Work

76 Tumor targeting and biodistribution of MK-4464, a CEACAM5-targeted NK cell engager, using [ 89 Zr]MK-4464 PET in preclinical models and cancer patients

Year: 2026

Type: conference-abstract

Abstract: Background MK-4464 is a bispecific, trifunctional antibody designed to target CEACAM5-expressing tumors while activating natural killer (NK) cells via NKG2D and CD16A engagement, with the potential to enhance both innate and adaptive antitumor immunity. We evaluated its biodistribution and tumor-targeting properties in preclinical models and cancer patients using zirconium-89–labeled MK-4464 ([ 89Zr]MK-4464).Methods Preclinical studies in CEACAM5-positive and CEACAM5-negative tumor–bearing hIL15 transgenic NSG mice engrafted with CD34 + human hematopoietic stem cells were conducted to evaluate target specificity and dose-dependent saturation. Studies in cynomolgus monkeys evaluated normal tissue distribution and estimated radiation dosimetry. In the imaging cohort of a Phase 1 study (NCT05514444), patients received a single dose of [89Zr]MK-4464 during cycle 1, followed by serial PET imaging over one week.Results In tumor-bearing mouse models, [ 89Zr]MK-4464 demonstrated selective uptake in CEACAM5-positive tumors with evidence of dose-dependent saturation. In cynomolgus monkeys, distribution was consistent with typical antibody pharmacokinetics, with highest uptake observed in the liver among normal tissues.Tumor uptake was detected in all four evaluable patients with pancreatic or colorectal cancer, with signal intensity exceeding that of the blood pool and increasing over time, reaching tumor-to-blood ratios greater than 2 at later time points. By cycle 1 day 8, mean tumor uptake (SUV 10.2 ± 4.9) exceeded spleen uptake (SUV 3.1 ± 1.0), supporting CEACAM5-mediated targeting with limited contribution from NKG2D-mediated lymphoid binding. Among normal tissues, liver uptake was highest (SUV 7.1 ± 1.9). Estimated radiation dosimetry (0.77 ± 0.04 mSv/MBq) was consistent with other [89Zr]-labeled antibodies.Conclusions [ 89Zr]MK-4464 demonstrates selective and sustained tumor uptake in CEACAM5-expressing cancers with a favorable biodistribution profile in both preclinical models and patients. These findings highlight the utility of immuno-PET for evaluating target engagement and tissue distribution of NK cell–engaging therapies.

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.0076