Cysteine metabolic engineering and selective disulfide reduction produce superior antibody-drug-conjugates.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
04 05 2022
04 05 2022
Historique:
received:
19
10
2021
accepted:
18
04
2022
entrez:
4
5
2022
pubmed:
5
5
2022
medline:
7
5
2022
Statut:
epublish
Résumé
Next-generation site-specific cysteine-based antibody-drug-conjugates (ADCs) broaden therapeutic index by precise drug-antibody attachments. However, manufacturing such ADCs for clinical validation requires complex full reduction and reoxidation processes, impacting product quality. To overcome this technical challenge, we developed a novel antibody manufacturing process through cysteine (Cys) metabolic engineering in Chinese hamster ovary cells implementing a unique cysteine-capping technology. This development enabled a direct conjugation of drugs after chemoselective-reduction with mild reductant tris(3-sulfonatophenyl)phosphine. This innovative platform produces clinical ADC products with superior quality through a simplified manufacturing process. This technology also has the potential to integrate Cys-based site-specific conjugation with other site-specific conjugation methodologies to develop multi-drug ADCs and exploit multi-mechanisms of action for effective cancer treatments.
Identifiants
pubmed: 35508689
doi: 10.1038/s41598-022-11344-z
pii: 10.1038/s41598-022-11344-z
pmc: PMC9068625
doi:
Substances chimiques
Antibodies
0
Antineoplastic Agents
0
Disulfides
0
Immunoconjugates
0
Cysteine
K848JZ4886
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
7262Informations de copyright
© 2022. The Author(s).
Références
J Cell Physiol. 2019 May;234(5):5628-5642
pubmed: 30478951
Nat Commun. 2021 Jun 10;12(1):3528
pubmed: 34112795
Methods Enzymol. 1995;251:8-28
pubmed: 7651233
Science. 2020 Nov 13;370(6518):865-869
pubmed: 33184216
MAbs. 2009 Nov-Dec;1(6):563-71
pubmed: 20068389
Biotechnol Prog. 2015 Nov-Dec;31(6):1645-56
pubmed: 26399954
PLoS Biol. 2010 Jun 29;8(6):e1000412
pubmed: 20613859
MAbs. 2014 Jan-Feb;6(1):34-45
pubmed: 24423619
Nat Biotechnol. 2015 Jul;33(7):694-6
pubmed: 26154005
J Clin Invest. 2011 Oct;121(10):3786-8
pubmed: 21965334
Antibodies (Basel). 2021 Mar 30;10(2):
pubmed: 33808165
Pharmaceuticals (Basel). 2020 Sep 14;13(9):
pubmed: 32937862
Annu Rev Nutr. 2004;24:539-77
pubmed: 15189131
Nat Rev Clin Oncol. 2015 Jul;12(7):381-94
pubmed: 25895611
Nat Biotechnol. 2008 Aug;26(8):925-32
pubmed: 18641636
Nat Biotechnol. 2019 May;37(5):523-526
pubmed: 30936563
Sci Adv. 2020 Jun 03;6(23):eaba6752
pubmed: 32537509
Protein Eng Des Sel. 2018 Feb 1;31(2):47-54
pubmed: 29370435
J Biotechnol. 2017 Apr 20;248:48-58
pubmed: 28300660
Science. 2017 Feb 10;355(6325):597-602
pubmed: 28183972
Nat Rev Drug Discov. 2017 May;16(5):315-337
pubmed: 28303026
Bioconjug Chem. 2018 Feb 21;29(2):473-485
pubmed: 29425028
Nature. 2015 Nov 19;527(7578):323-8
pubmed: 26536114
Nat Biotechnol. 2015 Jul;33(7):733-5
pubmed: 26076429
SLAS Discov. 2020 Sep;25(8):843-868
pubmed: 32192384
Nat Chem. 2016 Feb;8(2):114-9
pubmed: 26791893
AAPS J. 2017 Jul;19(4):1123-1135
pubmed: 28439809
Molecules. 2021 Sep 27;26(19):
pubmed: 34641391
Biotechnol Bioeng. 2011 Jun;108(6):1328-37
pubmed: 21328318
Rapid Commun Mass Spectrom. 2010 Feb;24(3):267-75
pubmed: 20049891
Antioxid Redox Signal. 2013 Feb 10;18(5):522-55
pubmed: 22667998
Nat Commun. 2017 Oct 24;8(1):1112
pubmed: 29062027
Nat Rev Clin Oncol. 2021 Jun;18(6):327-344
pubmed: 33558752