Improved targeting of an anti-TAG-72 antibody drug conjugate for the treatment of ovarian cancer.
Acetates
/ chemistry
Animals
Antibodies, Neoplasm
/ blood
Antigens, Neoplasm
/ immunology
Cell Line, Tumor
Female
HT29 Cells
Humans
Immunoconjugates
/ therapeutic use
Immunologic Factors
/ pharmacokinetics
Mice
Oligopeptides
/ blood
Ovarian Neoplasms
/ blood
Positron-Emission Tomography
Random Allocation
Sulfones
/ chemistry
TAG72
antibody drug conjugate
ovarian cancer
Journal
Cancer medicine
ISSN: 2045-7634
Titre abrégé: Cancer Med
Pays: United States
ID NLM: 101595310
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
24
11
2019
revised:
18
01
2020
accepted:
29
01
2020
pubmed:
6
5
2020
medline:
4
5
2021
entrez:
6
5
2020
Statut:
ppublish
Résumé
Ovarian cancer has only a 17% 5-year survival rate in patients diagnosed with late stage disease. Tumor-associated glycoprotein-72 (TAG72), expressed in 88% of all stages of ovarian cancer, is an excellent candidate for antibody-targeted therapy, as it is not expressed in normal human adult tissues, except in the secretory endometrium. Using the clinically relevant anti-TAG72 murine monoclonal antibody CC49, we evaluated antibody drug conjugates (ADCs) incorporating the highly potent, synthetic antimitotic agent monomethylauristatin E (MMAE). MMAE was conjugated to CC49 via reduced disulfides in the hinge region, using three different types of linker chemistry, vinylsulfone (VS-MMAE), bromoacetamido (Br-MMAE), and maleimido (mal-MMAE). The drug antibody ratios (DARs) of the three ADCs were 2.3 for VS-MMAE, 10 for Br-MMAE, and 9.5 for mal-MMAE. All three ADCs exhibited excellent tumor to blood ratios on PET imaging, but the absolute uptake of CC49-mal-MMAE (3.3%ID/g) was low compared to CC49-Br-MMAE (6.43%ID/g), at 142 hours. Blood clearance at 43 hours was 38% for intact CC49, about 24% for both CC49-VS-MMAE and CC49-Br-MMAE, and 7% for CC49-mal-MMAE. CC49-VS-MMAE was not further studied due to its low DAR, while CC49-mal-MMAE was ineffective in the OVCAR3 xenograft likely due to its rapid blood clearance. In contrast, CC49-Br-MMAE treated mice exhibited an average of a 15.6 day tumor growth delay and a 40% increase in survival vs controls with four doses of 7.5 or 15 mg/kg of CC49-Br-MMAE. We conclude that CC49-Br-MMAE with a high DAR and stable linker performs well in a difficult to treat solid tumor model.
Identifiants
pubmed: 32368864
doi: 10.1002/cam4.3078
pmc: PMC7333846
doi:
Substances chimiques
Acetates
0
Antibodies, Neoplasm
0
Antigens, Neoplasm
0
B72.3 antibody
0
Immunoconjugates
0
Immunologic Factors
0
Oligopeptides
0
Sulfones
0
tumor-associated antigen 72
0
divinyl sulfone
5PFN71LP8M
bromoacetate
68-10-0
monomethyl auristatin E
V7I58RC5EJ
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
4756-4767Subventions
Organisme : NCI NIH HHS
ID : P30 CA033572
Pays : United States
Informations de copyright
© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
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