Abstract CT245: Clinical development of a novel form of interleukin-12 with extended pharmacokinetics
Authors: Chawla Sant P. , Chua Victoria S. , Gordon Erlinda M. , Cini John , Dexter Susan , DaFonseca Manual , Bingham Justus , Hogeland Grantham W. , Kenney Richard T. 
Published: April 2023

Recombinant interleukins (IL) have had limited clinical success due to inefficient tumor targeting and short pharmacokinetics (PK), requiring frequent dosing that leads to aberrant immunostimulation and toxicity. IL-12 is a promising cancer treatment due to its activation of T and natural killer (NK) lymphocytes to produce interferon (IFN)-γ, yet dosing strategies have failed to provide adequate therapeutic benefit in humans. To address these issues, we developed a novel platform that delivers either mono- or bifunctional immunomodulator(s) linked to a Fully-Human, Albumin Binding scFv domain (FHAB®), which provides enhanced tumor targeting and retention through albumin binding to over-expressed FcRn, GP60, and SPARC, an improved PK profile, a dose-sparing effect that decreases the toxicity risk, and a broader therapeutic index. Excellent tumor growth inhibition was seen using a “cold” immunosuppressive B16F10 melanoma model for comparing the efficacy of IL12-FHAB with rIL-12, resulting in significant increases in activated NK, NKT, Th1, and cytotoxic CD8 T cells.

We are conducting a first-in-human, dose-escalation trial to evaluate the safety and tolerability of SON-1010 (IL12-FHAB) and to determine the maximum tolerated dose (MTD) in patients with advanced solid tumors. The study has a traditional 3+3 design, modified to take advantage of the known tachyphylaxis of IL-12 with the introduction of a desensitizing first dose to allow administration of higher maintenance doses. No dose-limiting toxicities have been encountered in the first 3 dose cohorts and the MTD is at least 300 ng/kg. While adverse events seen in other studies of IL-12 have occurred, they have been transient and tolerable, allowing further dose escalation. Increases in IFN-γ were dose-related, controlled, and prolonged. The levels peaked at 24 to 48 hours and returned to baseline after 2 to 4 weeks. Low levels of IL-10 were induced in a dose-dependent manner. No drug-related increase was seen with IL-1β, IL-6, IL-8, or TNF-α and there was no evidence of cytokine release syndrome at these doses. The preliminary geomean elimination half-life (T½) was 122 hrs with first-order kinetics, compared with 12 hrs for SC rhIL-12. The accumulation estimates are within the margin of error and are not likely to be physiologically significant with subcutaneous dosing of SON-1010 every 3 weeks. Eight of 11 patients had stable disease at the first follow-up CT, 4 of whom were progressing at study entry. Two patients were stable at 4 months and 2 had unconfirmed progressive disease; 1 patient remains stable after 8 months on SON-1010 with evidence of tumor regression.

SON-1010 may have a positive synergistic effect with an immune checkpoint inhibitor (ICI), particularly with ‘cold’ tumors that over-express SPARC. The next stage of development will be to explore the MTD of SON-1010 in combination with an ICI, then to compare that approach with the standard of care in Phase 2.

Citation Format: Sant P. Chawla, Victoria S. Chua, Erlinda M. Gordon, John Cini, Susan Dexter, Manual DaFonseca, Justus Bingham, Grantham W. Hogeland, Richard T. Kenney. Clinical development of a novel form of interleukin-12 with extended pharmacokinetics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT245.