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Pre-existing anti-drug antibodies in Fabry disease show less affinity for pegunigalsidase alfa

We analyzed the cross-reactivity of anti-drug antibodies (ADAs) against agalsidase-alfa and -beta from 49 patients with Fabry disease (FD) against the novel PEGylated enzyme pegunigalsidase-alfa (PRX-102). The affinity of purified anti-AGAL antibodies from pooled patient sera was significantly lower...

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Autores principales: Lenders, Malte, Pollmann, Solvey, Terlinden, Melina, Brand, Eva
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9379515/
https://www.ncbi.nlm.nih.gov/pubmed/35990747
http://dx.doi.org/10.1016/j.omtm.2022.07.009
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author Lenders, Malte
Pollmann, Solvey
Terlinden, Melina
Brand, Eva
author_facet Lenders, Malte
Pollmann, Solvey
Terlinden, Melina
Brand, Eva
author_sort Lenders, Malte
collection PubMed
description We analyzed the cross-reactivity of anti-drug antibodies (ADAs) against agalsidase-alfa and -beta from 49 patients with Fabry disease (FD) against the novel PEGylated enzyme pegunigalsidase-alfa (PRX-102). The affinity of purified anti-AGAL antibodies from pooled patient sera was significantly lower for PRX-102 compared to agalsidase-alfa and -beta (both p < 0.05). Pull-down experiments revealed the presence of masked epitopes on PRX-102, possibly due to PEGylation. ADA titers in serum (μg/mL) and corresponding inhibitory capacities against agalsidase-alfa and -beta were measured in male patients with FD, showing strong correlations (r(2) = 0.9978 and 0.4930, both p < 0.001). Affinities of ADAs of individual patients against PRX-102 (K(d): 3.55 ± 2.72 μmol) were significantly lower compared to agalsidase alfa (K(d): 1.99 ± 1.26 μmol) and -beta (K(d): 2.18 ± 1.51 μmol) (both p < 0.0001). Cross-ELISAs supported the presence of masked epitopes on PRX-102. Importantly, inhibition measurements also revealed a 30% reduction in inhibitory capacity of pre-existing ADAs towards PRX-102. Enzyme-uptake experiments in AGAL-deficient EA.hy926 cells demonstrated less effects of ADAs on cellular PRX-102 uptake compared with agalsidase beta. We conclude that due to the reduced affinity of pre-existing ADAs against agalsidase-alfa or -beta, ADA-affected patients might benefit from a therapy switch to PRX-102, which is currently evaluated in clinical trials.
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spelling pubmed-93795152022-08-18 Pre-existing anti-drug antibodies in Fabry disease show less affinity for pegunigalsidase alfa Lenders, Malte Pollmann, Solvey Terlinden, Melina Brand, Eva Mol Ther Methods Clin Dev Original Article We analyzed the cross-reactivity of anti-drug antibodies (ADAs) against agalsidase-alfa and -beta from 49 patients with Fabry disease (FD) against the novel PEGylated enzyme pegunigalsidase-alfa (PRX-102). The affinity of purified anti-AGAL antibodies from pooled patient sera was significantly lower for PRX-102 compared to agalsidase-alfa and -beta (both p < 0.05). Pull-down experiments revealed the presence of masked epitopes on PRX-102, possibly due to PEGylation. ADA titers in serum (μg/mL) and corresponding inhibitory capacities against agalsidase-alfa and -beta were measured in male patients with FD, showing strong correlations (r(2) = 0.9978 and 0.4930, both p < 0.001). Affinities of ADAs of individual patients against PRX-102 (K(d): 3.55 ± 2.72 μmol) were significantly lower compared to agalsidase alfa (K(d): 1.99 ± 1.26 μmol) and -beta (K(d): 2.18 ± 1.51 μmol) (both p < 0.0001). Cross-ELISAs supported the presence of masked epitopes on PRX-102. Importantly, inhibition measurements also revealed a 30% reduction in inhibitory capacity of pre-existing ADAs towards PRX-102. Enzyme-uptake experiments in AGAL-deficient EA.hy926 cells demonstrated less effects of ADAs on cellular PRX-102 uptake compared with agalsidase beta. We conclude that due to the reduced affinity of pre-existing ADAs against agalsidase-alfa or -beta, ADA-affected patients might benefit from a therapy switch to PRX-102, which is currently evaluated in clinical trials. American Society of Gene & Cell Therapy 2022-07-31 /pmc/articles/PMC9379515/ /pubmed/35990747 http://dx.doi.org/10.1016/j.omtm.2022.07.009 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Lenders, Malte
Pollmann, Solvey
Terlinden, Melina
Brand, Eva
Pre-existing anti-drug antibodies in Fabry disease show less affinity for pegunigalsidase alfa
title Pre-existing anti-drug antibodies in Fabry disease show less affinity for pegunigalsidase alfa
title_full Pre-existing anti-drug antibodies in Fabry disease show less affinity for pegunigalsidase alfa
title_fullStr Pre-existing anti-drug antibodies in Fabry disease show less affinity for pegunigalsidase alfa
title_full_unstemmed Pre-existing anti-drug antibodies in Fabry disease show less affinity for pegunigalsidase alfa
title_short Pre-existing anti-drug antibodies in Fabry disease show less affinity for pegunigalsidase alfa
title_sort pre-existing anti-drug antibodies in fabry disease show less affinity for pegunigalsidase alfa
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9379515/
https://www.ncbi.nlm.nih.gov/pubmed/35990747
http://dx.doi.org/10.1016/j.omtm.2022.07.009
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