Immunotoxins (ITs) consisting of a binding and toxin moiety were developed as a new class of biological anti-tumor agents to improve adjuvant therapy. Hodgkin's disease (HD) has been demonstrated to be an excellent target for ITs due to expression of lymphocyte activation markers such as CD25 and CD30. Our group has evaluated several ITs directed against CD25 and CD30 for possible clinical use. The ITs demonstrating the most promising effects in vitro against L540Cy derived Hodgkin cells and in a disseminated SCID/Hodgkin model were RFT5.dgA (anti CD25) and Ki-4.dgA (anti CD30). Both ITs were constructed by linking the Moabs RFT5 or Ki-4 to deglycosylated ricin A-chain. In two independent phase I trials we treated refractory HD patients with escalating doses of both ITs. The ITs were administered every second day (1-3-5-7) i.v. over 4 hours. Objectives were documentation of dose limiting toxicities to define the maximum tolerated dose (MTD), pharmacokinetics and immune response to the IT. We performed a subsequent phase II study with RFTS.dgA at MTD to evaluate clinical response. 27 patients were included in the RFTS.dgA study and 17 patients in the Ki-4.dgA trial. Patient characteristics were very similar. Most patients were heavily pretreated with advanced disease and massive tumor burden at study entry. The MTD in these patients was 15mg/m2 for RFTS.dgA and 5mg/m2 for Ki-4.dgA. Dose-limiting toxicities were primarily due to vascular leak syndrome with edema, tachycardia, dyspnea, weakness and myalgia. Measurement of serum levels (RFTS.dgA) demonstrated a Cmax of 0.2-9.7mg/ml, half-life varied from 4 -10.5 h. In both trials, 50% of patients developed human anti mouse and/or anti-ricin antibodies. 16/18 patients treated at MTD in the phase-II trial with RFTS.dgA received two or more cycles and were évaluable for clinical response. These included two partial remissions, one minor response, and five stable diseases. The median time to tumor progression of responding patients was 142 days. The median survival time of all patients was 742 days. 15/17 patients treated with Ki-4.dgA were évaluable for clinical response demonstrating 2 minor responese and one stable disease. All other patients had progressive disease. The chemically linked ricin A-chain ITs RFTS.dgA and Ki-4.dgA were of moderate activity in pts with advanced refractory HD and massive tumor burden.
|Original language||English (US)|
|Issue number||11 PART II|
|State||Published - Dec 1 2000|
ASJC Scopus subject areas
- Cell Biology