Abstract 5667: CYT-303 FLEX-NKTM engager dose response efficacy mechanisms in HCC tumor model and safety in cynomolgus monkey toxicology studies support clinical evaluation in hepato-cellular carcinoma

Abstract BACKGROUND: CYT-303 is a multifunctional bispecific NK engager (NKE) targeting NK cell activating receptor NKp46 and tumor antigen Glypican-3 (GPC3) expressed in HCC (hepatocellular carcinoma). Cytovia’s proprietary FLEX-NKTM platform utilizes a novel FLEX-linker and human IgG1 back bone to allow for simultaneous binding to targeted cancer cells and NK cells. We evaluated CYT-303 dose response pharmacology efficacy mechanisms in HCC tumor models and conducted safety assessment studies in cynomolgus monkeys to support first in human clinical studies in HCC patients. METHODS: CYT-303 dose response pharmacology mechanistic studies were conducted in NSG-hIL-15 mice bearing Hep3B tumors and flow cytometry was used to assess bold and tumor NK cells. A 4-week CYT-303 repeat dose GLP toxicology study in cynomolgus monkeys at 6, 20 and 60 mg/kg dose was conducted following weekly intravenous infusions followed by a 6-week recovery period. CYT-303 toxicokinetic and anti-drug antibody (ADA) assessments were conducted using validated immunoassays. RESULTS: CYT-303 dose response in HCC tumor models showed increased tumor growth inhibition at the lower 2-3 mg/kg doses compared to higher 5-10 mg/kg doses consistent with the dose response previously reported in NK cell redirected cytotoxicity assays against HCC tumors. The increased anti- tumor efficacy observed at the lower doses were associated increased infiltration of PBNK’s to the tumor and corresponding reductions in PBNK’s in blood suggesting CYT-303 facilitates PBNK entry and retention in HCC tumors expressing GPC3 tumor antigen. CYT-303 safety assessment in the 4-week toxicology study in cynomolgous monkeys showed no treatment related toxicities or cytokine release and the NOAEL was determined to 60 mg/kg/week the highest dose administered in the study. No treatment related clinical signs, clinical pathology (hematology and clinical chemistry) and anatomic pathology (macroscopic, microscopic and organ weights) changes were observed. CYT-303 toxicokinetic analysis showed dose dependent increases in Cmax and AUC’s and no evidence for CYT-303 accumulation. CYT-303 anti-drug antibodies in monkeys were minimal and only observed in one low dose animal (1 out of 22) which also showed reduced CYT-303 exposures. Based on these pharmacology and toxicology results a pharmacologically active dose (PAD) based approach together with pharmacokinetic modeling would be utilized to estimate first in human dosing in HCC patients. CONCLUSIONS: CYT-303 efficacious doses identified in the HCC model together with safety in cynomolgus monkeys and planned human pharmacokinetic modeling studies support clinical evaluation of CYT-303 in first in human HCC clinical trials. Citation Format: Vishal Khairnar, Christine Waters, Solgalim Diaz, David De Franco, Jean Kadouche, Daniel Teper, Wei Li, Antonio Arulanandam. CYT-303 FLEX-NKTM engager dose response efficacy mechanisms in HCC tumor model and safety in cynomolgus monkey toxicology studies support clinical evaluation in hepato-cellular carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5667.