This proposal will develop and perform pre-clinical evaluation of antibody-toxin conjugates (immunotoxins) for in vivo and in vitro therapy of hematologic malignancies. We plan to: (a) Compare the effectiveness of specific anti-B-cell conjugates produced with antibodies BA2, BA3, and J5 and whole ricin or ricin A-chain and synthesized with either reducible or non-reducible cross-linking reagents; (b) Evaluate the effectiveness of T- and B-cell-directed ricin A-and B-chain conjugates, synthesized using antibodies T101 and 3A1 and BA2 and BA3, respectively, in treating tumor xenografts in athymic mice; (c) Produce hybridomas secreting hybrid monoclonal antibodies posessing both anti-T-cell antigen and anti-ricin A-chain binding sites and compare the in vitro and in vivo efficacy of these reagents once incubated with ricin A- chain, with conventional A-chain conjugates of similar specificities; (d) Prepare immunotoxins with the plant toxin Illudin using illudin congeners and test their efficacy and stability in vitro and in athymic mouse tumor models; and (e) Screen all immunotoxin reagents, alone and in combinations, for specific cytotoxicity against cell-line targets and human bone marrow progenitors (CFU-GM/-GEMM; BFU-E) using liquid cultures and clonogenic assays. This work forms part of a coordinated effort to develop effective antibody-toxin conjugates which could be used as therapeutic agents in cancer treatment.
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