INTERLEUKIN-2 FUSION PROTEIN - AN INVESTIGATIONAL THERAPY FOR INTERLEUKIN-2 RECEPTOR-EXPRESSING MALIGNANCIES

DAB(389)IL-2 is an interleukin-2 receptor (IL-2R) specific fusion prot ein with a molecular weight of 58 kD containing the enzymatic and tran slocation domains of diphtheria toxin (DT) and human IL-2. This fusion protein is able to direct the cytocidal action of the DT enzymatic re gion only to cells which bear the IL-2R. The human IL-2R exists in thr ee forms: low, intermediate and high affinity. The high-affinity form is believed to be the biologically relevant form on mature, activated T-lymphocytes, B-lymphocytes and monocytes. DAB(389)IL-2 is able to bi nd selectively to the high-affinity IL-2R in a concentration-dependent manner, and once bound is internalised via receptor-mediated endocyto sis. Upon acidification of the formed vesicle, the enzymatic portion o f the fusion protein is believed to pass into the cytosol where it ult imately inhibits protein synthesis by inactivation of elongation facto r-2, resulting in cell death. The constitutive expression of the IL-2R on certain leukaemic and lymphomatous cells of T and B cell origin ha s been reported to occur in patients with chronic lymphocytic leukaemi a, cutaneous T cell lymphoma (CTCL), Hodgkin's disease and non-Hodgkin 's lymphomas (NHLs). A multicentre DAB(389)IL-2 dose-escalation study of patients with IL-2R expressing lymphomas has been conducted. A 10-f old range of doses were evaluated on a five-daily dose schedule. Patie nts received up to six courses, with an additional two courses permitt ed for patients with partial responses that appeared to be still impro ving after six courses. Most adverse experiences were transient and mi ld. Preliminary assessment of response indicated five complete respons es (CR, duration ongoing at 20, 11, 7, 5 and 4 months) and seven parti al responses (PR, duration 3-20 months) in the 35 patients with CTCL. One CR (duration > 20 months) in a patient with NHL (Lennett's lymphom a) and two PR (duration 9 and 2 months) in 17 patients with B-cell NHL have been observed. Based on the mode of action of DAB(389)IL-2, its safety profile, and the patient responses associated with the phase I/ II clinical trials, a phase III programme in CTCL patients has been in itiated and plans for additional trials in NHL patients are targeted f or 1996. (C) 1997 Elsevier Science Ltd.