Cargando…

Early Phase Clinical Immunogenicity of Valoctocogene Roxaparvovec, an AAV5-Mediated Gene Therapy for Hemophilia A

Evaluation of immune responses to adeno-associated virus (AAV)-mediated gene therapies prior to and following dose administration plays a key role in determining therapeutic safety and efficacy. This report describes up to 3 years of immunogenicity data following administration of valoctocogene roxa...

Descripción completa

Detalles Bibliográficos
Autores principales: Long, Brian R., Veron, Philippe, Kuranda, Klaudia, Hardet, Romain, Mitchell, Nina, Hayes, Gregory M., Wong, Wing Yen, Lau, Kelly, Li, Mingjin, Hock, M. Benjamin, Zoog, Stephen J., Vettermann, Christian, Mingozzi, Federico, Schweighardt, Becky
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854299/
https://www.ncbi.nlm.nih.gov/pubmed/33309883
http://dx.doi.org/10.1016/j.ymthe.2020.12.008
_version_ 1783646063047999488
author Long, Brian R.
Veron, Philippe
Kuranda, Klaudia
Hardet, Romain
Mitchell, Nina
Hayes, Gregory M.
Wong, Wing Yen
Lau, Kelly
Li, Mingjin
Hock, M. Benjamin
Zoog, Stephen J.
Vettermann, Christian
Mingozzi, Federico
Schweighardt, Becky
author_facet Long, Brian R.
Veron, Philippe
Kuranda, Klaudia
Hardet, Romain
Mitchell, Nina
Hayes, Gregory M.
Wong, Wing Yen
Lau, Kelly
Li, Mingjin
Hock, M. Benjamin
Zoog, Stephen J.
Vettermann, Christian
Mingozzi, Federico
Schweighardt, Becky
author_sort Long, Brian R.
collection PubMed
description Evaluation of immune responses to adeno-associated virus (AAV)-mediated gene therapies prior to and following dose administration plays a key role in determining therapeutic safety and efficacy. This report describes up to 3 years of immunogenicity data following administration of valoctocogene roxaparvovec (BMN 270), an AAV5-mediated gene therapy encoding human B domain-deleted FVIII (hFVIII-SQ) in a phase 1/2 clinical study of adult males with severe hemophilia A. Patients with pre-existing humoral immunity to AAV5 or with a history of FVIII inhibitors were excluded from the trial. Blood plasma and peripheral blood mononuclear cell (PBMC) samples were collected at regular intervals following dose administration for assessment of humoral and cellular immune responses to both the AAV5 vector and transgene-expressed hFVIII-SQ. The predominant immune response elicited by BMN 270 administration was largely limited to the development of antibodies against the AAV5 capsid that were cross-reactive with other common AAV serotypes. No FVIII inhibitor responses were observed within 3 years following dose administration. In a context of prophylactic or on-demand corticosteroid immunosuppression given after vector infusion, AAV5 and hFVIII-SQ peptide-specific cellular immune responses were intermittently detected by an interferon (IFN)-γ and tumor necrosis factor (TNF)-α FluoroSpot assay, but they were not clearly associated with detrimental safety events or changes in efficacy measures.
format Online
Article
Text
id pubmed-7854299
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher American Society of Gene & Cell Therapy
record_format MEDLINE/PubMed
spelling pubmed-78542992022-02-03 Early Phase Clinical Immunogenicity of Valoctocogene Roxaparvovec, an AAV5-Mediated Gene Therapy for Hemophilia A Long, Brian R. Veron, Philippe Kuranda, Klaudia Hardet, Romain Mitchell, Nina Hayes, Gregory M. Wong, Wing Yen Lau, Kelly Li, Mingjin Hock, M. Benjamin Zoog, Stephen J. Vettermann, Christian Mingozzi, Federico Schweighardt, Becky Mol Ther Original Article Evaluation of immune responses to adeno-associated virus (AAV)-mediated gene therapies prior to and following dose administration plays a key role in determining therapeutic safety and efficacy. This report describes up to 3 years of immunogenicity data following administration of valoctocogene roxaparvovec (BMN 270), an AAV5-mediated gene therapy encoding human B domain-deleted FVIII (hFVIII-SQ) in a phase 1/2 clinical study of adult males with severe hemophilia A. Patients with pre-existing humoral immunity to AAV5 or with a history of FVIII inhibitors were excluded from the trial. Blood plasma and peripheral blood mononuclear cell (PBMC) samples were collected at regular intervals following dose administration for assessment of humoral and cellular immune responses to both the AAV5 vector and transgene-expressed hFVIII-SQ. The predominant immune response elicited by BMN 270 administration was largely limited to the development of antibodies against the AAV5 capsid that were cross-reactive with other common AAV serotypes. No FVIII inhibitor responses were observed within 3 years following dose administration. In a context of prophylactic or on-demand corticosteroid immunosuppression given after vector infusion, AAV5 and hFVIII-SQ peptide-specific cellular immune responses were intermittently detected by an interferon (IFN)-γ and tumor necrosis factor (TNF)-α FluoroSpot assay, but they were not clearly associated with detrimental safety events or changes in efficacy measures. American Society of Gene & Cell Therapy 2021-02-03 2020-12-10 /pmc/articles/PMC7854299/ /pubmed/33309883 http://dx.doi.org/10.1016/j.ymthe.2020.12.008 Text en © 2020 The Author(s) http://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
Long, Brian R.
Veron, Philippe
Kuranda, Klaudia
Hardet, Romain
Mitchell, Nina
Hayes, Gregory M.
Wong, Wing Yen
Lau, Kelly
Li, Mingjin
Hock, M. Benjamin
Zoog, Stephen J.
Vettermann, Christian
Mingozzi, Federico
Schweighardt, Becky
Early Phase Clinical Immunogenicity of Valoctocogene Roxaparvovec, an AAV5-Mediated Gene Therapy for Hemophilia A
title Early Phase Clinical Immunogenicity of Valoctocogene Roxaparvovec, an AAV5-Mediated Gene Therapy for Hemophilia A
title_full Early Phase Clinical Immunogenicity of Valoctocogene Roxaparvovec, an AAV5-Mediated Gene Therapy for Hemophilia A
title_fullStr Early Phase Clinical Immunogenicity of Valoctocogene Roxaparvovec, an AAV5-Mediated Gene Therapy for Hemophilia A
title_full_unstemmed Early Phase Clinical Immunogenicity of Valoctocogene Roxaparvovec, an AAV5-Mediated Gene Therapy for Hemophilia A
title_short Early Phase Clinical Immunogenicity of Valoctocogene Roxaparvovec, an AAV5-Mediated Gene Therapy for Hemophilia A
title_sort early phase clinical immunogenicity of valoctocogene roxaparvovec, an aav5-mediated gene therapy for hemophilia a
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854299/
https://www.ncbi.nlm.nih.gov/pubmed/33309883
http://dx.doi.org/10.1016/j.ymthe.2020.12.008
work_keys_str_mv AT longbrianr earlyphaseclinicalimmunogenicityofvaloctocogeneroxaparvovecanaav5mediatedgenetherapyforhemophiliaa
AT veronphilippe earlyphaseclinicalimmunogenicityofvaloctocogeneroxaparvovecanaav5mediatedgenetherapyforhemophiliaa
AT kurandaklaudia earlyphaseclinicalimmunogenicityofvaloctocogeneroxaparvovecanaav5mediatedgenetherapyforhemophiliaa
AT hardetromain earlyphaseclinicalimmunogenicityofvaloctocogeneroxaparvovecanaav5mediatedgenetherapyforhemophiliaa
AT mitchellnina earlyphaseclinicalimmunogenicityofvaloctocogeneroxaparvovecanaav5mediatedgenetherapyforhemophiliaa
AT hayesgregorym earlyphaseclinicalimmunogenicityofvaloctocogeneroxaparvovecanaav5mediatedgenetherapyforhemophiliaa
AT wongwingyen earlyphaseclinicalimmunogenicityofvaloctocogeneroxaparvovecanaav5mediatedgenetherapyforhemophiliaa
AT laukelly earlyphaseclinicalimmunogenicityofvaloctocogeneroxaparvovecanaav5mediatedgenetherapyforhemophiliaa
AT limingjin earlyphaseclinicalimmunogenicityofvaloctocogeneroxaparvovecanaav5mediatedgenetherapyforhemophiliaa
AT hockmbenjamin earlyphaseclinicalimmunogenicityofvaloctocogeneroxaparvovecanaav5mediatedgenetherapyforhemophiliaa
AT zoogstephenj earlyphaseclinicalimmunogenicityofvaloctocogeneroxaparvovecanaav5mediatedgenetherapyforhemophiliaa
AT vettermannchristian earlyphaseclinicalimmunogenicityofvaloctocogeneroxaparvovecanaav5mediatedgenetherapyforhemophiliaa
AT mingozzifederico earlyphaseclinicalimmunogenicityofvaloctocogeneroxaparvovecanaav5mediatedgenetherapyforhemophiliaa
AT schweighardtbecky earlyphaseclinicalimmunogenicityofvaloctocogeneroxaparvovecanaav5mediatedgenetherapyforhemophiliaa