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INTRODUCTION

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Tositumomab is a monoclonal antibody that selectively binds to CD20 antigen on the surface of normal and malignant B cells. Tositumomab can be labelled with iodine-131 (131I) to yield 131I-labelled tositumomab [1]. The combination of unlabelled and I 131-labelled tositumomab is registered as tositumomab and 131I-tositumomab or Bexxar therapeutic regimen. 131I-tositumomab belongs to a novel class of therapy for non-Hodgkin’s lymphomas (NHLs) known as radioimmunotherapy (RIT). The activity of 131I-tositumomab depends on several mechanisms of action, including ionising radiation from 131I and on antibody-mediated mechanisms, such as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and induction of apoptosis. In June 2003, 131I-tositumomab was approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with CD20–positive, follicular, NHL, with and without transformation, whose disease is refractory to rituximab and has relapsed following chemotherapy. On January 3, 2005, the FDA approved an expanded indication for 131I-tositumomab. 131I-tositumomab is now indicated for the treatment of patients with CD20 antigen-expressing relapsed or refractory, low-grade, follicular, or transformed NHL including patients with rituximab-refractory NHL.

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RATIONALE

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Unlabelled monoclonal antibodies have shown promising efficacy in the treatment of NHL. However, unlabelled antibodies, when used alone, rarely produce complete responses, presumably due to variable and incomplete penetration of antibodies into lymphoma cells. One of the ways of improving the efficacy of unlabelled antibodies is to use them as carriers of radiation. It is well established that lymphomas are exquisitely sensitive to ionising radiation and that relapses rarely occur in irradiated sites of disease. Radiolabelled antibodies can retain immune-mediated and other mechanisms of action against lymphoma cells and at the same time can overcome some of the inherent limitations of unlabelled antibodies. Because ionising particles emitted from the radioisotope can travel through a number of cell diameters, many tumour cells within a tumour can be killed by a single radiolabelled antibody bound to a tumour cell. In addition, crossfire of ionising particles is created from multiple radiolabelled antibodies bound to cells within a tumour, further intensifying the radiation dose to tumour cells (Figure 12.1). This effect is particularly important in bulkier tumours in which vascular access for antibodies to reach cells deep within a tumour may be limited. Furthermore, tumour cells either lacking the target antigen or expressing a small amount of antigen can be killed by crossfiring particles. Moreover, radiation from radiolabelled antibodies could be effective against tumour cells that have developed resistance to either immune or direct antibody cell killing. Therefore, radiolabelled antibodies can make use of multiple mechanisms of attack on tumour cells. Because systemic treatment with radiolabelled antibodies results in targeting of radiation to tumour sites via the specificity of the antibody, RIT, in contrast to conventional whole body irradiation, delivers more radiation to tumour sites than to normal tissues. Finally, in contrast to conventional external beam radiation therapy, in which radiation ...

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