Abstract 4364: Preclinical pharmacokinetics and pharmacodynamics of MK-4464, a novel NK cell engager targeting CEACAM5

MK-4464 is a bispecific, trifunctional antibody designed to direct NK cells to a tumor with a CEACAM5-specific scFv arm, and to activate the NK cells to kill tumors by simultaneously binding to NK cell costimulatory receptors NKG2D and CD16A. To support clinical translation, preclinical pharmacokinetics and pharmacodynamics studies were performed. In-vitro characterization was performed using cell-based assays, in-vivo efficacy was performed in B16F10-hCEACAM5 tumor-bearing hCEACAM5 transgenic mice. PET imaging studies were performed with 89Zr-labeled MK-4464 in CEACAM5+ve and CEACAM-ve tumor bearing hIL-15 transgenic NSG mice engrafted with CD34+ human hematopoietic stem cells. In vitro cytolytic activity assay demonstrated the ability of MK-4464 to kill CEACAM5-expressing tumor cell lines. The EC50 values for cytolytic activity in tumor cell lines MKN-45, SK-CO-1, and BxPC3 were 0.61 nM, 0.61 nM, and 4.45 nM, respectively. The cytolytic activity was higher in cell lines with higher CEACAM5 expression. MK-4464-mediated NK-cell activation was demonstrated by increased IFNγ production and CD107a expression. The activation was shown to be dependent on the binding to CEACAM5, NKG2D, and CD16A. The cytolytic activity of MK-4464 increased with a higher effector/target cell ratio. A mouse surrogate of MK-4464 induced significant tumor growth inhibition in B16F10-hCEACAM5 tumor-bearing hCEACAM5 transgenic mice, number of remaining animals was significantly greater in mice treated with murine MK-4464 at 15 mg/kg (p<0.0001), at 5 mg/kg (p=0.0004), and at 1.5 mg/kg (p=0.0274) compared with the isotype control group. PET imaging studies demonstrated high target-mediated localization in the tumor with relatively low uptake in normal tissues. [89Zr]MK-4464 demonstrated 2.5-fold greater tumor uptake than 89Zr-labeled control antibody in CEACAM5+ve tumors, while no significant difference was observed in CEACAM5-ve tumors. Dose-dependent tumor saturation was observed in CEACAM5+ve tumors with near complete saturation at 10 mg/kg. Accumulation in spleen and lymphoid tissues were significantly lower than CEACAM5+ve tumors. After IV bolus administration of MK-4464 on Study Days 1 and 15, mean AUC and Cmax values were approximately dose-proportional from 1 to 10 mg/kg/week and slightly greater than dose-proportional from 10 to 100 mg/kg/week. The MABEL approach was used to determine the first-in-human starting dose. These findings collectively demonstrate the potent and specific activity of MK-4464 in targeting and killing CEACAM5-expressing tumor cells through NK cell activation and cytokine release. These preclinical studies facilitated the clinical translation of MK-4464 and [89Zr]MK-4464 (ClinicalTrials.gov ID NCT05514444). Citation Format: Tapan Nayak, Yanyan Zheng, Li Li, Sophie Li, Smita Mauze, Mingmei Cai, Ruban Mangadu, Kerry Riffel, Xiangjun Meng, SuChun Hseih, Konstantin Dobrenkov, Amy Beebe. Preclinical pharmacokinetics and pharmacodynamics of MK-4464, a novel NK cell engager targeting CEACAM5 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4364.