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Therapy of human carcinoma xenografts with antibodies to EGFr and HER-2 conjugated to radionuclides emitting low-energy electrons

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Low-energy electrons (10–50 keV) can be effective and specific cytotoxic agents when delivered to the cell surface by antibodies, because their path length in tissue is comparable to a cell diameter. In this study, we have begun to evaluate the therapeutic potential of antibodies (Abs) conjugated to 111In against carcinoma xenografts in nude mice.

Methods

Abs to EGFr or HER-2 were labeled with 111In to a high specific activity of approximately 1.48 GBq/mg (40 mCi/mg). They were injected into nude mice 5–6 days after inoculation of human carcinoma cells, either A431 or SK-OV-3, and tumor growth was monitored. In preliminary in vitro experiments, we calculated the cumulative decays per cell, estimated the centigray dose delivered to the nucleus, and related this to the fraction surviving.

Results

Abs to both antigens provided significant protection in nude mouse xenograft models (p values ranging from <0.05 to <0.001). Some mice appeared to be cured, but most had delayed tumor growth. The specificity of the effect was demonstrated by testing non-reactive Abs labeled in the same way. The radioactivity was required, because unconjugated Abs had no therapeutic effect. The maximum tolerated dose was required in order for therapy to be effective, but most of the treated mice had no significant weight loss or other overt signs of toxicity.

Conclusion

Abs labeled with nuclides emitting low-energy electrons, such as 111In, can be effective therapeutic agents against microscopic s.c. tumors. This strategy should be considered for clinical applications.

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Acknowledgments

We are grateful to Rosana B. Michel and Maria Zalath for expert and dedicated technical assistance; to Dr. Rhona Stein for providing the Abs to EGFr, EGP-1, and EGP-2; to Thomas Jackson and Dion Yeldel for radiolabeling; and to Louis Osorio for assistance with the animal work. This work was supported in part by a grant from the Komen Foundation BCTR0503639 (to MJM).

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Authors and Affiliations

  1. Garden State Cancer Center at the Center for Molecular Medicine and Immunology, 520 Belleville Avenue, Belleville, NJ, 07109, USA

    M. Jules Mattes & David M. Goldenberg

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  1. M. Jules Mattes
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  2. David M. Goldenberg
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Correspondence to M. Jules Mattes.

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Mattes, M.J., Goldenberg, D.M. Therapy of human carcinoma xenografts with antibodies to EGFr and HER-2 conjugated to radionuclides emitting low-energy electrons. Eur J Nucl Med Mol Imaging 35, 1249–1258 (2008). https://doi.org/10.1007/s00259-008-0731-3

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  • DOI: https://doi.org/10.1007/s00259-008-0731-3

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