Interleukin-2 fusion protein: an investigational therapy for interleukin-2 receptor expressing malignancies.
DAB389IL-2 is an interleukin-2 receptor (IL-2R) specific fusion protein with a molecular weight of 58 kD containing the enzymatic and translocation domains of diphtheria toxin (DT) and human IL-2. This fusion protein is able to direct the cytocidal action of the DT enzymatic region only to cells which bear the IL-2R. The human IL-2R exists in three 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. DAB389IL-2 is able to bind selectively to the high-affinity IL-2R in a concentration-dependent manner, and once bound is internalised via receptor-mediated endocytosis. Upon acidification of the formed vesicle, the enzymatic portion of the fusion protein is believed to pass into the cytosol where it ultimately inhibits protein synthesis by inactivation of elongation factor-2, resulting in cell death. The constitutive expression of the IL-2R on certain leukaemic and lymphomatous cells of T and B cell origin has been reported to occur in patients with chronic lymphocytic leukaemia, cutaneous T cell lymphoma (CTCL), Hodgkin's disease and non-Hodgkin's lymphomas (NHLs). A multicentre DAB389IL-2 dose-escalation study of patients with IL-2R expressing lymphomas has been conducted. A 10-fold range of doses were evaluated on a five-daily dose schedule. Patients received up to six courses, with an additional two courses permitted for patients with partial responses that appeared to be still improving after six courses. Most adverse experiences were transient and mild. Preliminary assessment of response indicated five complete responses (CR, duration ongoing at 20, 11, 7, 5 and 4 months) and seven partial responses (PR, duration 3-20 months) in the 35 patients with CTCL. One CR (duration > 20 months) in a patient with NHL (Lennett's lymphoma) 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 DAB389IL-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 initiated and plans for additional trials in NHL patients are targeted for 1996.
Nichols
J
J
Seragen Inc., Hopkinton, Massachusetts 01748, USA.
Foss
F
F
Kuzel
T M
TM
LeMaistre
C F
CF
Platanias
L
L
Ratain
M J
MJ
Rook
A
A
Saleh
M
M
Schwartz
G
G
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004167:Diphtheria Toxin / Q000627:therapeutic use*; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000627:therapeutic use*; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism / Q000628:therapy*; D016410:Lymphoma, T-Cell, Cutaneous / Q000628:therapy; D009363:Neoplasm Proteins / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000628:therapy
D000970:Antineoplastic Agents; D004167:Diphtheria Toxin; D000922:Immunotoxins; D007376:Interleukin-2; D009363:Neoplasm Proteins; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; C078456:denileukin diftitox