IMMUNOTOXIN THERAPY OF OLID TUMORS--PRECLINICAL STUDIES

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We produce recombinant immunotoxins by fusing the Fv fragments of antibodies to a mutant form of Pseudomoans exotoxin A termed PE38. For immunotoxin therapy or other targeted therapies of cancer to be successful, it is necessary to detect antigenic targets on solid tumors. Our efforts to detect new antigenic targets are summarized as follows: (1) Ovarian cancers and mesotheliomas express a differentiation antigen termed mesothelin. We have used phage display techniques to identify new single chain antibodies to mesothelin. One of these binds with high affinity (Kd approximate 10 nm). An immunotoxin containing this Fv is very cytotoxic to mesothelin containing cells. Further preclinical evaluation is in progress. (2) Glioblastomas: Phage display was used to isolate an Fv (MR1) that binds to a mutant form of the EGF receptor commonly present on glioblastomas and some carcinomas. MR1(Fv)PE38 is only cytotoxic to cells expressing the mutant receptor. Mutagenesis procedures are being used to increase the affinity of MR1. (3) Prostate cancer: We constructed conventional and single chain immunotoxins with MAb E4 which was thought to be prostate specific. The immunotoxins were cytotoxic to prostate cancer cell lines and also to several other epithelial cancers. Unfortunately recent studies show that MAb E4 may react with normal intestine. (4) Intracellular mutant proteins: Many mutant proteins that act as oncogenes are located within the cell. Since mutant peptides derived from these proteins are located on the cell surface it should be possible to produce antibodies that recognize these complexes and use these to target cytotoxic agents to the cell. To determine if such an approach is feasible, we have made a recombinant immunotoxin with a Fab that specifically recognizes a MHC-peptide complex but not the MHC or the peptide alone. This recombinant immunotoxin was only cytotoxic to cells expressing the specific complex. These studies show that cytotoxic agents can be designed that recognize intracellular proteins displayed as MHC- peptide complexes on the cell surface, and also indicate that antibodies which recognize MHC-peptide complexes on cancer cells could be useful for cancer therapy. We are trying to isolate such antibodies. A disulfide stabilized immunotoxin (e23(dsFv)PE38) has been made that binds to the erb B2 oncoprotein present on breast cancers and several other types of cancer. The agent produces complete regressions of xenografts growing in nude mice and is well tolerated by primates. A clinical batch of the immunotoxin has been prepared and an IND will be filed in late 1997. Because immunotoxins are such potent and specific cytotoxic agents, they have other uses besides cancer therapy. We have developed an approach to create new disease models by using an immunotoxin (anti-Tac(Fv)PE38) to treat transgenic mice which express the human IL2 receptor in a tissue specific manner. In a recent experiment, mice with peripheral autonomic neuropathy have been produced.