IMMUNOTOXIN AND RECOMBINANT TOXIN THERAPY OF CANCER

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For the treatment of human cancer, we have developed an immunotoxin, termed LMB-1, in which monoclonal B3 is coupled to LysPE38. LMB-1 has been approved by the FDA and is ready to enter clinical trials. A second generation recombinant immunotoxin, LMB-7, combines the variable region of the B3 antibody with PE38. This agent is very active in mice bearing human tumor xenografts, and is well tolerated by monkeys. Efforts are underway to prepare material for clinical use. Mutant forms of PE have been created which can be selectively derivatized by polyethylene glycol to reduce immunogenicity and increase survival in the blood. Several of these mutations will be subcloned into LMB-7 to see if this recombinant immunotoxin retains activity and is less immunogenic. In addition, we have begun to identify the principle immunogenic epitopes in LMB-7. A chelate of the B3 antibody has been prepared and when labeled with 111In will image tumors in mice. A clinical grade radioconjugate is currently being prepared. Single chain immunotoxins directed at the IL2 receptor have been made and shown to cause complete regression of tumors bearing 1L2 receptors in mice. One of these, anti-Tac(Fv)-PE38, is being prepared for clinical development. A new antibody that reacts with an antigen on normal prostate and prostate carcinomas has been developed. The antibody is an IgM and the variable regions have been cloned and grafted onto a human IgG1 constant region. The possible usefulness of this antibody for therapy or diagnosis of prostate cancer is being examined. Other immunotoxins directed against the EGF receptor, the erbB2 protein, the IL6 receptor, and the IL4 receptor are also being developed. We have previously proposed that a 37 kD fragment of PE (aa 280-613) translocates to the cytosol through pores in the endoplasmic reticulum. Using a cell-free system containing microsomes, direct evidence for an interaction between PE (280- 613) with microsomal protein transport pores has been obtained.