title: Chimeric fusion protein toxin DAB486IL-2 in advanced mycosis fungoides and the Sezary syndrome: correlation of activity and interleukin-2 receptor expression in a phase II study.
abstract: DAB486IL-2 is a recombinant toxin with the cell surface-binding domain of diphtheria toxin (DT) replaced by interleukin-2 (IL-2). To correlate clinical response with expression of components of the IL-2 receptor (IL-2R), 14 patients with cutaneous T-cell lymphoma (CTCL) received five daily 90-minute infusions every 21 days. There were no complete responses, 1 partial response (PR), 2 major biologic effects (major cutaneous improvement without change in circulating neoplastic cells), 3 stable disease (SD), and 8 progressive disease (PD). Responders had easily detected expression of CD25 (Tac; alpha-chain of IL-2R) in skin, and in two responders expression of the beta chain of the IL-2 receptor (beta-IL-2R) was detectable by reverse transcriptase-polymerase chain reaction. CD25 was also detected in 8 of 11 SD or PD patients, with beta-IL-2R in 3 of 8 SD or PD patients. Two of the three responders had anti-DT antibodies before treatment. Reversible increased hepatic transaminases occurred in 13 of 14 patients during the first course, with decreased frequency in repeated courses. The maximal serum concentration after the first infusion of DAB486IL-2 varied (1,369 +/- 1,155 ng/mL [mean +/- SD]; n = 14; range, 55 to 3,999 ng/mL) with a short half-life (T1/2 beta = 0.21 +/- 0.12 h [mean +/- SD]; range, 0.099 to 0.57 h). The area under the concentration curve varied inversely with anti-DT antibody titer. We conclude that DA-B486IL-2 has valuable activity in certain patients with CTCL. Expression of the IL-2R may be necessary but is not sufficient to predict response.
authors.affiliation: US Naval Hospital, Bethesda, MD.
authors.forename: F M
authors.initials: FM
authors.lastname: Foss
authors.forename: T A
authors.initials: TA
authors.lastname: Borkowski
authors.forename: M
authors.initials: M
authors.lastname: Gilliom
authors.forename: M
authors.initials: M
authors.lastname: Stetler-Stevenson
authors.forename: E S
authors.initials: ES
authors.lastname: Jaffe
authors.forename: W D
authors.initials: WD
authors.lastname: Figg
authors.forename: A
authors.initials: A
authors.lastname: Tompkins
authors.forename: A
authors.initials: A
authors.lastname: Bastian
authors.forename: P
authors.initials: P
authors.lastname: Nylen
authors.forename: T
authors.initials: T
authors.lastname: Woodworth
mesh_terms: D004167:Diphtheria Toxin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007376:Interleukin-2 / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009182:Mycosis Fungoides / Q000188:drug therapy* / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012074:Remission Induction; D012751:Sezary Syndrome / Q000188:drug therapy*; D012878:Skin Neoplasms / Q000188:drug therapy*
chemical_list: C054780:DAB(486)-interleukin 2; D004167:Diphtheria Toxin; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins