Approximately 14,000 new cases of multiple myeloma (MM) and 1,500 new cases of Waldenstrom's Macroglobulinemia (WM) occur each year in the U.S., making these incurable plasma cell disorders the second most common hematological malignancies. A novel treatment approach for MM and WM patients involves use of antibody mediated immunotherapy (serotherapy) and radioimmunotherapy. As part of our efforts to develop serotherapy for PCD, we have sought to target tumor selective antigens on MM and WM malignant cells. These efforts have focused on Muc-1 core protein, a tumor selective antigen found on most MM plasma cells, and CD20, a B- cell specific antigen found on the plasma cells of most WM patients (75-100 percent), and certain MM patients (20 percent). In addition, we have identified clinically useful inducers for these antigens which have potential use as adjunct agents far serotherapy of PCD. As part of these studies, we will be conducting a Phase II clinical trial examining the efficacy of the anti-CD20 monoclonal antibody (mAb) Rituxan in WM. In view of our previous in vivo data which showed that IFN-gamma is a potent inducer of CD20 on MM plasma cells and augmented Rituxan binding to these cells, a clinical trial will also be initiated that will examine the combined use of IFN-gamma and Rituxan in patients with MM. Important corollary studies will also be performed as part of these trials which will examine CD20 expression pre- and post Rituxan therapy, and post-IFN-gamma therapy for the IFN-gamma/ Rituxan study in MM; presence of tumor defensive antigens (CD46, CD55, CD59, FasL, Muc-1, TRAIL) which may lead to serotherapy resistance; and enhancement of immune effector mechanisms by IFN-gamma. Pre-clinical studies will also be undertaken using the 90Yttrium conjugated anti-CD20 mAb Zevilan, and an 131Iodine conjugated anti-Muc-1 core protein mAb (VU-4H5) so as to determine the feasibility of using radioimmunotherapy for bone marrow centered diseases like MM and WM. In an effort to develop effective unconjugated serotherapy for MM and WM, we will also generate humanized mAbs to Muc-1 core protein. These mAbs will be examined for binding selectivity to MM and WM plasma cells, ability to block ICAM-1/Muc-1 binding, as well as the ability to enact complement dependent and antibody dependent cell mediated cytotoxicity. Analogous to our work with Muc-1, we will also attempt to identify other PCD selective targets by generating and examining mAbs specific to the plasma cell glycoform of CD138.
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