title: Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-gamma production.
abstract: Interleukin-12 (IL-12) is a key regulator of cell-mediated immunity that has therapeutic potential in cancer and infectious disease. In a previous Phase 1 dose escalation study of a single test dose of recombinant human IL-12 (rhIL-12) followed 14 days later by cycles of five consecutive daily intravenous injections every 3 weeks, we showed that a dose level up to 500 ng/kg could be administered with acceptable levels of safety. Based on these results, a Phase 2 study was conducted. In the Phase 2 study, however, administration of rhIL-12 at this same dose level resulted in severe toxicities with some patients unable to tolerate more than two successive doses. Of the 17 patients receiving rhIL-12 in the Phase 2 study, 12 patients were hospitalized and two patients died. A thorough scientific investigation to determine the cause of this unexpected toxicity failed to identify any difference in the drug products used or the patient populations enrolled in the Phase 1 and Phase 2 studies that could have accounted for the profound difference in toxicity. The focus of the investigation therefore shifted to the schedule of rhIL-12 administration. We determined that a single injection of rhIL-12 2 weeks before consecutive dosing included in the Phase 1 study, but not in the schedule of administration in the Phase 2 study, has a profound abrogating effect on IL-12-induced interferon-gamma (IFN-gamma) production and toxicity. This observation of schedule-dependent toxicity of IL-12 has been verified in mice, as well as nonhuman primates. In this regard, a single injection of IL-12 before consecutive daily dosing protected mice and cynomolgus monkeys from acute toxicity including mortality and was associated with an attenuated IFN-gamma response. Because of this unique biologic response, careful attention to the schedule of administration is required to assure safe and effective clinical development of this highly promising cytokine.
authors.affiliation: Department of Preclinical Research, Genetics Institute, Cambridge, MA 02140, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Leonard
authors.forename: M L
authors.initials: ML
authors.lastname: Sherman
authors.forename: G L
authors.initials: GL
authors.lastname: Fisher
authors.forename: L J
authors.initials: LJ
authors.lastname: Buchanan
authors.forename: G
authors.initials: G
authors.lastname: Larsen
authors.forename: M B
authors.initials: MB
authors.lastname: Atkins
authors.forename: J A
authors.initials: JA
authors.lastname: Sosman
authors.forename: J P
authors.initials: JP
authors.lastname: Dutcher
authors.forename: N J
authors.initials: NJ
authors.lastname: Vogelzang
authors.forename: J L
authors.initials: JL
authors.lastname: Ryan
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D003092:Colitis / Q000139:chemically induced; D004334:Drug Administration Schedule; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000009:adverse effects* / Q000494:pharmacology / Q000633:toxicity; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008875:Middle Aged; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000633:toxicity; D012449:Safety; D013280:Stomatitis / Q000139:chemically induced; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D007155:Immunologic Factors; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma