Recent results of cancer radioimmunotherapy (using radiolabeled antibodies) have been encouraging, especially for B-cell lymphoma. However, the selection of the optimal Ab and radionuclide remains uncertain. While high energy beta-emitters, which have been widely used, can kill large tumor masses, the radiation dose delivered is primarily due to the cross-fire from neighboring cells and such radiation is unable to efficiently and specially kill single cells in vitro. This of course represents a significant clinical problem, since it implies that single cells or small clusters of cells cannot be effectively targeted by RAIT. Radioisotopes emitting Auger and conversion electrons, which are very low energy electrons, are potentially able to kill single target cells if sufficient radioactivity is delivered intracellularly. The investigators have characterized an Ab, LL1, anti-MHC class II invariant chain (CD74), which reacts with B-cell lymphomas and is internalized by cells in large amounts, approximately 107 Ab molecules internalized per cell per day. The investigators have demonstrated that this Ab conjugated to 111 In or 99mTc, which are Auger electron-emitters, kills B-cell lymphoma cells specifically and efficiently. Conjugates with 125I are also effective, but only if a residualizing form of 125I is used (which is trapped in lysosomes after catabolism of the Ab to which it was attached). Conjugates with beta-particle emitters, 131 I and 90Y, are also able to kill cells specifically, although with a higher level of non-specific toxicity. The investigators propose herein to further test, in a more quantitative assay, the ability of these conjugates to kill tumor cells, in order to select the optimal isotope. In addition to in vitro studies, toxicity in vivo will also be evaluated, using nude or SCID mice bearing human tumor xenografts. Preliminary data shows effective therapy of systemic B cell lymphoma in SCID mice by 111In-LL1. Since the antigen recognized is also expressed on melanomas and carcinoma cells, after induction by interferon-gamma, these target cells will also be tested. They will also attempt to extend these experiments to other Abs, particularly those that react with high-density antigens, labeled to a high specific activity. This study may lead to the development of more effective radio-conjugates for the therapy of cancer and other diseases. Also, it will provide basic information about the toxic effects of intracellular (really lysosomal) radionuclides.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA087059-01
Application #
6166028
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Stone, Helen B
Project Start
2000-05-01
Project End
2003-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
1
Fiscal Year
2000
Total Cost
$299,250
Indirect Cost
Name
Center for Molecular Medicine/Immunology
Department
Type
DUNS #
City
Belleville
State
NJ
Country
United States
Zip Code
07950
Michel, Rosana B; Andrews, Philip M; Rosario, Adriane V et al. (2005) 177Lu-antibody conjugates for single-cell kill of B-lymphoma cells in vitro and for therapy of micrometastases in vivo. Nucl Med Biol 32:269-78
Jules Mattes, M (2005) High-sensitivity cytotoxicity assays for nonadherent cells. Methods Mol Med 110:29-37
Govindan, Serengulam V; Michel, Rosana B; Griffiths, Gary L et al. (2005) Deferoxamine as a chelator for 67Ga in the preparation of antibody conjugates. Nucl Med Biol 32:513-9
Michel, Rosana B; Andrews, Philip M; Castillo, Mary Ellen et al. (2005) In vitro cytotoxicity of carcinoma cells with 111In-labeled antibodies to HER-2. Mol Cancer Ther 4:927-37
Michel, Rosana B; Rosario, Adriane V; Andrews, Philip M et al. (2005) Therapy of small subcutaneous B-lymphoma xenografts with antibodies conjugated to radionuclides emitting low-energy electrons. Clin Cancer Res 11:777-86
Michel, R B; Mattes, M J (2004) Antibodies to CD20 and MHC class II antigen bound to B-lymphoma cells accumulate in shed cytoplasmic fragments. Br J Cancer 91:1500-7
Michel, Rosana B; Castillo, Mary Ellen; Andrews, Philip M et al. (2004) In vitro toxicity of A-431 carcinoma cells with antibodies to epidermal growth factor receptor and epithelial glycoprotein-1 conjugated to radionuclides emitting low-energy electrons. Clin Cancer Res 10:5957-66
Michel, Rosana B; Brechbiel, Martin W; Mattes, M Jules (2003) A comparison of 4 radionuclides conjugated to antibodies for single-cell kill. J Nucl Med 44:632-40
Michel, Rosana B; Rosario, Adriane V; Brechbiel, Martin W et al. (2003) Experimental therapy of disseminated B-Cell lymphoma xenografts with 213Bi-labeled anti-CD74. Nucl Med Biol 30:715-23
Michel, Rosana B; Mattes, M Jules (2002) Intracellular accumulation of the anti-CD20 antibody 1F5 in B-lymphoma cells. Clin Cancer Res 8:2701-13

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