Structural basis and preclinical efficacy of MG1124, a novel CEACAM1-targeting antibody synergizing with PD-1 blockade

Vollständiger Abstract

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Abstract CEACAM1 homodimerization mediates tumor immune evasion, presenting a compelling target to overcome resistance to PD-1 blockade. However, defining a precise structural and pharmacological blueprint for CEACAM1 targeting has remained challenging. Here, we report the discovery and comprehensive preclinical characterization of MG1124, a highly specific, fully human monoclonal antibody targeting the CEACAM1 IgV domain. X-ray crystallographic analysis at a 1.8 Å resolution revealed that MG1124 binds the homodimerization interface with robust affinity (KD = 37.8 nM), physically disrupting both homophilic and heterophilic inhibitory interactions without cross-reacting with highly homologous CEACAM members. This targeted structural blockade effectively reversed CEACAM1-mediated suppression of T-cell receptor signaling, restoring ZAP70 phosphorylation and IL-2 production, while potently enhancing NK- and CD8⁺ T-cell cytotoxicity against CEACAM1-high tumor cells. In vivo, MG1124 reprogrammed the tumor immune microenvironment by increasing effector cytokine production in human CEACAM1 knock-in mice. It also demonstrated robust tumor growth inhibition in humanized non-small cell lung cancer (NSCLC) patient-derived xenograft (PDX) models, synergizing profoundly with PD-1 blockade. Furthermore, multiplex immunofluorescence profiling of human NSCLC tissues confirmed robust CEACAM1 expression across tumor and immune compartments, reinforcing its translational validity. Finally, MG1124 exhibited a highly favorable, drug-like pharmacokinetic profile in cynomolgus monkeys, characterized by prolonged systemic exposure and low clearance. By defining the structural basis of CEACAM1 blockade and demonstrating translational efficacy, this study introduces MG1124 as a novel therapeutic antibody, providing a robust pharmacological foundation for cancer immunotherapy.