High dose
interleukin-2 alone or in combination with lymphokine activated killer (LAK) cells has demonstrated antitumor activity in a variety of malignant diseases. The currently formulated recombinant human
interleukin-2 (IL-2) has limited solubility and short circulatory half life resulting in limited bioavailability. To improve the bioavailability of
IL-2 the
protein was covalently bound to activated Polyethylenglycol (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 two weeks, and to determine safety, efficacy, and the maximum tolerated dose (MTD) in patients with advanced
malignancies. Assessment of
cytokine levels, phenotypic analyses and differential blood counts were performed 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 proliferation, cytotolytic activity, morphology, and phenotype of
cytokine activated lymphocytes. Among seven patients treated with
PEG-IL-2, there was no objective remission, three patients exhibited stabilisation of disease. Four patients presented with further
disease progression. Treatment-related toxicity was mild to moderate (mainly WHO grades I and II) in patients receiving dose levels up to 10 x 10(6) IU/m2 (maximum tolerated single dose in the outpatient setting). No toxic deaths occurred. In comparison to
IL-2, the pharmacokinetic profile of
PEG-IL-2 exhibited 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 significant
biologic activity both in vitro, and in man.