© 2003 European Society for Medical Oncology Clinical evaluation of ricin A-chain immunotoxins in patients with Hodgkin’s lymphoma

Background: Immunotoxins (ITs) consist of cell binding ligands coupled to toxins or their subunits. Hodgkin’s lymphoma (HL) is an excellent target for ITs since lymphocyte activation markers such as CD25 and CD30 are expressed in large numbers. The ITs RFT5.dgA (anti CD25) and Ki-4.dgA (anti CD30) were constructed by linking the monoclonal antibodies RFT5 and Ki-4 to deglycosylated ricin A-chain (dgA). Both ITs showed potent specific activity against HL cells in vitro and in vivo in animal models, and were subsequently evaluated in phase I/II clinical trials in humans. Patients and methods: In two separate trials, the ITs were administered i.v. four times every other day over 4 h. The objectives of the phase I trials included the determination of the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, antitumor activity and immune response against the IT. Results: Twenty-seven patients with refractory HL were included in the phase I/II study of RFT5.dgA and 17 patients were included in the phase I study of Ki-4.dgA. The MTD of RFT5.dgA was 15 mg/m2, whereas that of Ki-4.dgA was 5 mg/m2. DLTs were related to vascular leak syndrome, consisting of edema, tachy-cardia, dyspnea, weakness and myalgia. Measurement of serum levels of RFT5.dgA demonstrated a Cmax of 0.2–9.7 µg/ml with a half-life (t) varying from 4 to 10.5 h. Peak serum concentration of Ki-4.dgA ranged from 0.23 to 1.7 µg/ml. In both trials ∼60 % of patients developed human anti-mouse and/or anti-dgA anti