Aldesleukin - Therapeutic Use of Recombinant Interleukins

Aldesleukin

Proleukin (aldesleukin), a nonglycosylated humanrecombinant IL-2 product, is a highly purified protein with a molecular weight of approximately 15 kDa. The chemical name is des-alanyl-1, serine-125 human IL-2. It is produced by recombinant DNA technology using a genetically engineered E. coli containing an analog of the human IL-2 gene. The modified human IL-2 gene encodes a modified human IL-2 differing from the native form: the molecule has no N-terminal alanine; the codon for this amino acid was deleted during the genetic engineering procedure; serine was substituted for cysteine at amino acid position 125. Aldesleukin exists as biologically active, noncovalently bound microaggregates with an average size of 27 recombi-nant IL-2 molecules. The pharmacokinetic profile of aldesleukin is characterized by high plasma concentra-tions following a short IV infusion, rapid distribution into the extravascular space and elimination from the body by metabolism in the kidneys with little or no bioactive protein excreted in the urine. Studies of IV aldesleukin indicate that upon completion of infusion, approximately 30% of the administered dose is detectable in plasma. Observed serum levels are dose proportional. The distribution and elimination half-life after a 5-min IV infusion are 13 and 85 min, respectively. In humans and animals, aldesleukin is cleared from the circulation by both glomerular filtration and peritub-ular extraction in the kidney. The rapid clearance of aldesleukin has led to dosage schedules characterized by frequent, short infusions. The adverse event profile of IL-2 is similar to that seen for IFNs and many ILs; it is generally reasonably well tolerated and subjectively consists primarily of the “influenza-like symptoms.” For a detailed reporting of all adverse events, rarely severe, the reader is referred to the product information for Proleukin.

Proleukin is supplied as a sterile, lyophilized cake in single-use vials intended for IV injection. After reconstitution with 1.2 mL sterile water for injection, each mL contains 18 MIU (1.1 mg) aldesleukin, 50 mg mannitol and 0.18 mg sodium dodecyl sulfate, with-out preservatives, buffered with approximately 0.17 mg monobasic and 0.89 mg dibasic sodium phosphate to a pH of 7.5. It is indicated for the treatment of adults with metastatic renal cell carcino-ma or metastatic melanoma. Each treatment course consists of two 5-day treatment cycles: 600,000 IU/kg (0.037 mg/kg) are administered every 8 hr by a 15-minIV infusion for a maximum of 14 doses. Following 9 days of rest, the schedule is repeated for another 14 doses, or a maximum of 28 doses per course, as tolerated.