Abstract

The ability of antibodies to target tumors in vivo and provide reduction in tumor burden has been well documented, but many of the issues pertaining to the selection of an optimal radionuclide-MAb conjugate remain unresolved.
The aim of this project is to examine important variables of radioimmunotherapy (RAIT) for the treatment of cancer which relate to the ability of a MAb to internalize into antigen bearing cells. RS7-3G11 is the primary antibody to be used in this project, and has been selected due to a number of promising characteristics. Our preliminary results indicate that RS7-3G11 demonstrates: a) a high frequency of antigen expression on a wide variety of tumor types, especially lung, bladder, breast, cervical, ovarian, prostate, and stomach cancers, with limited expression on normal human tissue; b) the ability to localize to tumor in an animal model; c) the ability to provide reduction in tumor burden in vivo when conjugated to 131I; and d) the ability to rapidly internalize into antigen-bearing cells. The ability to internalize into target cells was not seen with many other MAbs possessing the other positive characteristics, and is a promising property of RS7-3G11 which will enable us to utilize RS7-3G11 in comparative studies on the importance of antibody internalization in RAIT. The proposal is divided into areas of evaluation which are designed to study the selection of radionuclide-MAb conjugate providing the best tumoricidal activity covering (a) choice of radionuclide and labeling technology in relationship to whether or not an antibody internalizes, and (b) evaluations of the biological effects of RAIT with these conjugates and the cellular processing of the radionuclide-MAb conjugates. These studies are designed taking into account the descriptions of the uptake and distribution of antibodies to solid tumors which have been generated using mathematical modeling, and we will assess whether the results we obtain experimentally conform to the predictions of the models.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA060039-02
Application #
2100646
Study Section
Radiation Study Section (RAD)
Project Start
1994-07-20
Project End
1997-06-30
Budget Start
1995-07-01
Budget End
1996-06-30
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost

  Institution

Name
Center for Molecular Medicine/Immunology
Department
Type
DUNS #
City
Belleville
State
NJ
Country
United States
Zip Code
07950

  Publications

Stein, Rhona; Govindan, Serengulam V; Mattes, M Jules et al. (2003) Improved iodine radiolabels for monoclonal antibody therapy. Cancer Res 63:111-8
Stein, R; Govindan, S V; Chen, S et al. (2001) Radioimmunotherapy of a human lung cancer xenograft with monoclonal antibody RS7: evaluation of (177)Lu and comparison of its efficacy with that of (90)Y and residualizing (131)I. J Nucl Med 42:967-74
Stein, R; Govindan, S V; Chen, S et al. (2001) Successful therapy of a human lung cancer xenograft using MAb RS7 labeled with residualizing radioiodine. Crit Rev Oncol Hematol 39:173-80
Govindan, S V; Mattes, M J; Stein, R et al. (1999) Labeling of monoclonal antibodies with diethylenetriaminepentaacetic acid-appended radioiodinated peptides containing D-amino acids. Bioconjug Chem 10:231-40
Patel, S; Stein, R; Ong, G L et al. (1999) Enhancement of tumor-to-nontumor localization ratios by hepatocyte-directed blood clearance of antibodies labeled with certain residualizing radiolabels. J Nucl Med 40:1392-401
Stein, R; Govindan, S V; Mattes, M J et al. (1999) Targeting human cancer xenografts with monoclonal antibodies labeled using radioiodinated, diethylenetriaminepentaacetic acid-appended peptides. Clin Cancer Res 5:3079s-3087s
Stein, R; Chen, S; Haim, S et al. (1997) Advantage of yttrium-90-labeled over iodine-131-labeled monoclonal antibodies in the treatment of a human lung carcinoma xenograft. Cancer 80:2636-41
Stein, R; Goldenberg, D M; Ong, G L et al. (1997) Manipulation of blood clearance to optimize delivery of residualizing label-antibody conjugates to tumor cells in vivo. J Nucl Med 38:1392-400
Blumenthal, R D; Sharkey, R M; Kashi, R et al. (1997) Changes in tumor vascular permeability in response to experimental radioimmunotherapy: a comparative study of 11 xenografts. Tumour Biol 18:367-77
Stein, R; Goldenberg, D M; Thorpe, S R et al. (1997) Advantage of a residualizing iodine radiolabel for radioimmunotherapy of xenografts of human non-small-cell carcinoma of the lung. J Nucl Med 38:391-5

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