We are conducting clinical trials in pateints with solid tumors using immunotoxins LMB-1 and LMB-7 (B3(Fv)-PE38) and initiated a clinical trial with LMB-2 (anti-Tac(Fv)-PE38) directed at leukemias and lymphomas. Radiolabeled MAb B3 (90-Y) is also being used to treat solid tumors. Over 100 patients have not been entered into clinical trials involving agents developed in LMB. LMB-1 is an immunotoxin in which MAb B3 is chemically coupled to LysPE38. Dr. Lee Pai has completed a Phase I clinical trial with LMB-1. The MTD is 60 mg/kilo x 3. Dose limiting toxicity is capillary damage resulting in vascular leak syndrome. Evidence of anti-tumor activity was observed in 7/46 patients treated. The most dramatic response was observed in a patient with colon cancer with marked shrinkage (greater than 75%) of retroperitoneal and cervical lymph nodes and relief of pain and diarrhea. LMB-7 (B3(Fv)-PE38) is a single chain immunotoxin in which the Fv portion of MAb B3 is fused to PE38. LMB-7 has been given to 39 patients. A MTD has been established; the dose limiting toxicity is diarrhea, nausea and vomiting due to damage to epithelial cells in the stomach. The clinical protocol has been modified to diminish stomach damage and the trial has been reopened. Because LMB-7 is unstable at 37 degrees C, a stablized form of LMB-7 has been designed and prepared (LMB-9 or B3(dsFv)-PE38) in which the Fv heterodimer is stabilized by a disulfide bond. This agent is well tolerated by monkeys and should enter the clinic in 1997. Another immunotoxin for treatment of solid tumors is directed at erbB2 and known as e23(dsFv)-PE38. It is a very active and very stable immunotoxin. It will be ready for clinical trials in 1997 or 1998. Dr. Robert Kreitman has developed an immunotoxin directed at the IL2 receptor a subunit (anti-Tac(Fv)-PE38, LMB-2) for the treatment of leukemias and lymphomas. A clinical trial has been initiated in collaboration with Dr. T. Waldmann; the first patient was treated in July 1996. Dr. Lee Pai, in collaboration with J. Carrasquillo (Nuclear Medicine) and O. Gansow (Radiation Oncology), is supervising a Phase I clinical trial with a radioconjugate of MAb B3 with 90-Y or 111-In. Over 15 patients have been treated. The current dose level is 15 mCi of 90-Y-MAb. The MTD has not yet been reached. In several patients, imaging of tumors in liver, lung and peritoneum has been demonstrated with 111-In-B3.
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