Successful therapy of human cancer with monoclonal antibodies (mAbs) has not yet been achieved, but remains a possibility. Our previous experiments demonstrated that, for most Abs reacting with cell surface antigens, binding is predominantly irreversible, and bound Ab is gradually internalized and degraded, with a half-life of approximately one day. We have also shown that, depending on the radioisotope used to label the Ab, the isotope may be either rapidly excreted from the cell after degradation (example: conventional 125I), or retained for prolonged periods (examples: 111 In or iodinated dilactitol-tyramine, DLT). These results suggest that the processing of a particular isotope after Ab catabolism is a critical factor. Iodinated molecules such as disaccharide derivatives are known to be trapped within lysosomes after catabolism of the protein to which they were linked. It seems likely that the use such """"""""residualizing"""""""" radiolabels can increase the radiation dose delivered from SAbs deposited within tumors, and the major purpose of this proposal is to evaluate this possibility. Labeled Abs will be injected into nude mice bearing human tumor xenografts, to determine whether they produce better tumor/non-tumor localization ratios and better immunotherapy results. These approaches should maximize the toxic effect of radiolabeled Abs at the tumor site, while minimizing their toxicity to normal tissues, and therefore will aid in the thorough evaluation of the potential of radioimmunotherapy. In addition to the DLT label, which was developed previously, we will also evaluate the 125 I-DTAF label. This label appears to be strongly retained within some but not all cell lines. The advantage of this label is that the configation efficiency is considerably higher that with DLT conjugation, and the specific activity approaches that obtained with conventional iodination. Widespread use of """"""""residualizing"""""""" labels will require not only proof of improved efficacy (relative to a conventional label), but also development of simple and efficient conjugation methods.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA063624-03
Application #
2008514
Study Section
Experimental Immunology Study Section (EI)
Project Start
1995-01-01
Project End
1998-06-30
Budget Start
1997-01-01
Budget End
1998-06-30
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Center for Molecular Medicine/Immunology
Department
Type
DUNS #
City
Belleville
State
NJ
Country
United States
Zip Code
07950
Ong, G L; Mattes, M J (2000) Limitations in the use of low pH extraction to distinguish internalized from cell surface-bound radiolabeled antibody. Nucl Med Biol 27:571-5
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
Ong, G L; Mattes, M J (1999) Processing of antibodies to the MHC class II antigen by B-cell lymphomas: release of Fab-like fragments into the medium. Mol Immunol 36:777-88
Griffiths, G L; Govindan, S V; Sgouros, G et al. (1999) Cytotoxicity with Auger electron-emitting radionuclides delivered by antibodies. Int J Cancer 81:985-92
Ong, G L; Mattes, M J (1998) The processing of antibodies bound to B-cell lymphomas: the effect of inadvertent mycoplasma contamination. In Vitro Cell Dev Biol Anim 34:527-8
Reddy, N; Ong, G L; Behr, T M et al. (1998) Rapid blood clearance of mouse IgG2a and human IgG1 in many nude and nu/+ mouse strains is due to low IgG2a serum concentrations. Cancer Immunol Immunother 46:25-33
Karacay, H; Ong, G L; Hansen, H J et al. (1998) Intracellular processing of 99Tcm-antibody conjugates. Nucl Med Commun 19:971-9
Vangeepuram, N; Ong, G L; Mattes, M J (1997) Processing of antibodies bound to B-cell lymphomas and lymphoblastoid cell lines. Cancer 80:2425-30
Mattes, M J; Shih, L B; Govindan, S V et al. (1997) The advantage of residualizing radiolabels for targeting B-cell lymphomas with a radiolabeled anti-CD22 monoclonal antibody. Int J Cancer 71:429-35
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

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