CLINICAL AND PRECLINICAL EVALUATION OF RECOMBINANT PEG-IL-2 IN HUMAN

High dose interleukin-2 alone or in combination with lymphokine activa ted killer (LAK) cells has demonstrated antitumor activity in a variet y of malignant diseases. The currently formulated recombinant human in terleukin-2 (IL-2) has limited solubility and short circulatory half l ife resulting in limited bioavailability. To improve the bioavailabili ty of IL-2 the protein was covalently bound to activated Polyethylengl ycol (PEG). We designed a phase I/II trial to evaluate the bioactivity of PEG-IL-2 in man, given as intravenous (iv) bolus injection every t wo weeks, and to determine safety, efficacy, and the maximum tolerated dose (MTD) in patients with advanced malignancies. Assessment of cyto kine levels, phenotypic analyses and differential blood counts were pe rformed to investigate the effects of PEG-IL-2 in-vivo. To compare in- vitro PEG-IL-2 activity to activities of IL-2 we evaluated proliferati on, cytotolytic activity, morphology, and phenotype of cytokine activa ted lymphocytes. Among seven patients treated with PEG-IL-2, there was no objective remission, three patients exhibited stabilisation of dis ease. Four patients presented with further disease progression. Treatm ent-related toxicity was mild to moderate (mainly WHO grades I and II) in patients receiving dose levels up to 10x10(6) IU/m2 (maximum toler ated single dose in the outpatient setting). No toxic deaths occurred. In comparison to IL-2, the pharmacokinetic profile of PEG-IL-2 exhibi ted increased plasma levels and a decreased clearance (alpha and beta half-life estimates of 4 and 14 hours, respectively). The analysis of a variety of immunologic parameters demonstrated that PEG-IL-2 has sig nificant biologic activity both in vitro, and in man.