Engineered Anti-GPC3 Immunotoxin, HN3-ABD-T20, Produces Regression in Mouse Liver Cancer Xenografts Through Prolonged Serum Retention.
ADP Ribose Transferases
/ chemistry
Animals
Bacterial Toxins
/ chemistry
Carcinoma, Hepatocellular
/ therapy
Cell Line, Tumor
Exotoxins
/ chemistry
Glypicans
/ antagonists & inhibitors
Humans
Immunotoxins
/ chemistry
Liver Neoplasms
/ therapy
Mice
Mice, Nude
Single-Domain Antibodies
/ chemistry
Virulence Factors
/ chemistry
Xenograft Model Antitumor Assays
Pseudomonas aeruginosa Exotoxin A
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
22
04
2019
accepted:
08
09
2019
pubmed:
15
9
2019
medline:
21
4
2021
entrez:
15
9
2019
Statut:
ppublish
Résumé
Treatment of hepatocellular carcinomas using our glypican-3 (GPC3)-targeting human nanobody (HN3) immunotoxins causes potent tumor regression by blocking protein synthesis and down-regulating the Wnt signaling pathway. However, immunogenicity and a short serum half-life may limit the ability of immunotoxins to transition to the clinic. To address these concerns, we engineered HN3-based immunotoxins to contain various deimmunized Pseudomonas exotoxin (PE) domains. This included HN3-T20, which was modified to remove T-cell epitopes and contains a PE domain II truncation. We compared them to our previously reported B-cell deimmunized immunotoxin (HN3-mPE24) and our original HN3-immunotoxin with a wild-type PE domain (HN3-PE38). All of our immunotoxins displayed high affinity to human GPC3, with HN3-T20 having a K These data indicate that ABD-containing deimmunized HN3-T20 immunotoxins are high-potency therapeutics ready to be evaluated in clinical trials for the treatment of liver cancer.
Sections du résumé
BACKGROUND AND AIMS
Treatment of hepatocellular carcinomas using our glypican-3 (GPC3)-targeting human nanobody (HN3) immunotoxins causes potent tumor regression by blocking protein synthesis and down-regulating the Wnt signaling pathway. However, immunogenicity and a short serum half-life may limit the ability of immunotoxins to transition to the clinic.
APPROACH AND RESULTS
To address these concerns, we engineered HN3-based immunotoxins to contain various deimmunized Pseudomonas exotoxin (PE) domains. This included HN3-T20, which was modified to remove T-cell epitopes and contains a PE domain II truncation. We compared them to our previously reported B-cell deimmunized immunotoxin (HN3-mPE24) and our original HN3-immunotoxin with a wild-type PE domain (HN3-PE38). All of our immunotoxins displayed high affinity to human GPC3, with HN3-T20 having a K
CONCLUSION
These data indicate that ABD-containing deimmunized HN3-T20 immunotoxins are high-potency therapeutics ready to be evaluated in clinical trials for the treatment of liver cancer.
Identifiants
pubmed: 31520528
doi: 10.1002/hep.30949
pmc: PMC7069773
mid: NIHMS1050659
doi:
Substances chimiques
Bacterial Toxins
0
Exotoxins
0
GPC3 protein, human
0
Glypicans
0
Immunotoxins
0
Single-Domain Antibodies
0
Virulence Factors
0
ADP Ribose Transferases
EC 2.4.2.-
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1696-1711Subventions
Organisme : Intramural NIH HHS
ID : Z01 BC010891
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC010891
Pays : United States
Organisme : NCI NIH HHS
Pays : United States
Informations de copyright
© 2019 by the American Association for the Study of Liver Diseases.
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