Relationship between MAN2B1 genotype/subcellular localization subgroups, antidrug antibody detection, and long‐term velmanase alfa treatment outcomes in patients with alpha‐mannosidosis
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 th...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-03-01
|
| Series: | JIMD Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jmd2.12349 |
| _version_ | 1811160937411903488 |
|---|---|
| author | Line Gutte Borgwardt Ferdinando Ceravolo Giulia Zardi Andrea Ballabeni Allan Meldgaard Lund |
| author_facet | Line Gutte Borgwardt Ferdinando Ceravolo Giulia Zardi Andrea Ballabeni Allan Meldgaard Lund |
| author_sort | Line Gutte Borgwardt |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T06:06:12Z |
| format | Article |
| id | doaj.art-70f1d07fdc024aabb477b895d1046324 |
| institution | Directory Open Access Journal |
| issn | 2192-8312 |
| language | English |
| last_indexed | 2024-04-10T06:06:12Z |
| publishDate | 2023-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | JIMD Reports |
| spelling | doaj.art-70f1d07fdc024aabb477b895d10463242023-03-03T02:28:07ZengWileyJIMD Reports2192-83122023-03-0164218719810.1002/jmd2.12349Relationship between MAN2B1 genotype/subcellular localization subgroups, antidrug antibody detection, and long‐term velmanase alfa treatment outcomes in patients with alpha‐mannosidosisLine Gutte Borgwardt0Ferdinando Ceravolo1Giulia Zardi2Andrea Ballabeni3Allan Meldgaard Lund4Department of Paediatrics and Adolescent Medicine Centre for Inherited Metabolic Diseases, Rigshospitalet Copenhagen DenmarkChiesi Farmaceutici S.p.A Parma ItalyCROS NT S.r.l Verona ItalyChiesi Farmaceutici S.p.A Parma ItalyDepartment of Paediatrics and Adolescent Medicine Centre for Inherited Metabolic Diseases, Rigshospitalet Copenhagen DenmarkAbstract 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.https://doi.org/10.1002/jmd2.12349alpha‐mannosidosisantidrug antibodyinfusion‐related reactionsMAN2B1velmanase alfa |
| spellingShingle | Line Gutte Borgwardt Ferdinando Ceravolo Giulia Zardi Andrea Ballabeni Allan Meldgaard Lund Relationship between MAN2B1 genotype/subcellular localization subgroups, antidrug antibody detection, and long‐term velmanase alfa treatment outcomes in patients with alpha‐mannosidosis JIMD Reports alpha‐mannosidosis antidrug antibody infusion‐related reactions MAN2B1 velmanase alfa |
| title | Relationship between MAN2B1 genotype/subcellular localization subgroups, antidrug antibody detection, and long‐term velmanase alfa treatment outcomes in patients with alpha‐mannosidosis |
| title_full | Relationship between MAN2B1 genotype/subcellular localization subgroups, antidrug antibody detection, and long‐term velmanase alfa treatment outcomes in patients with alpha‐mannosidosis |
| title_fullStr | Relationship between MAN2B1 genotype/subcellular localization subgroups, antidrug antibody detection, and long‐term velmanase alfa treatment outcomes in patients with alpha‐mannosidosis |
| title_full_unstemmed | Relationship between MAN2B1 genotype/subcellular localization subgroups, antidrug antibody detection, and long‐term velmanase alfa treatment outcomes in patients with alpha‐mannosidosis |
| title_short | Relationship between MAN2B1 genotype/subcellular localization subgroups, antidrug antibody detection, and long‐term velmanase alfa treatment outcomes in patients with alpha‐mannosidosis |
| title_sort | relationship between man2b1 genotype subcellular localization subgroups antidrug antibody detection and long term velmanase alfa treatment outcomes in patients with alpha mannosidosis |
| topic | alpha‐mannosidosis antidrug antibody infusion‐related reactions MAN2B1 velmanase alfa |
| url | https://doi.org/10.1002/jmd2.12349 |
| work_keys_str_mv | AT linegutteborgwardt relationshipbetweenman2b1genotypesubcellularlocalizationsubgroupsantidrugantibodydetectionandlongtermvelmanasealfatreatmentoutcomesinpatientswithalphamannosidosis AT ferdinandoceravolo relationshipbetweenman2b1genotypesubcellularlocalizationsubgroupsantidrugantibodydetectionandlongtermvelmanasealfatreatmentoutcomesinpatientswithalphamannosidosis AT giuliazardi relationshipbetweenman2b1genotypesubcellularlocalizationsubgroupsantidrugantibodydetectionandlongtermvelmanasealfatreatmentoutcomesinpatientswithalphamannosidosis AT andreaballabeni relationshipbetweenman2b1genotypesubcellularlocalizationsubgroupsantidrugantibodydetectionandlongtermvelmanasealfatreatmentoutcomesinpatientswithalphamannosidosis AT allanmeldgaardlund relationshipbetweenman2b1genotypesubcellularlocalizationsubgroupsantidrugantibodydetectionandlongtermvelmanasealfatreatmentoutcomesinpatientswithalphamannosidosis |