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Pharmaceuticals 2012, 5(1), 1-15; doi:10.3390/ph5010001

Pre-Clinical Assessment of 177Lu-Labeled Trastuzumab Targeting HER2 for Treatment and Management of Cancer Patients with Disseminated Intraperitoneal Disease

1 Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA 2 Biostatistics and Bioinformatics Branch, Division of Epidemiology, Statistics & Prevention, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA
* Author to whom correspondence should be addressed.
Received: 4 November 2011 / Revised: 6 December 2011 / Accepted: 14 December 2011 / Published: 22 December 2011
(This article belongs to the Special Issue Antibody Conjugates)
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Studies from this laboratory have demonstrated the potential of targeting HER2 for therapeutic and imaging applications with medically relevant radionuclides. To expand the repertoire of trastuzumab as a radioimmunoconjugate (RIC) vector, use of 177Lu was investigated. The combination of a 6.7 d half-life, lower energy β-emissions (500 keV max; 130 keV ave), and an imagable γ-emission make 177Lu an attractive candidate for radioimmunotherapy (RIT) regimens for treatment of larger tumor burdens not possible with α-particle radiation. Radiolabeling trastuzumab-CHX-A″-DTPA with 177Lu was efficient with a specific binding of 60.8 ± 6.8% with HER2 positive SKOV-3 cells. Direct quantitation of tumor targeting and normal tissue uptake was performed with athymic mice bearing subcutaneous and intraperitoneal LS-174T xenografts; a peak tumor %ID/g of 24.70 ± 10.29 (96 h) and 31.70 ± 16.20 (72 h), respectively, was obtained. Normal tissue uptake of the RIC was minimal. Tumor targeting was also demonstrated by γ-scintigraphy. A therapy study administering escalating doses of 177Lu-trastuzumab to mice bearing three day LS-174T i.p. xenografts established the effective therapeutic dose of i.p. administered 177Lu-trastuzumab at 375 μCi with a median survival of 124.5 d while a median survival of 10 d was noted for the control (untreated) group. In conclusion, trastuzumab radiolabeled with 177Lu has potential for treatment of disseminated, HER2 positive, peritoneal disease.
Keywords: 177Lutetium; radioimmunotherapy; trastuzumab; HER2; intraperitoneal disease 177Lutetium; radioimmunotherapy; trastuzumab; HER2; intraperitoneal disease
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Ray, G.L.; Baidoo, K.E.; Keller, L.M.M.; Albert, P.S.; Brechbiel, M.W.; Milenic, D.E. Pre-Clinical Assessment of 177Lu-Labeled Trastuzumab Targeting HER2 for Treatment and Management of Cancer Patients with Disseminated Intraperitoneal Disease. Pharmaceuticals 2012, 5, 1-15.

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