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

Abstract
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.