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Preclinical evaluation of a monoclonal antibody targeting the epidermal growth factor receptor as a radioimmunodiagnostic and radioimmunotherapeutic agent
Author(s) -
Ray GL,
Baidoo KE,
Wong KJ,
Williams M,
Garmestani K,
Brechbiel MW,
Milenic DE
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00327.x
Subject(s) - panitumumab , epidermal growth factor receptor , in vivo , monoclonal antibody , a431 cells , epidermal growth factor , cancer research , radioimmunotherapy , chemistry , in vitro , cell culture , microbiology and biotechnology , receptor , pathology , medicine , antibody , biology , immunology , cell , cetuximab , biochemistry , cell cycle , oncogene , genetics
Background and purpose: The studies described here are the first to evaluate the in vitro and in vivo properties of 111 In‐CHX‐A″‐panitumumab for radioimmunotherapy (α‐ and β ‐ ‐emitters) and radioimmunoimaging (single photon emission computed tomography and positron emission tomography). Experimental approach: Twenty‐seven human carcinoma cell lines were analysed for expression of epidermal growth factor receptors by flow cytometry. Panitumumab was conjugated with CHX‐A″‐DTPA (diethylenetriamine‐pentaacetic acid) and radiolabelled with 111 In. Immunoreactivity of the CHX‐A″‐DTPA‐panitumumab and 111 In‐CHX‐A″‐DTPA‐panitumumab was evaluated by radioimmunoassays. Tumour targeting was determined in vivo by direct quantitation of tumour and normal tissues and by γ‐scintigraphy. Key results: For 26 of 27 human tumour cell lines, 95% of the cells expressed epidermal growth factor receptors over a range of intensity. Immunoreactivity of panitumumab was retained after modification with CHX‐A″‐DTPA. Radiolabelling of the immunoconjugate with 111 In was efficient with a specific activity of 19.5 ± 8.9 mCi·mg −1 obtained. Immunoreactivity and specificity of binding of the 111 In‐panitumumab was shown with A431 cells. Tumour targeting by 111 In‐panitumumab was demonstrated in athymic mice bearing A431, HT‐29, LS‐174T, SHAW or SKOV‐3 s.c. xenografts with little uptake observed in normal tissues. The 111 In‐panitumumab was also evaluated in non‐tumour‐bearing mice. Pharmacokinetic studies compared the plasma retention time of the 111 In‐panitumumab in both non‐tumour‐bearing and A431 tumour‐bearing mice. Tumour targeting was also visualized by γ‐scintigraphy. Conclusions and implications: Panitumumab can be efficiently radiolabelled with 111 In with high labelling yields. Based on the efficiency in tumour targeting and low normal tissue uptake, panitumumab may be an effective targeting component for radioimmunodiagnostic and radioimmunotherapeutic applications.