Relationship between MAN2B1 genotype/subcellular localization subgroups, antidrug antibody detection, and long-term velmanase alfa treatment outcomes in patients with alpha-mannosidosis.

Autor: Borgwardt LG; Department of Paediatrics and Adolescent Medicine Centre for Inherited Metabolic Diseases, Rigshospitalet Copenhagen Denmark.; Center for Genomic Medicine Copenhagen University Hospital, Rigshospitalet Copenhagen Denmark., Ceravolo F; Chiesi Farmaceutici S.p.A Parma Italy., Zardi G; CROS NT S.r.l Verona Italy., Ballabeni A; Chiesi Farmaceutici S.p.A Parma Italy., Lund AM; Department of Paediatrics and Adolescent Medicine Centre for Inherited Metabolic Diseases, Rigshospitalet Copenhagen Denmark.; Department of Clinical Genetics, Centre for Inherited Metabolic Diseases Copenhagen University Hospital, Rigshospitalet Copenhagen Denmark.; European Reference Network for Hereditary Metabolic Disorders (MetabERN) Udine Italy.
Jazyk: angličtina
Zdroj: JIMD reports [JIMD Rep] 2022 Nov 25; Vol. 64 (2), pp. 187-198. Date of Electronic Publication: 2022 Nov 25 (Print Publication: 2023).
DOI: 10.1002/jmd2.12349
Abstrakt: 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.
Competing Interests: Line Gutte Borgwardt has received consulting fees from Chiesi, the sponsor of the study; Ferdinando Ceravolo was an employee of Chiesi Farmaceutici S.p.A., the sponsor of the study; Giulia Zardi has received consulting fees from Chiesi Farmaceutici S.p.A., the sponsor of the study; Andrea Ballabeni is an employee of Chiesi Farmaceutici S.p.A., the sponsor of the study; Allan Meldgaard Lund has received consulting fees and/or honoraria/travel support from Amicus, BioMarin, Chiesi, Sanofi Genzyme, Shire/Takeda, Recordati, and Sobi as well as grant/research support from Sanofi Genzyme and Shire/Takeda.
(© 2022 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)
Databáze: MEDLINE
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