The IgG-degrading enzyme, Imlifidase, restores the therapeutic activity of FVIII in inhibitor-positive hemophilia A mice
(2023) In Haematologica 108(5). p.1322-1334- Abstract
Neutralizing anti-factor VIII (FVIII) antibodies, known as FVIII inhibitors, represent a major drawback of replacement therapy in persons with congenital hemophilia A (PwHA), rendering further infusions of FVIII ineffective. FVIII inhibitors can also appear in non-hemophilic individuals causing acquired hemophilia A (AHA). The use of non-FVIII bypassing agents in cases of bleeds or surgery in inhibitor-positive patients is complicated by the lack of reliable biological monitoring and increased thrombotic risk. Imlifidase (IdeS) is an endopeptidase that degrades human immunoglobulin G (IgG); it was recently approved for hyperimmune patients undergoing renal transplants. Here we investigated the ability of IdeS to eliminate FVIII... (More)
Neutralizing anti-factor VIII (FVIII) antibodies, known as FVIII inhibitors, represent a major drawback of replacement therapy in persons with congenital hemophilia A (PwHA), rendering further infusions of FVIII ineffective. FVIII inhibitors can also appear in non-hemophilic individuals causing acquired hemophilia A (AHA). The use of non-FVIII bypassing agents in cases of bleeds or surgery in inhibitor-positive patients is complicated by the lack of reliable biological monitoring and increased thrombotic risk. Imlifidase (IdeS) is an endopeptidase that degrades human immunoglobulin G (IgG); it was recently approved for hyperimmune patients undergoing renal transplants. Here we investigated the ability of IdeS to eliminate FVIII inhibitors in vitro and in a model of inhibitor-positive HA mice. IdeS cleaved anti-FVIII plasma IgG from PwHA and AHA patients, and hydrolyzed recombinant human anti-FVIII IgG independently from their subclass or specificity for the A2, A3, C1 or C2 domains of FVIII. In HA mice passively immunized with recombinant human anti-FVIII IgG, IdeS restored the hemostatic efficacy of FVIII, as evidenced by the correction of the bleeding tendency. Our results provide the proof of concept for the transient removal of FVIII inhibitors by IdeS, thereby opening a therapeutic window for efficient FVIII replacement therapy in inhibitor-positive patients.
(Less)
- author
- Bou-Jaoudeh, Melissa ; Delignat, Sandrine ; Daventure, Victoria ; Astermark, Jan LU ; Lévesque, Hervé ; Dimitrov, Jordan D. ; Deligne, Claire ; Proulle, Valérie and Lacroix-Desmazes, Sébastien
- organization
- publishing date
- 2023-05
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Haematologica
- volume
- 108
- issue
- 5
- pages
- 13 pages
- publisher
- Ferrata Storti Foundation
- external identifiers
-
- pmid:36655430
- scopus:85158146311
- ISSN
- 0390-6078
- DOI
- 10.3324/haematol.2022.281895
- language
- English
- LU publication?
- yes
- id
- d5ba0862-9ce5-47f1-b090-c1bc205baa40
- date added to LUP
- 2023-08-11 10:29:46
- date last changed
- 2024-04-20 00:23:59
@article{d5ba0862-9ce5-47f1-b090-c1bc205baa40,
abstract = {{<p>Neutralizing anti-factor VIII (FVIII) antibodies, known as FVIII inhibitors, represent a major drawback of replacement therapy in persons with congenital hemophilia A (PwHA), rendering further infusions of FVIII ineffective. FVIII inhibitors can also appear in non-hemophilic individuals causing acquired hemophilia A (AHA). The use of non-FVIII bypassing agents in cases of bleeds or surgery in inhibitor-positive patients is complicated by the lack of reliable biological monitoring and increased thrombotic risk. Imlifidase (IdeS) is an endopeptidase that degrades human immunoglobulin G (IgG); it was recently approved for hyperimmune patients undergoing renal transplants. Here we investigated the ability of IdeS to eliminate FVIII inhibitors in vitro and in a model of inhibitor-positive HA mice. IdeS cleaved anti-FVIII plasma IgG from PwHA and AHA patients, and hydrolyzed recombinant human anti-FVIII IgG independently from their subclass or specificity for the A2, A3, C1 or C2 domains of FVIII. In HA mice passively immunized with recombinant human anti-FVIII IgG, IdeS restored the hemostatic efficacy of FVIII, as evidenced by the correction of the bleeding tendency. Our results provide the proof of concept for the transient removal of FVIII inhibitors by IdeS, thereby opening a therapeutic window for efficient FVIII replacement therapy in inhibitor-positive patients.</p>}},
author = {{Bou-Jaoudeh, Melissa and Delignat, Sandrine and Daventure, Victoria and Astermark, Jan and Lévesque, Hervé and Dimitrov, Jordan D. and Deligne, Claire and Proulle, Valérie and Lacroix-Desmazes, Sébastien}},
issn = {{0390-6078}},
language = {{eng}},
number = {{5}},
pages = {{1322--1334}},
publisher = {{Ferrata Storti Foundation}},
series = {{Haematologica}},
title = {{The IgG-degrading enzyme, Imlifidase, restores the therapeutic activity of FVIII in inhibitor-positive hemophilia A mice}},
url = {{http://dx.doi.org/10.3324/haematol.2022.281895}},
doi = {{10.3324/haematol.2022.281895}},
volume = {{108}},
year = {{2023}},
}