Aggregates Associated with Instability of Antibodies during Aerosolization Induce Adverse Immunological Effects.
aerosol
aggregates
immunogenicity
therapeutic antibody
Journal
Pharmaceutics
ISSN: 1999-4923
Titre abrégé: Pharmaceutics
Pays: Switzerland
ID NLM: 101534003
Informations de publication
Date de publication:
18 Mar 2022
18 Mar 2022
Historique:
received:
21
02
2022
revised:
11
03
2022
accepted:
16
03
2022
entrez:
26
3
2022
pubmed:
27
3
2022
medline:
27
3
2022
Statut:
epublish
Résumé
Immunogenicity refers to the inherent ability of a molecule to stimulate an immune response. Aggregates are one of the major risk factors for the undesired immunogenicity of therapeutic antibodies (Ab) and may ultimately result in immune-mediated adverse effects. For Ab delivered by inhalation, it is necessary to consider the interaction between aggregates resulting from the instability of the Ab during aerosolization and the lung mucosa. The aim of this study was to determine the impact of aggregates produced during aerosolization of therapeutic Ab on the immune system. Human and murine immunoglobulin G (IgG) were aerosolized using a clinically-relevant nebulizer and their immunogenic potency was assessed, both in vitro using a standard human monocyte-derived dendritic cell (MoDC) reporter assay and in vivo in immune cells in the airway compartment, lung parenchyma and spleen of healthy C57BL/6 mice after pulmonary administration. IgG aggregates, produced during nebulization, induced a dose-dependent activation of MoDC characterized by the enhanced production of cytokines and expression of co-stimulatory markers. Interestingly, in vivo administration of high amounts of nebulization-mediated IgG aggregates resulted in a profound and sustained local and systemic depletion of immune cells, which was attributable to cell death. This cytotoxic effect was observed when nebulized IgG was administered locally in the airways as compared to a systemic administration but was mitigated by improving IgG stability during nebulization, through the addition of polysorbates to the formulation. Although inhalation delivery represents an attractive alternative route for delivering Ab to treat respiratory infections, our findings indicate that it is critical to prevent IgG aggregation during the nebulization process to avoid pro-inflammatory and cytotoxic effects. The optimization of Ab formulation can mitigate adverse effects induced by nebulization.
Sections du résumé
BACKGROUND
BACKGROUND
Immunogenicity refers to the inherent ability of a molecule to stimulate an immune response. Aggregates are one of the major risk factors for the undesired immunogenicity of therapeutic antibodies (Ab) and may ultimately result in immune-mediated adverse effects. For Ab delivered by inhalation, it is necessary to consider the interaction between aggregates resulting from the instability of the Ab during aerosolization and the lung mucosa. The aim of this study was to determine the impact of aggregates produced during aerosolization of therapeutic Ab on the immune system.
METHODS
METHODS
Human and murine immunoglobulin G (IgG) were aerosolized using a clinically-relevant nebulizer and their immunogenic potency was assessed, both in vitro using a standard human monocyte-derived dendritic cell (MoDC) reporter assay and in vivo in immune cells in the airway compartment, lung parenchyma and spleen of healthy C57BL/6 mice after pulmonary administration.
RESULTS
RESULTS
IgG aggregates, produced during nebulization, induced a dose-dependent activation of MoDC characterized by the enhanced production of cytokines and expression of co-stimulatory markers. Interestingly, in vivo administration of high amounts of nebulization-mediated IgG aggregates resulted in a profound and sustained local and systemic depletion of immune cells, which was attributable to cell death. This cytotoxic effect was observed when nebulized IgG was administered locally in the airways as compared to a systemic administration but was mitigated by improving IgG stability during nebulization, through the addition of polysorbates to the formulation.
CONCLUSION
CONCLUSIONS
Although inhalation delivery represents an attractive alternative route for delivering Ab to treat respiratory infections, our findings indicate that it is critical to prevent IgG aggregation during the nebulization process to avoid pro-inflammatory and cytotoxic effects. The optimization of Ab formulation can mitigate adverse effects induced by nebulization.
Identifiants
pubmed: 35336045
pii: pharmaceutics14030671
doi: 10.3390/pharmaceutics14030671
pmc: PMC8949695
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : Agence Nationale de la Recherche
ID : ANR-10-LABX-53-01
Références
Ann Neurol. 2000 Nov;48(5):706-12
pubmed: 11079533
Pharm Res. 2003 Dec;20(12):1903-7
pubmed: 14725351
J Mol Biol. 2013 Feb 8;425(3):577-93
pubmed: 23219467
J Pharm Sci. 2009 Apr;98(4):1201-5
pubmed: 18704929
MAbs. 2014;6(5):1347-55
pubmed: 25517319
Front Immunol. 2019 Nov 29;10:2760
pubmed: 31849954
J Pharm Sci. 2014 Jan;103(1):78-89
pubmed: 24227137
J Pharm Sci. 2016 Feb;105(2):417-430
pubmed: 26869409
J Control Release. 2019 Jun 10;303:24-33
pubmed: 30981816
J Pharm Sci. 2008 Oct;97(10):4347-66
pubmed: 18240293
Small. 2010 Aug 2;6(15):1669-78
pubmed: 20602428
J Clin Immunol. 2013 Oct;33(7):1192-203
pubmed: 23832582
Int J Pharm. 2005 Jan 31;289(1-2):1-30
pubmed: 15652195
Regul Toxicol Pharmacol. 2009 Jul;54(2):164-82
pubmed: 19345250
Vaccine. 2014 Nov 20;32(49):6711-23
pubmed: 25454857
Nat Rev Drug Discov. 2019 Jan;18(1):19-40
pubmed: 30498202
Eur J Pharm Biopharm. 2020 Jul;152:23-34
pubmed: 32289493
Cell Death Differ. 2015 Jan;22(1):58-73
pubmed: 25236395
J Allergy Clin Immunol. 2001 Aug;108(2):250-7
pubmed: 11496242
Dev Cell. 2015 Feb 23;32(4):491-501
pubmed: 25710535
Int J Pharm. 2019 Mar 25;559:192-200
pubmed: 30665000
Blood. 2001 Dec 1;98(12):3241-8
pubmed: 11719360
Methods. 2006 Sep;40(1):1-9
pubmed: 16997708
Pharm Res. 1997 Oct;14(10):1472-8
pubmed: 9358564
J Infect Dis. 2002 Jul 1;186(1):64-73
pubmed: 12089663
Int J Pharm. 2013 Apr 15;447(1-2):251-80
pubmed: 23499756
J Biol Chem. 2004 Jul 23;279(30):31374-82
pubmed: 15133040
J Biol Chem. 2012 Jul 20;287(30):25266-79
pubmed: 22584577
J Pharm Sci. 2009 Sep;98(9):2909-34
pubmed: 18823031
J Thromb Haemost. 2015 Nov;13(11):1989-98
pubmed: 26362483
J Biol Chem. 2006 Aug 18;281(33):23514-24
pubmed: 16793771
AAPS J. 2013 Oct;15(4):897-900
pubmed: 23856740
Pharm Res. 2015 Feb;32(2):430-44
pubmed: 25123991
J Pharm Sci. 2015 Feb;104(2):495-507
pubmed: 25522000
Nat Rev Drug Discov. 2002 Jun;1(6):457-62
pubmed: 12119747
Adv Drug Deliv Rev. 2015 Oct 1;93:79-94
pubmed: 25312674
Cell Mol Life Sci. 2016 Jun;73(11-12):2405-10
pubmed: 27048813
Am J Respir Cell Mol Biol. 2014 Oct;51(4):526-35
pubmed: 24773184
J Immunotoxicol. 2014 Apr-Jun;11(2):99-109
pubmed: 23919460
Toxicol Appl Pharmacol. 2010 Jan 1;242(1):56-65
pubmed: 19796648
Pharm Res. 2008 Jun;25(6):1318-26
pubmed: 18030605
J Biol Chem. 2011 Jul 15;286(28):25118-33
pubmed: 21454532
J Pharm Sci. 2019 May;108(5):1637-1654
pubmed: 30599169
Pharmacotherapy. 2006 Jun;26(6):813-27
pubmed: 16716135
Eur J Pharm Biopharm. 2006 Feb;62(2):121-30
pubmed: 16221544
Int J Pharm. 2017 Oct 30;532(1):537-546
pubmed: 28917988
J Immunol Methods. 1995 Jul 17;184(1):39-51
pubmed: 7622868
Expert Opin Drug Deliv. 2018 Aug;15(8):729-736
pubmed: 30025210
AAPS J. 2006 Sep 15;8(3):E572-9
pubmed: 17025275
J Pharm Pharmacol. 2017 Oct;69(10):1341-1351
pubmed: 28639328
J Pharm Sci. 2012 Mar;101(3):914-35
pubmed: 22161573
Bioinformatics. 2017 Aug 01;33(15):2424-2426
pubmed: 28369169