaccharides. Velmanase alfa (VA), a recombinant human lysosomal alpha‐mannosidase, is the first enzyme replacement therapy for non‐neurological symptoms of AM. Previously, a potential relationship was identified between three MAN2B1 genotype/subcellular localization subgroups (G1, G2, and G3) and AM disease severity. In VA‐treated patients with AM, it is unknown if a relationship exists between MAN2B1 genotype/subcellular localization subgroups, antidrug antibodies (ADAs), and infusion‐related reactions (IRRs). This pooled analysis evaluated data from 33 VA‐treated patients with AM to investigate this relationship. Overall, 10 patients were positive for ADAs, 4 of whom had treatment‐emergent ADAs (G1: 3/7 [43%]; G2: 1/17 [6%]; G3: 0/9). Treatment‐emergent ADA‐positive patients with relatively high titers (n = 2; G1: 1012 U/ml and G2: 440 U/ml) experienced mild/moderate IRRs that were well‐managed; patients with lower titers (n = 2) experienced no IRRs. Overall, changes from baseline in serum oligosaccharides and immunoglobulin G levels did not vary between ADA‐positive and ADA‐negative patients, suggesting a similar effect of VA treatment regardless of ADA status in most patients. Clinical outcomes (3MSCT and 6MWT) were also similar in most patients regardless of ADA status. While further studies are needed, these data suggest a relationship between MAN2B1 genotype/subcellular localization subgroups and ADA development, with G1 and G2 subgroups more likely to develop ADAs and IRRs. Regardless, this study suggests that ADAs have limited effect on the clinical impact of VA in most patients with AM. |
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| AbstractList | Alpha-mannosidosis (AM), an autosomal recessive disorder caused by pathogenic biallelic variants in the MAN2B1 gene, leads to lysosomal alpha-mannosidase deficiency and accumulation of mannose-rich oligosaccharides. Velmanase alfa (VA), a recombinant human lysosomal alpha-mannosidase, is the first enzyme replacement therapy for non-neurological symptoms of AM. Previously, a potential relationship was identified between three MAN2B1 genotype/subcellular localization subgroups (G1, G2, and G3) and AM disease severity. In VA-treated patients with AM, it is unknown if a relationship exists between MAN2B1 genotype/subcellular localization subgroups, antidrug antibodies (ADAs), and infusion-related reactions (IRRs). This pooled analysis evaluated data from 33 VA-treated patients with AM to investigate this relationship. Overall, 10 patients were positive for ADAs, 4 of whom had treatment-emergent ADAs (G1: 3/7 [43%]; G2: 1/17 [6%]; G3: 0/9). Treatment-emergent ADA-positive patients with relatively high titers (n = 2; G1: 1012 U/ml and G2: 440 U/ml) experienced mild/moderate IRRs that were well-managed; patients with lower titers (n = 2) experienced no IRRs. Overall, changes from baseline in serum oligosaccharides and immunoglobulin G levels did not vary between ADA-positive and ADA-negative patients, suggesting a similar effect of VA treatment regardless of ADA status in most patients. Clinical outcomes (3MSCT and 6MWT) were also similar in most patients regardless of ADA status. While further studies are needed, these data suggest a relationship between MAN2B1 genotype/subcellular localization subgroups and ADA development, with G1 and G2 subgroups more likely to develop ADAs and IRRs. Regardless, this study suggests that ADAs have limited effect on the clinical impact of VA in most patients with AM.Alpha-mannosidosis (AM), an autosomal recessive disorder caused by pathogenic biallelic variants in the MAN2B1 gene, leads to lysosomal alpha-mannosidase deficiency and accumulation of mannose-rich oligosaccharides. Velmanase alfa (VA), a recombinant human lysosomal alpha-mannosidase, is the first enzyme replacement therapy for non-neurological symptoms of AM. Previously, a potential relationship was identified between three MAN2B1 genotype/subcellular localization subgroups (G1, G2, and G3) and AM disease severity. In VA-treated patients with AM, it is unknown if a relationship exists between MAN2B1 genotype/subcellular localization subgroups, antidrug antibodies (ADAs), and infusion-related reactions (IRRs). This pooled analysis evaluated data from 33 VA-treated patients with AM to investigate this relationship. Overall, 10 patients were positive for ADAs, 4 of whom had treatment-emergent ADAs (G1: 3/7 [43%]; G2: 1/17 [6%]; G3: 0/9). Treatment-emergent ADA-positive patients with relatively high titers (n = 2; G1: 1012 U/ml and G2: 440 U/ml) experienced mild/moderate IRRs that were well-managed; patients with lower titers (n = 2) experienced no IRRs. Overall, changes from baseline in serum oligosaccharides and immunoglobulin G levels did not vary between ADA-positive and ADA-negative patients, suggesting a similar effect of VA treatment regardless of ADA status in most patients. Clinical outcomes (3MSCT and 6MWT) were also similar in most patients regardless of ADA status. While further studies are needed, these data suggest a relationship between MAN2B1 genotype/subcellular localization subgroups and ADA development, with G1 and G2 subgroups more likely to develop ADAs and IRRs. Regardless, this study suggests that ADAs have limited effect on the clinical impact of VA in most patients with AM. Alpha-mannosidosis (AM), an autosomal recessive disorder caused by pathogenic biallelic variants in the MAN2B1 gene, leads to lysosomal alpha-mannosidase deficiency and accumulation of mannose-rich oligosaccharides. Velmanase alfa (VA), a recombinant human lysosomal alpha-mannosidase, is the first enzyme replacement therapy for non-neurological symptoms of AM. Previously, a potential relationship was identified between three MAN2B1 genotype/subcellular localization subgroups (G1, G2, and G3) and AM disease severity. In VA-treated patients with AM, it is unknown if a relationship exists between MAN2B1 genotype/subcellular localization subgroups, antidrug antibodies (ADAs), and infusion-related reactions (IRRs). This pooled analysis evaluated data from 33 VA-treated patients with AM to investigate this relationship. Overall, 10 patients were positive for ADAs, 4 of whom had treatment-emergent ADAs (G1: 3/7 [43%]; G2: 1/17 [6%]; G3: 0/9). Treatment-emergent ADA-positive patients with relatively high titers (n = 2; G1: 1012 U/ml and G2: 440 U/ml) experienced mild/moderate IRRs that were well-managed; patients with lower titers (n = 2) experienced no IRRs. Overall, changes from baseline in serum oligosaccharides and immunoglobulin G levels did not vary between ADA-positive and ADA-negative patients, suggesting a similar effect of VA treatment regardless of ADA status in most patients. Clinical outcomes (3MSCT and 6MWT) were also similar in most patients regardless of ADA status. While further studies are needed, these data suggest a relationship between MAN2B1 genotype/subcellular localization subgroups and ADA development, with G1 and G2 subgroups more likely to develop ADAs and IRRs. Regardless, this study suggests that ADAs have limited effect on the clinical impact of VA in most patients with AM. Abstract Alpha‐mannosidosis (AM), an autosomal recessive disorder caused by pathogenic biallelic variants in the MAN2B1 gene, leads to lysosomal alpha‐mannosidase deficiency and accumulation of mannose‐rich oligosaccharides. Velmanase alfa (VA), a recombinant human lysosomal alpha‐mannosidase, is the first enzyme replacement therapy for non‐neurological symptoms of AM. Previously, a potential relationship was identified between three MAN2B1 genotype/subcellular localization subgroups (G1, G2, and G3) and AM disease severity. In VA‐treated patients with AM, it is unknown if a relationship exists between MAN2B1 genotype/subcellular localization subgroups, antidrug antibodies (ADAs), and infusion‐related reactions (IRRs). This pooled analysis evaluated data from 33 VA‐treated patients with AM to investigate this relationship. Overall, 10 patients were positive for ADAs, 4 of whom had treatment‐emergent ADAs (G1: 3/7 [43%]; G2: 1/17 [6%]; G3: 0/9). Treatment‐emergent ADA‐positive patients with relatively high titers (n = 2; G1: 1012 U/ml and G2: 440 U/ml) experienced mild/moderate IRRs that were well‐managed; patients with lower titers (n = 2) experienced no IRRs. Overall, changes from baseline in serum oligosaccharides and immunoglobulin G levels did not vary between ADA‐positive and ADA‐negative patients, suggesting a similar effect of VA treatment regardless of ADA status in most patients. Clinical outcomes (3MSCT and 6MWT) were also similar in most patients regardless of ADA status. While further studies are needed, these data suggest a relationship between MAN2B1 genotype/subcellular localization subgroups and ADA development, with G1 and G2 subgroups more likely to develop ADAs and IRRs. Regardless, this study suggests that ADAs have limited effect on the clinical impact of VA in most patients with AM. Alpha‐mannosidosis (AM), an autosomal recessive disorder caused by pathogenic biallelic variants in the MAN2B1 gene, leads to lysosomal alpha‐mannosidase deficiency and accumulation of mannose‐rich oligosaccharides. Velmanase alfa (VA), a recombinant human lysosomal alpha‐mannosidase, is the first enzyme replacement therapy for non‐neurological symptoms of AM. Previously, a potential relationship was identified between three MAN2B1 genotype/subcellular localization subgroups (G1, G2, and G3) and AM disease severity. In VA‐treated patients with AM, it is unknown if a relationship exists between MAN2B1 genotype/subcellular localization subgroups, antidrug antibodies (ADAs), and infusion‐related reactions (IRRs). This pooled analysis evaluated data from 33 VA‐treated patients with AM to investigate this relationship. Overall, 10 patients were positive for ADAs, 4 of whom had treatment‐emergent ADAs (G1: 3/7 [43%]; G2: 1/17 [6%]; G3: 0/9). Treatment‐emergent ADA‐positive patients with relatively high titers (n = 2; G1: 1012 U/ml and G2: 440 U/ml) experienced mild/moderate IRRs that were well‐managed; patients with lower titers (n = 2) experienced no IRRs. Overall, changes from baseline in serum oligosaccharides and immunoglobulin G levels did not vary between ADA‐positive and ADA‐negative patients, suggesting a similar effect of VA treatment regardless of ADA status in most patients. Clinical outcomes (3MSCT and 6MWT) were also similar in most patients regardless of ADA status. While further studies are needed, these data suggest a relationship between MAN2B1 genotype/subcellular localization subgroups and ADA development, with G1 and G2 subgroups more likely to develop ADAs and IRRs. Regardless, this study suggests that ADAs have limited effect on the clinical impact of VA in most patients with AM. Alpha‐mannosidosis (AM), an autosomal recessive disorder caused by pathogenic biallelic variants in the MAN2B1 gene, leads to lysosomal alpha‐mannosidase deficiency and accumulation of mannose‐rich oligosaccharides. Velmanase alfa (VA), a recombinant human lysosomal alpha‐mannosidase, is the first enzyme replacement therapy for non‐neurological symptoms of AM. Previously, a potential relationship was identified between three MAN2B1 genotype/subcellular localization subgroups (G1, G2, and G3) and AM disease severity. In VA‐treated patients with AM, it is unknown if a relationship exists between MAN2B1 genotype/subcellular localization subgroups, antidrug antibodies (ADAs), and infusion‐related reactions (IRRs). This pooled analysis evaluated data from 33 VA‐treated patients with AM to investigate this relationship. Overall, 10 patients were positive for ADAs, 4 of whom had treatment‐emergent ADAs (G1: 3/7 [43%]; G2: 1/17 [6%]; G3: 0/9). Treatment‐emergent ADA‐positive patients with relatively high titers ( n = 2; G1: 1012 U/ml and G2: 440 U/ml) experienced mild/moderate IRRs that were well‐managed; patients with lower titers ( n = 2) experienced no IRRs. Overall, changes from baseline in serum oligosaccharides and immunoglobulin G levels did not vary between ADA‐positive and ADA‐negative patients, suggesting a similar effect of VA treatment regardless of ADA status in most patients. Clinical outcomes (3MSCT and 6MWT) were also similar in most patients regardless of ADA status. While further studies are needed, these data suggest a relationship between MAN2B1 genotype/subcellular localization subgroups and ADA development, with G1 and G2 subgroups more likely to develop ADAs and IRRs. Regardless, this study suggests that ADAs have limited effect on the clinical impact of VA in most patients with AM. Alpha-mannosidosis (AM), an autosomal recessive disorder caused by pathogenic biallelic variants in the gene, leads to lysosomal alpha-mannosidase deficiency and accumulation of mannose-rich oligosaccharides. Velmanase alfa (VA), a recombinant human lysosomal alpha-mannosidase, is the first enzyme replacement therapy for non-neurological symptoms of AM. Previously, a potential relationship was identified between three genotype/subcellular localization subgroups (G1, G2, and G3) and AM disease severity. In VA-treated patients with AM, it is unknown if a relationship exists between genotype/subcellular localization subgroups, antidrug antibodies (ADAs), and infusion-related reactions (IRRs). This pooled analysis evaluated data from 33 VA-treated patients with AM to investigate this relationship. Overall, 10 patients were positive for ADAs, 4 of whom had treatment-emergent ADAs (G1: 3/7 [43%]; G2: 1/17 [6%]; G3: 0/9). Treatment-emergent ADA-positive patients with relatively high titers ( = 2; G1: 1012 U/ml and G2: 440 U/ml) experienced mild/moderate IRRs that were well-managed; patients with lower titers ( = 2) experienced no IRRs. Overall, changes from baseline in serum oligosaccharides and immunoglobulin G levels did not vary between ADA-positive and ADA-negative patients, suggesting a similar effect of VA treatment regardless of ADA status in most patients. Clinical outcomes (3MSCT and 6MWT) were also similar in most patients regardless of ADA status. While further studies are needed, these data suggest a relationship between genotype/subcellular localization subgroups and ADA development, with G1 and G2 subgroups more likely to develop ADAs and IRRs. Regardless, this study suggests that ADAs have limited effect on the clinical impact of VA in most patients with AM. |
| Author | Borgwardt, Line Gutte Ballabeni, Andrea Ceravolo, Ferdinando Zardi, Giulia Lund, Allan Meldgaard |
| AuthorAffiliation | 3 Chiesi Farmaceutici S.p.A Parma Italy 1 Department of Paediatrics and Adolescent Medicine Centre for Inherited Metabolic Diseases, Rigshospitalet Copenhagen Denmark 4 CROS NT S.r.l Verona Italy 6 European Reference Network for Hereditary Metabolic Disorders (MetabERN) Udine Italy 2 Center for Genomic Medicine Copenhagen University Hospital, Rigshospitalet Copenhagen Denmark 5 Department of Clinical Genetics, Centre for Inherited Metabolic Diseases Copenhagen University Hospital, Rigshospitalet Copenhagen Denmark |
| AuthorAffiliation_xml | – name: 5 Department of Clinical Genetics, Centre for Inherited Metabolic Diseases Copenhagen University Hospital, Rigshospitalet Copenhagen Denmark – name: 2 Center for Genomic Medicine Copenhagen University Hospital, Rigshospitalet Copenhagen Denmark – name: 4 CROS NT S.r.l Verona Italy – name: 1 Department of Paediatrics and Adolescent Medicine Centre for Inherited Metabolic Diseases, Rigshospitalet Copenhagen Denmark – name: 3 Chiesi Farmaceutici S.p.A Parma Italy – name: 6 European Reference Network for Hereditary Metabolic Disorders (MetabERN) Udine Italy |
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| Cites_doi | 10.1186/s13023‐015‐0286‐x 10.1002/humu.22005 10.4161/hv.21405 10.1002/ajmg.c.31319 10.1038/nbt.1484 10.1007/s10545‐018‐0175‐2 10.1007/s10545‐013‐9595‐1 10.1007/s10545‐018‐0185‐0 |
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| Keywords | infusion‐related reactions alpha‐mannosidosis antidrug antibody velmanase alfa MAN2B1 |
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| References | 2019 2008; 26 2018 2018; 41 2013; 36 2012; 160C 2012; 33 2012; 8 2015; 10 e_1_2_12_4_1 e_1_2_12_6_1 e_1_2_12_5_1 e_1_2_12_19_1 e_1_2_12_18_1 e_1_2_12_2_1 e_1_2_12_17_1 e_1_2_12_16_1 e_1_2_12_15_1 e_1_2_12_14_1 e_1_2_12_13_1 e_1_2_12_12_1 e_1_2_12_8_1 e_1_2_12_11_1 e_1_2_12_7_1 e_1_2_12_10_1 Malm D (e_1_2_12_3_1) 2019 e_1_2_12_9_1 |
| References_xml | – volume: 26 start-page: 901 issue: 8 year: 2008 end-page: 908 article-title: Neutralizing antibodies to therapeutic enzymes: considerations for testing, prevention and treatment publication-title: Nat Biotechnol – volume: 41 start-page: 1215 issue: 6 year: 2018 end-page: 1223 article-title: Efficacy and safety of velmanase alfa in the treatment of patients with alpha‐mannosidosis: results from the core and extension phase analysis of a phase III multicentre, double‐blind, randomised, placebo‐controlled trial publication-title: J Inherit Metab Dis – volume: 160C start-page: 40 issue: 1 year: 2012 end-page: 49 article-title: Predicting cross‐reactive immunological material (CRIM) status in Pompe disease using GAA mutations: lessons learned from 10 years of clinical laboratory testing experience publication-title: Am J Med Genet C Semin Med Genet – volume: 36 start-page: 1015 issue: 6 year: 2013 end-page: 1024 article-title: Enzyme replacement therapy for alpha‐mannosidosis: 12 months follow‐up of a single centre, randomised, multiple dose study publication-title: J Inherit Metab Dis – volume: 8 start-page: 1459 issue: 10 year: 2012 end-page: 1464 article-title: Teaching tolerance: new approaches to enzyme replacement therapy for Pompe disease publication-title: Hum Vaccin Immunother – volume: 41 start-page: 1225 issue: 6 year: 2018 end-page: 1233 article-title: Comprehensive long‐term efficacy and safety of recombinant human alpha‐mannosidase (velmanase alfa) treatment in patients with alpha‐mannosidosis publication-title: J Inherit Metab Dis – volume: 10 start-page: 70 year: 2015 article-title: Alpha‐mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation publication-title: Orphanet J Rare Dis – year: 2018 – year: 2019 – volume: 33 start-page: 511 issue: 3 year: 2012 end-page: 520 article-title: Identification of 83 novel alpha‐mannosidosis‐associated sequence variants: functional analysis of MAN2B1 missense mutations publication-title: Hum Mutat – ident: e_1_2_12_10_1 – ident: e_1_2_12_13_1 – volume-title: GeneReviews year: 2019 ident: e_1_2_12_3_1 – ident: e_1_2_12_2_1 doi: 10.1186/s13023‐015‐0286‐x – ident: e_1_2_12_17_1 doi: 10.1002/humu.22005 – ident: e_1_2_12_9_1 – ident: e_1_2_12_16_1 – ident: e_1_2_12_4_1 – ident: e_1_2_12_19_1 doi: 10.4161/hv.21405 – ident: e_1_2_12_7_1 doi: 10.1002/ajmg.c.31319 – ident: e_1_2_12_11_1 – ident: e_1_2_12_15_1 – ident: e_1_2_12_6_1 doi: 10.1038/nbt.1484 – ident: e_1_2_12_18_1 doi: 10.1007/s10545‐018‐0175‐2 – ident: e_1_2_12_14_1 – ident: e_1_2_12_5_1 – ident: e_1_2_12_8_1 doi: 10.1007/s10545‐013‐9595‐1 – ident: e_1_2_12_12_1 doi: 10.1007/s10545‐018‐0185‐0 |
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| Snippet | Alpha‐mannosidosis (AM), an autosomal recessive disorder caused by pathogenic biallelic variants in the MAN2B1 gene, leads to lysosomal alpha‐mannosidase... Alpha‐mannosidosis (AM), an autosomal recessive disorder caused by pathogenic biallelic variants in the MAN2B1 gene, leads to lysosomal alpha‐mannosidase... Alpha-mannosidosis (AM), an autosomal recessive disorder caused by pathogenic biallelic variants in the gene, leads to lysosomal alpha-mannosidase deficiency... Alpha-mannosidosis (AM), an autosomal recessive disorder caused by pathogenic biallelic variants in the MAN2B1 gene, leads to lysosomal alpha-mannosidase... Abstract Alpha‐mannosidosis (AM), an autosomal recessive disorder caused by pathogenic biallelic variants in the MAN2B1 gene, leads to lysosomal... |
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| SubjectTerms | alpha‐mannosidosis Amino acids Antibodies antidrug antibody Clinical trials Enzymes Genotype & phenotype Immunoglobulins infusion‐related reactions Localization MAN2B1 Patients Pediatrics Proteins Research Report Research Reports velmanase alfa |
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| Title | Relationship between MAN2B1 genotype/subcellular localization subgroups, antidrug antibody detection, and long‐term velmanase alfa treatment outcomes in patients with alpha‐mannosidosis |
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