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

Pharmaceuticals

Geoffrey L. Ray¹  Kwamena E. Baidoo¹  Lanea M. M. Keller¹  Paul S. Albert²  Martin W. Brechbiel¹ 

[1] 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;

关键词: ¹⁷⁷Lutetium;    radioimmunotherapy;    trastuzumab;    HER2;    intraperitoneal disease;   

DOI  :  10.3390/ph5010001

来源: mdpi

【 摘 要 】

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 administeringescalating 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.

【 授权许可】

CC BY   
© 2012 by the authors; licensee MDPI, Basel, Switzerland.