The long goal of this Program Project Grant is to improve therapy for B cell lymphomas by optimizing regimens of immunotoxin (IT) therapy and, eventually, combining this regimen with conventional chemotherapy in an effort to reduce mortality and morbidity from these diseases. Principles that emanate from such studies should be applicable to other types of cancer. The Program Project involves a core facility in which preparation, purification and pre-clinical testing of the immunotoxins is accomplished. Two immunotoxins that differ in antigenic specificity will be prepared for this project. Both consist of intact murine monoclonal IgG antibodies but one is directed to CD22 and the other to CD19. Each of these intact antibodies is covalently conjugated by a heterobifunctional crosslinker containing a hindered disulfide bond (SMPT) to the deglycosylated form of ricin A chain (dgA). A Phase I clinical trial is close to completion for the IgG-CD22 dgA. We have ben able to administer up to 50% of the calculated human LD50 dose with predictable and modest side effects and have not yet reached MTD. We believe that MTD may be reached with the next two dose escalations. Significant efficacy has been demonstrated. It is now planned to obtain FDA approval for a Phase II clinical trial. A Phase I clinical trial is planned for the IgG-CD19-SMPT-dgA. Approval has already been obtained from the FDA for this trial. Finally, a level covered under the aegis of another grant will help us evaluate strategies for designing optimal clinical trials and in particular, the potential combined use of both immunotoxins with conventional therapy.
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