Lymphomas and leukemias contain differentiation antigens which are not found outside the immune system or on stem cells and therefore are useful targets for targeted cancer therapy. To target T cell malignancies, we have fused the Fv fragment of the anti-Tac antibody to a mutant form of Pseudomonas exotoxin A (PE38) to make anti-Tac(Fv)PE38 (LMB-2). This recombinant immunotoxin shows very good antitumor activity in animal models and is now in a Phase I clinical trial. To treat B cell malignancies which express CD22, the Fv regions of MAb RFB4 have been cloned and used to make a disulfide stablized immunotoxin that is very cytotoxic to malignant B cells expressing CD22. In addition, the immunotoxin produces complete regressions of CD22 positive tumors in mice. Toxicology studies have been carried out in monkeys which contain CD22 on their B cells and the recombinant immunotoxin was well tolerated. A clinical trial is planned for 1998. Bone marrow transplantation is used in the treatment of various leukemias. Frequently mismatched donors need to be used resulting in graft vs host disease. We have used anti-Tac(Fv)PE38 (LMB-2) to purge bone marrows of donor cells of alloreactive T cells while leaving other nonactivated T cells unaffected. A clinical trial using this approach to purging has been planned for 1998. To image T cell malignancies, a disulfide stabilized Fv of the anti-Tac antibody was prepared in E. coli and labeled with 99mTc, 131I or 18F. Specific tumor uptake in mice was accomplished with the 131I and 99mTc labeled molecule. However, the yields of the anti-Tac(dsFv) were low. We have reengineered the molecule so that it contains both a peptide linker and a disulfide bond. The peptide linker enhances disulfide bond formation leading to greatly increased yields of the anti-TacFv.
