Clinical and Preclinical Evaluation of Recombinant PEG-IL-2 in Human

Abstract

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.

Targeting Regulatory T Cells to Treat Patients With Systemic Lupus Erythematosus

“…To overcome this disadvantage, modified IL-2 such as polyethy-lene glycol-modified IL-2 (PEG-IL-2), which prolongs the half-life of IL-2, has been constructed. PEG-IL-2 has been developed in the 1990s and undergone phase I/II clinical trials in cancer patients ( 73 ) and was recently revisited and tried in mice with asthma ( 74 ). Bell et al recently developed monovalent or bivalent IL-2-fused with non-FcR binding IgG1 molecules which had a prolonged half-life in vivo and caused prolonged activation and proliferation of Tregs after a single ultra-low dose ( 75 ).…”

Efficient strategies for the conjugation of oligonucleotides to antibodies enabling highly sensitive protein detection

“…Attempts to achieve sustained delivery of IL‐2 adequate for T cell activation via subcutaneous and intraperatoneal delivery have proven unsuccessful, mainly because of the inability to achieve adequate peak concentrations 10,19. Also, covalent modification of IL‐2 with poly(ethylene glycol) (PEG) to increase the circulation time of the protein had the unfortunate effect of severely decreasing its activity 20–23…”

Microparticulate Formulations for the Controlled Release of Interleukin-2

“…10,19 Also, covalent modification of IL-2 with poly(ethylene glycol) (PEG) to increase the circulation time of the protein had the unfortunate effect of severely decreasing its activity. [20][21][22][23] Controlled-release technology lends itself naturally to this type of medical problem. Systems can be designed that provide release of molecules over days to weeks, including proteins such as growth hormone, 24 in such a manner that a systemic effect is achieved without toxicity.…”