Single low-dose rHuIL-12 safely triggers multilineage hematopoietic and immune-mediated effects

Abstract

BackgroundRecombinant human interleukin 12 (rHuIL-12) regulates hematopoiesis and cell-mediated immunity. Based on these hematopoietic and immunomodulatory activities, a recombinant human IL-12 (rHuIL-12) is now under development to address the unmet need for a medical countermeasure against the hematopoietic syndrome of the acute radiation syndrome (HSARS) that occurs in individuals exposed to lethal radiation, and also to serve as adjuvant therapy that could provide dual hematopoietic and immunotherapeutic benefits in patients with cancer receiving chemotherapy. We sought to demonstrate in healthy subjects the safety of rHuIL-12 at single, low doses that are appropriate for use as a medical countermeasure for humans exposed to lethal radiation and as an immunomodulatory anti-cancer agent.MethodsTwo placebo-controlled, double-blinded studies assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of rHuIL-12. The first-in-human (FIH) dose-escalation study randomized subjects to single subcutaneous injections of placebo or rHuIL-12 at 2, 5, 10, and 20 μg doses. Due to toxicity, dose was reduced to 15 μg and then to 12 μg. The phase 1b expansion study randomized subjects to the highest safe and well tolerated dose of 12 μg.ResultsThirty-two subjects were enrolled in the FIH study: 4 active and 2 placebo at rHuIL-12 doses of 2, 5, 10, 12, and 15 μg; 1 active and 1 placebo at 20 μg. Sixty subjects were enrolled in the expansion study: 48 active and 12 placebo at 12 μg dose of rHuIL-12. In both studies, the most common adverse events (AEs) related to rHuIL-12 were headache, dizziness, and chills. No immunogenicity was observed. Elimination of rHuIL-12 was biphasic, suggesting significant distribution into extravascular spaces. rHuIL-12 triggered transient changes in neutrophils, platelets, reticulocytes, lymphocytes, natural killer cells, and CD34+ hematopoietic progenitor cells, and induced increases in interferon-γ and C-X-C motif chemokine 10.ConclusionA single low dose of rHuIl-12 administered subcutaneously can elicit hematological and immune-mediated effects without undue toxicity. The safety and the potent multilineage hematopoietic/immunologic effects triggered by low-dose rHuIL-12 support the development of rHuIL-12 both as a radiation medical countermeasure and as adjuvant immunotherapy for cancer.Trial registrationClinicalTrials.gov: NCT01742221

Recombinant interleukin‐12, but not granulocyte‐colony stimulating factor, improves survival in lethally irradiated nonhuman primates in the absence of supportive care: Evidence for the development of a frontline radiation medical countermeasure

“…This 12 mg human dose was well tolerated in both the studies of healthy humans [14], indicating that a single, low dose of rHuIL-12 has potential as a safe and efficacious medical countermeasure against HSARS. The final confirmation of the safety and efficacy of rHuIL-12 for HSARS awaits the completion of pivotal, Phase 3-equivalent, studies of safety in humans and efficacy in NHP, as directed by the Animal Rule.…”

Medical Countermeasures for Radiation Exposure and Related Injuries

“…These data demonstrate that G-CSF can be safely administered after rhuIL‐12. To demonstrate the safety of HemaMax, Neumedicines, Inc., conducted a Phase-Ib study where healthy human volunteers were administered a single dose predicted to be effective in humans for treating hematopoietic syndrome based on NHP data; this trial suggests rhuIL‐12 to be safe and well tolerated at this dose ( Gokhale et al 2014 ; Neumedicines 2014 ). An additional study, investigating the mechanism of action of rhuIL‐12 in healthy human subjects, suggests that rhuIL‐12 administration induced IL‐12Rβ2 + , CD16 + CD56 + natural killer cell migration from the peripheral blood into the tissue compartment, through a mechanism facilitated by interferon-γ-induced CXCL10 chemokine and its receptor CXCR3 ( Neumedicines 2014 ).…”

Use of Growth Factors and Other Cytokines for Treatment of Injuries During a Radiation Public Health Emergency

“…The pleiotropic effects of IL-12, originally known as natural killer (NK) cell stimulatory factor, on innate and adaptive immune cells have been extensively studied. More recently however, its ability to stimulate hematopoiesis has been identified, thereby increasing lymphoid and myeloid progenitor cell generation (75). Both lymphoid and myeloid lineages give rise to dendritic cells (76), which are key sensors of the environment, responding to the antigenic determinants from pathogens such as viruses, bacteria and cancer cells with the production of IL-12.…”