Despite the early safety challenges in Phase 2 ( 2), the clinical development of recombinant human (r)IL-12 and related compounds has been extensive in cancer and immunotherapy indications over the past two decades ( 3, 4).Īs a cytokine, IL-12 has multiple effector functions that bridge the innate and adaptive immune responses in cancer ( 5) to promote the activation of NK and NKT cells and to polarize CD4 + and CD8 + T cells. Its extended half-life leads to a prolonged but controlled IFNγ response, which may be important for tumor control in patients.Ĭlinical trial registration:, identifier NCT05408572.ġ Introduction: Interleukin-12 and SON-1010įirst discovered in the late 1980s, Natural Killer Cell Stimulatory Factor, eventually renamed interleukin-12 (IL-12), is a proinflammatory cytokine produced by activated phagocytes and dendritic cells and is a key regulator of cell-mediated immunity ( 1). There was no evidence of cytokine release syndrome based on minimal participant symptoms and responses observed with other cytokines.Ĭonclusion: SON-1010, a novel presentation for rIL-12, was safe and well-tolerated in healthy volunteers up to 300 ng/kg. PK analysis showed two-compartment elimination in SB102 with mean T ½ of 104 h, compared with one-compartment elimination in SB101, which correlated with prolonged but controlled and dose-related increases in interferon-gamma (IFNγ). As expected with rIL-12, initial decreases in neutrophils and lymphocytes returned to baseline by days 9-11. All TEAEs were transient and no other dose relationship was noted. Results: Participants receiving SON-1010 at 100 ng/kg or higher tolerated the injection but generally experienced more treatment-emergent adverse effects (TEAEs) than those receiving the lowest dose. A non-compartmental analysis of PK was performed and correlations with the PD results were explored, along with a comparison of the SON-1010 PK profile in SB101. Safety was reviewed after day 22, before enrolling the next cohort. SON-1010 at 50-300 ng/kg or placebo administered subcutaneously on day 1 was studied at a ratio of 6:2, starting with two sentinels participants were followed through day 29. Methods: SB102 (NCT05408572) focused on safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) endpoints. After initiating a dose-escalation trial in patients with cancer (SB101), a randomized, double-blind, placebo-controlled, single-ascending dose (SAD) phase 1 trial in healthy volunteers (SB102) was conducted. We developed a strategy to extend the rIL-12 T ½ that depends on binding albumin in vivo to target tumor tissue, using single-chain rIL-12 linked to a fully human albumin binding (F HAB) domain (SON-1010). Despite some signs of efficacy since then, most rIL-12 clinical trials have encountered hurdles such as short terminal elimination half-life (T ½), limited tumor microenvironment targeting, and substantial systemic toxicity. Unexpected toxicity in the first phase 2 study required careful attention to revised dosing strategies. 6Nucleus Network Pty Ltd, Melbourne, VIC, Australiaīackground: The benefits of recombinant interleukin-12 (rIL-12) as a multifunctional cytokine and potential immunotherapy for cancer have been sought for decades based on its efficacy in multiple mouse models.
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