We conducted phase I clinical studies to determine the safety, the pharmacokinetics, the immunogenicity and the activity of several recombinant immunotoxins for adult patients with epithelial carcinomas. These clinical efforts are summarized as follow: (1) a phase I trial of single chain immunotoxin LMB-7: this is an immunotoxin made by fusing the Fv fragment of the anti-Lewis Y monoclonal antibody, B3, to a mutant form of Pseudomonas exotoxin termed PE38. Patients with colo-rectal, breast, lung and other gastrointestinal malignancies received LMB-7 at the doses ranging from 2-48 mcg/kg every other day x 3 doses. The dose limiting toxicity was gastrointestinal, due to the targeting of gastric mucosa by LMB-7. Pre-treatment with omeprazole and anti-emetic greatly ameliorated the symptoms. LMB-7 was found to be less immunogenic than a similar immunotoxin termed LMB-1, made of whole IgG B3. Evidence of biological activity was observed in one patient with colon cancer. (2) Immunotoxin LMB-9: because LMB-7 is unstable in human serum at 37oC, a disulfide stabilized immunotoxin, B3 (dsFv) PE38 termed LMB-9 was produced. Pre-clinical testing was completed early this year and the IND was filled and approved on 5/98. Patient accrual for this study is ongoing. (3) Erb-38: this is a disulfide stabilized recombinant immunotoxin, e23 (dsFv) PE38 that targets Her2 neu. Six patients with tumors that express Her2 neu received erb-38 intravenously. The dose limiting side effect was found to be transient elevation of liver transaminases, probably due to the expression of Her2 neu on normal hepatocytes. Erb-38 is cleared monoexponentially from the circulation with T1/2 of 3.1 hr. At 2mcg/kg, plasma concentrations of 47- 105ng/ml were achieved. In collaboration with the Nuclear Medicine Dept, at the Clinical Center, NIH, and the Radiation Oncology Branch, DCS, we conducted an Imaging and Phase I therapy study using mAb B3 radiolabeled with 111In and 90Y . 21/26 patients (85%) had antibody localization in known sites of disease. Sites of disease imaged included liver, lung, bone, soft tissue mass and lymph nodes. The MTD for 90Y -B3 was 20mCi, and the dose limiting side effect was neutropenia and thrombocytopenia. A clinical study in which patients will receive autologous stem cell support after 90Y-B3 is being planned.
