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Title: Yttrium-90-Labeled Anti-Glypican 3 Radioimmunotherapy Halts Tumor Growth in an Orthotopic Xenograft Model of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the second most lethal malignancy globally and is increasing in incidence in the United States. Unfortunately, there are few effective systemic treatment options, particularly for disseminated disease. Glypican-3 (GPC3) is a proteoglycan cell surface receptor overexpressed in most HCCs and provides a unique target for molecular therapies. We have previously demonstrated that PET imaging using a 89Zr-conjugated monoclonal anti-GPC3 antibody (αGPC3) can bind to minute tumors and allow imaging with high sensitivity and specificity in an orthotopic xenograft mouse model of HCC and that serum alpha-fetoprotein (AFP) levels are highly correlated with tumor size in this model. In the present study, we conjugated 90Y, a high-energy beta-particle-emitting radionuclide, to our αGPC3 antibody to develop a novel antibody-directed radiotherapeutic approach for HCC. Luciferase-expressing HepG2 human hepatoblastoma cells were orthotopically implanted in the livers of athymic nude mice, and tumor establishment was verified at 6 weeks after implantation by bioluminescent imaging and serum AFP concentration. Tumor burden by bioluminescence and serum AFP concentration was highly correlated in our model. Yttrium-90 was conjugated to αGPC3 using the chelating agent 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and injected via the tail vein into the experimental mice at a dose of 200 μCi/mouse ormore » 300 μCi/mouse. Control mice received DOTA-αGPC3 without radionuclide. At 30 days after a single dose of the radioimmunotherapy agent, mean serum AFP levels in control animals increased dramatically, while animals treated with 200 μCi only experienced a minor increase, indicating cessation of tumor growth, and animals treated with 300 μCi experienced a reduction in serum AFP concentration, indicating tumor shrinkage. Mean tumor-bearing liver weight in control animals was also significantly greater than that in animals that received either dose of 90Y-αGPC3. These results were achieved without significant toxicity as measured by body condition scoring and body weight. The results of this preclinical pilot demonstrate that GPC3 can be used as a target for radioimmunotherapy in an orthotopic mouse model of HCC and may be a target of clinical significance, particularly for disseminated HCC.« less

Authors:
ORCiD logo [1];  [1];  [1];  [1];  [1];  [1]; ORCiD logo [1];  [1];  [1]
  1. Univ. of Washington, Seattle, WA (United States)
Publication Date:
Research Org.:
Univ. of Washington, Seattle, WA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1611807
Grant/Contract Number:  
SC0012445
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Oncology
Additional Journal Information:
Journal Volume: 2019; Journal ID: ISSN 1687-8450
Publisher:
Hindawi
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Oncology

Citation Formats

Ludwig, Andrew D., Labadie, Kevin P., Seo, Y. David, Hamlin, Donald K., Nguyen, Holly M., Mahadev, Vimukta M., Yeung, Raymond S., Wilbur, D. S., and Park, James O. Yttrium-90-Labeled Anti-Glypican 3 Radioimmunotherapy Halts Tumor Growth in an Orthotopic Xenograft Model of Hepatocellular Carcinoma. United States: N. p., 2019. Web. https://doi.org/10.1155/2019/4564707.
Ludwig, Andrew D., Labadie, Kevin P., Seo, Y. David, Hamlin, Donald K., Nguyen, Holly M., Mahadev, Vimukta M., Yeung, Raymond S., Wilbur, D. S., & Park, James O. Yttrium-90-Labeled Anti-Glypican 3 Radioimmunotherapy Halts Tumor Growth in an Orthotopic Xenograft Model of Hepatocellular Carcinoma. United States. https://doi.org/10.1155/2019/4564707
Ludwig, Andrew D., Labadie, Kevin P., Seo, Y. David, Hamlin, Donald K., Nguyen, Holly M., Mahadev, Vimukta M., Yeung, Raymond S., Wilbur, D. S., and Park, James O. Sun . "Yttrium-90-Labeled Anti-Glypican 3 Radioimmunotherapy Halts Tumor Growth in an Orthotopic Xenograft Model of Hepatocellular Carcinoma". United States. https://doi.org/10.1155/2019/4564707. https://www.osti.gov/servlets/purl/1611807.
@article{osti_1611807,
title = {Yttrium-90-Labeled Anti-Glypican 3 Radioimmunotherapy Halts Tumor Growth in an Orthotopic Xenograft Model of Hepatocellular Carcinoma},
author = {Ludwig, Andrew D. and Labadie, Kevin P. and Seo, Y. David and Hamlin, Donald K. and Nguyen, Holly M. and Mahadev, Vimukta M. and Yeung, Raymond S. and Wilbur, D. S. and Park, James O.},
abstractNote = {Hepatocellular carcinoma (HCC) is the second most lethal malignancy globally and is increasing in incidence in the United States. Unfortunately, there are few effective systemic treatment options, particularly for disseminated disease. Glypican-3 (GPC3) is a proteoglycan cell surface receptor overexpressed in most HCCs and provides a unique target for molecular therapies. We have previously demonstrated that PET imaging using a 89Zr-conjugated monoclonal anti-GPC3 antibody (αGPC3) can bind to minute tumors and allow imaging with high sensitivity and specificity in an orthotopic xenograft mouse model of HCC and that serum alpha-fetoprotein (AFP) levels are highly correlated with tumor size in this model. In the present study, we conjugated 90Y, a high-energy beta-particle-emitting radionuclide, to our αGPC3 antibody to develop a novel antibody-directed radiotherapeutic approach for HCC. Luciferase-expressing HepG2 human hepatoblastoma cells were orthotopically implanted in the livers of athymic nude mice, and tumor establishment was verified at 6 weeks after implantation by bioluminescent imaging and serum AFP concentration. Tumor burden by bioluminescence and serum AFP concentration was highly correlated in our model. Yttrium-90 was conjugated to αGPC3 using the chelating agent 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and injected via the tail vein into the experimental mice at a dose of 200 μCi/mouse or 300 μCi/mouse. Control mice received DOTA-αGPC3 without radionuclide. At 30 days after a single dose of the radioimmunotherapy agent, mean serum AFP levels in control animals increased dramatically, while animals treated with 200 μCi only experienced a minor increase, indicating cessation of tumor growth, and animals treated with 300 μCi experienced a reduction in serum AFP concentration, indicating tumor shrinkage. Mean tumor-bearing liver weight in control animals was also significantly greater than that in animals that received either dose of 90Y-αGPC3. These results were achieved without significant toxicity as measured by body condition scoring and body weight. The results of this preclinical pilot demonstrate that GPC3 can be used as a target for radioimmunotherapy in an orthotopic mouse model of HCC and may be a target of clinical significance, particularly for disseminated HCC.},
doi = {10.1155/2019/4564707},
journal = {Journal of Oncology},
number = ,
volume = 2019,
place = {United States},
year = {2019},
month = {9}
}

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