Preparing interleukin-2 (IL-2) for pharmaceutical use, by adding sodium dodecyl sulfate to composition comprising IL-2, removing precipitated covalently-linked IL-2 multimers, and reducing sodium dodecyl sulfate concentration

摘要

Preparing (M1) interleukin-2 (IL-2) for pharmaceutical use, comprises adding sodium dodecyl sulfate (SDS) to a composition comprising IL-2 with intramolecular disulfide bridges, to give a final SDS concentration of at least 500 mu g SDS/mg of IL-2, removing any precipitated covalently-linked IL-2 multimers by gel filtration, and reducing the SDS concentration to remove some but not all SDS from the composition, to give a composition that contains 95-250 mu g SDS/mg of IL-2. Independent claims are also included for: (1) preparing (M2) a composition comprising IL-2 and sodium dodecyl sulfate, where IL-2 and SDS in the composition are present in the form of aggregates, comprising adding SDS to a composition comprising IL-2 with intramolecular disulfide bridges, where sufficient SDS is added to give monomeric solubilized IL-2, removing any precipitated covalently-lined IL-2 multimers by gel filtration, and reducing the concentration of SDS to a level where the IL-2 forms aggregates with sodium dodecyl sulfate, such that the composition, after lyophilization and reconstitution, has a specific turbidity (tau ) of less than 1.1 cm2/g; (2) a composition, comprising IL-2 and sodium dodecyl sulfate, where IL-2 and SDS are present in the form of aggregates, and where the composition has specific turbidity (tau ) less than 1.1 cm2/g, and contains SDS/IL-2 aggregates with a mean hydrodynamic diameter of 8-20 nm, 95-250 mu g SDS/mg of IL-2, and/or the aggregates obtained by (M1) or (M2); (3) a lyophilized composition, comprising IL-2 and sodium dodecyl sulfate, where the composition can be reconstituted with an aqueous medium to give the composition, comprising IL-2 and sodium dodecyl sulfate; (4) a lyophilized pharmaceutical composition which, when reconstituted with 1.2 ml sterile water for injection, contains in each ml 1.1 mg non-glycosylated des-alanyl-1, serine-125 human IL-2, 50 mg mannitol, 0.18 mg SDS, 0.17 mg monobasic sodium phosphate, and 0.89 mg dibasic sodium phosphate to pH 7.5, where the IL-2 and SDS are in the form of aggregates such that the reconstituted composition has a specific turbidity (tau ) less than 1.1 cm2/g; (5) an aqueous pharmaceutical composition, obtainable by reconstituting the lyophilized pharmaceutical composition with 1.2 ml sterile water for injection; (6) a kit comprising the lyophilized composition, lyophilized pharmaceutical composition and aqueous pharmaceutical composition, and second pharmaceutical agent; (7) use of microaggregates of IL-2 and sodium dodecyl sulfate, in the manufacture of a medicament for administration to a patient, where the microaggregates have a mean hydrodynamic diameter of 8-20 nm; (8) use of a composition comprising both IL-2 and sodium dodecyl sulfate, in the manufacture of a medicament for administration to a patient, where the IL-2 SDS are present in the form of aggregates, and where the composition has a specific turbidity (tau ) less than 1.1 cm2/g, contains SDS/IL-2 aggregates with a mean hydrodynamic diameter of 8-20 nm, and/or contains 95-250 mu g SDS/mg of IL-2; (9) use of a second pharmaceutical agent, in the manufacture of a combination medicament for administration to a patient, where the patient has been pre-treated with lyophilized composition, lyophilized pharmaceutical composition and aqueous pharmaceutical composition; (10) use of a second pharmaceutical agent, in the manufacture of a combination medicament for administration to a patient, where the medicament is co-administered with the lyophilized composition, lyophilized pharmaceutical composition and aqueous pharmaceutical composition; and (11) use of microaggregates of IL-2 and sodium dodecyl sulfate, and a second pharmaceutical agent, in the manufacture of a combination medicament, where the microaggregates have a mean hydrodynamic diameter of 8-20 nm. ACTIVITY : Cytostatic. No biological data given. MECHANISM OF ACTION : Promotes the growth and differentiation of T cells; Enhances cytotoxicity of CD8+T cells and natural killer cells.