Abstract 1589: Toxicity profile of interleukin 12 attached to a fully human albumin binding domain (FHABTM) in Cynomolgus macaques
Authors: Cini John K. , Rezac Darrel J. , McAndrew Stephen , Dexter Susan , Huebner Robert , Borghaei Hossein 
Published: July 2021

Abstract
Interleukin 12 (IL12) and other cytokines offer a potent and well characterized immunomodulatory therapy potential against multiple tumor types. Early efforts to advance recombinant human IL12 (rhIL12) were met with limited success in the clinic, due to a short circulating half life that led developers to employ a dosing regimen that often resulted in unacceptable safety outcomes. As a result, Sonnet has developed a novel platform to enhance the delivery and activity of immunomodulators such as IL12. The platform, a fully human serum albumin-binding scFv domain (FHAB), results in an improved pharmacokinetic profile, and targets tumor tissue by binding GP60 and SPARC, providing a dose sparing effect which decreases the risk of toxicity, with a broader therapeutic window. In a B16F10 mouse melanoma model, compared to rIL12, mouse IL12FHAB displayed 30 to 50 fold greater tumor inhibition at a common dose level. Similar in vivo efficacy was also observed with other cytokines: IL15, GMcSF and IL18, and bispecific combinations. Sonnet is now advancing a fully human version of IL12FHAB toward clinical evaluation. In preparation for human trials, species specific target tissue compatibility studies indicated only Cynomolgus macaques were appropriate for conducting preclinical toxicology assessments of IL12FHAB. A single dose escalation study was conducted with IL12FHAB at 250, 125 and 62.5 µg/kg by either the IV or SC route and observed for 21 days post exposure. A dose and route dependent, clinical response was observed. Animals in the 250 µg/kg IV group were euthanized on Day 10 to assess pathology. All other animals recovered to normal by Day 21 post dose. Toxicokinetic analysis indicated a mean T1/2 of 40.0 (±6.9) hours for SC and 27.45 (±2.8) hours for IV dose routes. Hematology assessments showed transient leukocytopenia and neutropenia which resolved by day 14. Elevated AST was observed at day 7 but resolved by day 14. Finally, cytokine analysis showed elevated IFNγ, an efficacy biomarker, at 96 hours with no signs of a cytokine imbalance at any dose. Results of a repeat dose study will be reported in poster. Sonnet mIL12FHAB in vivo mouse studies have proven enhanced efficacy of the IL12FHAB through targeted delivery, increased retention within the tumor micro environment and extended T1/2 through albumin binding. In contrast to prior clinical studies with rhIL12, these data demonstrate an improved toxicokinetic profile when hIL12 is linked to the FHAB platform, thus leading to the potential for a broader therapeutic window with an improved safety profile.
Citation Format: John K. Cini, Darrel J. Rezac, Stephen McAndrew, Susan Dexter, Robert Huebner, Hossein Borghaei. Toxicity profile of interleukin 12 attached to a fully human albumin binding domain (FHABTM) in Cynomolgus macaques [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1589.