ANTIBODY THERAPY OF MICROMETASTASES

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Objectives: Evaluate antibodies labeled with alpha particle emitters in the adjuvant or consolidation treatment of micrometastases. Background: Antibodies against tumor-cell associated antigens have been used in the treatment of cancer as carries of radioactivity. Delivery of intravenously administered antibody to antigen-positive cells in bulky disease is hindered by a number o barriers (e.g., capillary basal lamina, interstitial fluid pressure). These barriers are diminished or eliminated when targeting single cells and small cell clusters. Radionuclides emitting highly effective, short-range particles are required to sterilize such individual cells. Alpha particle-emitters met these requirements, but have not been investigated, clinically. Radiolabeled antibody targeting of micrometastases has also not been investigated clinically. The design of a trial that combines these two novel approaches must be supported by a strong experimental and theoretical rationale. Methods: Humanized S193 (anti-Lewis gamma, breast), CC49 (anti-tag-72, Colorectal), and the single- chain fragment (sFv) of CC49 will be labeled with bismuth-213 (alpha- emitter, 46 min half-life), bismuth-205 (15.3 d) and indium-111 (2.8 d) using the CHXA-DTPA chelate (aim 1). Breast and colorectal carcinoma cells (MCF-7, LS174T) in suspension and as spheroids will be used with the longer-liver Bi-205 and In-111 labels to measure the kinetics of antibody binding, internalization and catabolism to single cells and penetration into spheroids. Using this data with previously developed mathematical models, antibody penetration and binding under a variety of conditions will be simulated (aim 2). Single cell and spheroid cytotoxicity with Bi-213- labeled antibodies will be measured and compared with the predictions of mathematical models that describe antibody kinetics, dosimetry and radiobiology (aim 3). The models and results obtained above, will be combined with estimates of normal-tissue toxicity to assess the potential efficacy of alpha-emitter labeled antibodies against micrometastases and to aid in the optimization of clinical trial design (aim 4). Summary: Radiolabeled antibodies have not been used, clinically, to eliminate metastatic spread. Antibodies labeled with alpha-particle emitters have not been administered to humans. Experimental animal work suggests that a combination of these two approaches may be highly effective with minimal toxicity. Completion of the work proposed in this grant application will make it possible to design a sell-founded clinical study of this promising treatment approach.