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Targeted Radioimmunotherapy For The Treatment Of Myeloma: A Preliminary Pharmacodynamic Study
By Kim Orchard, Royal Free Hospital
We propose to study the pharmacodynamics of a radiolabelled mouse monoclonal antibody termed B-B4, which has specificity for syndecan-1, an antigen expressed abundantly on human myeloma cells. This forms a preliminary study prior to developing targeted radioimmunotherapy for the treatment of patients with multiple myeloma.

The results of current treatment options for patients with symptomatic multiple myeloma are disappointing. New treatment strategies directed at the malignant cell population are required.

Radioimmunotherapy (RIT) has been used for the treatment of human malignancies. Tumour targeting and response to treatment has been demonstrated for many malignancies including lymphoma and acute leukemia. Myeloma cells are sensitive to radiation even after the development of resistance to chemotherapy and traditional external beam radiotherapy has an important role in the treatment of localized bone lesions. Antibodies with specificity for antigens present on myeloma cells can be used to deliver therapeutic doses of radiation to sites of disease involvement. The recent description of monoclonal antibodies specific for antigens on myeloma cells provides potential targeting information. One antibody, B-B4, has specificity for syndecan-1 (CD138), an antigen expressed abundantly on mature plasma cells, myeloma cell lines and on myeloma cells from 80 - 100% of patients with myeloma. Syndecan-1 is a member of a family of transmembrane proteins, which are heparan sulphate proteoglycans, it has been shown to interact with type 1 collagen and may function as an adhesion molecule. In addition to mature plasma cells syndecan-1 is also expressed on epithelial cells, fibroblasts and endothelial cells. By immunohistochemistry and FACS analysis, using B-B4, Syndecan-1 expression is most abundant on plasma cells, less on epithelial cells and weak on endothelial cells. However the usefulness of this antigen as a target for immunotherapy will depend upon the relative accessibility and abundance of antigen on myeloma cells in comparison to other cells in vivo, as has been shown for other antigens expressed on epithelial cells. The monoclonal antibody B-B4 has not yet been administered to humans, indeed there are no published reports of RIT targeted to myeloma cells with any antibody vectors.

This study will provide toxicological and pharmacological data for this antibody and allow future development of a RIT protocol for the treatment of patients with multiple myeloma.
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