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:

Ludwig, Andrew D.  ^[1];

• Search DOE PAGES for author "Ludwig, Andrew D."
• Search DOE PAGES for ORCID "0000-0001-6567-5031"

Labadie, Kevin P. ^[1]; Seo, Y. David ^[1]; Hamlin, Donald K. ^[1]; Nguyen, Holly M. ^[1]; Mahadev, Vimukta M. ^[1]; Yeung, Raymond S.  ^[1];

• Search DOE PAGES for author "Yeung, Raymond S."
• Search DOE PAGES for ORCID "0000-0001-5090-3046"

Wilbur, D. S. ^[1]; Park, James O. ^[1]

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+ Show Author Affiliations

1. Univ. of Washington, Seattle, WA (United States)

Publication Date:

Sun Sep 15 00:00:00 EDT 2019

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