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Pharmaceuticals 2012, 5(1), 1-15;

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

Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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. View Full-Text
Keywords: 177Lutetium; radioimmunotherapy; trastuzumab; HER2; intraperitoneal disease 177Lutetium; radioimmunotherapy; trastuzumab; HER2; intraperitoneal disease

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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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