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177Lu/90Y Intermediate-Affinity Monoclonal Antibodies Targeting EGFR and HER2/c-neu: Preparation and Preclinical Evaluation

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Theranostics, Gallium-68, and Other Radionuclides

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 194))

Abstract

The epidermal growth factor receptor (EGFR) is a rational target of anticancer therapies due to its overexpression in a variety of malignant epithelial tumors. Nevertheless, this antigen is also present in normal tissues. Consequently, monoclonal antibodies which selectively bind to EGFR-overexpressing tumors will be choice drug candidates for development of radioimmunoconjugates (RIC). Nimotuzumab (h-R3) and trastuzumab are monoclonal antibodies (mAbs) which would preferentially target tissues with EGFR and HER2 overexpression, respectively. In this chapter, we describe preparation and evaluation of the targeting properties of RIC formed by 177Lu/90Y and monoclonal antibodies which selectively target EGFR- and HER2/c-neu-overexpressing tissues. mAbs were labeled with n.c.a. 177Lu/90Y using bifunctional chelating agents. RIC binding properties and toxicity were evaluated in vitro using cell lines with varying antigen expression. In vivo tumor targeting properties of RIC were evaluated in mice bearing colorectal (SNU-C2B) and A431 tumor xenografts. RICs were prepared with specific activities up to 2 GBq/mg without significant loss in biological activity. 90Y-h-R3/trastuzumab increased cell growth inhibition compared with unmodified mAbs or 90YCl3 alone in cell lines with overexpression of the target antigen. 177Lu-h-R3 showed significantly higher uptake in A431 (22.8 ± 3.1% ID/g) than in SNU-C2B (8.8 ± 4.1% ID/g) xenografts at 72 h post injection, indicating strong association between tumor uptake and EGFR expression levels.

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Acknowledgments

We gratefully acknowledge Isotope Technologies Garching GmbH (ITG), Munich, Germany for providing the 177Lu n.c.a. The authors would like to thank Dr. Normando Iznaga and Dr. Angel Casacó (Center of Molecular Immunology) for their outstanding support in the flow cytometric study.

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Authors and Affiliations

  1. Department of Radiopharmaceuticals, Nuclear Physics Institute, Academy of Sciences of the Czech Republic, 250 68 Rez, Prague, Czech Republic

    Denis R. Beckford Vera, Sebastian Eigner, Katerina Eigner Henke, Frantisek Melichar & Milos Beran

  2. Department of Radiopharmacy, Center of Isotopes, Guanabacoa, Ciudad de La Habana, Cuba

    Rene Leyva Montaña

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  1. Denis R. Beckford Vera
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  2. Sebastian Eigner
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  3. Katerina Eigner Henke
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  4. Rene Leyva Montaña
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  5. Frantisek Melichar
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  6. Milos Beran
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Correspondence to Denis R. Beckford Vera .

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  1. , THERANOSTICS Center for Molecular,, ENETS Center of Excellence, Zentralklinik Bad Berka, Bad Berka, 99437, Germany

    Richard P. Baum

  2. Inst. Kernchemie, Universität Mainz, Fritz-Straßmann-Weg 2, Mainz, 55128, Germany

    Frank Rösch

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Beckford Vera, D.R., Eigner, S., Eigner Henke, K., Leyva Montaña, R., Melichar, F., Beran, M. (2013). 177Lu/90Y Intermediate-Affinity Monoclonal Antibodies Targeting EGFR and HER2/c-neu: Preparation and Preclinical Evaluation. In: Baum, R., Rösch, F. (eds) Theranostics, Gallium-68, and Other Radionuclides. Recent Results in Cancer Research, vol 194. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-27994-2_16

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