203 Preclinical characterization and development of MG1124, a Novel Immune Checkpoint inhibitor targeting CEACAM1 for NSCLC patients

Abstract

BackgroundCEACAM1 is the only member of CEACAM family which is expressed on lymphocytes such as T cells and NK cells that mediate suppression of inflammatory T cell response. It is known that CEACAM1-CEACAM1 homophilic interaction induces downregulation of ZAP70 phosphorylation in response to T cell receptor (TCR) stimulation. There is a wealth of research demonstrating the correlation between CEACAM1 expression and cancer progression, in a wide range of indications. We developed a fully human monoclonal antibody (mAb) MG1124 that specifically binds to CEACAM1 but not to other CEA family members, thereby exerting anti-tumor effect via triggering immune response.MethodsT cell activation of MG1124 was determined by an NFAT-luciferase reporter assay with CEACAM1 overexpressing Jurkat stable cells. In vitro efficacy of MG1124 was examined using an NK cell- or cytotoxic T cell-mediated tumor cell killing assay. The anti-tumor efficacy of MG1124 alone or in combination was studied in a humanized mouse model. As MG1124 binds to monkey CEACAM1 with high affinity, pharmacokinetics assessment of MG1124 was performed in cynomolgus monkeys.ResultsAn anti-CEACAM1 antibody MG1124 bound to CEACAM1 but not to other CEA family members. MG1124 blocked CEACAM1 homophilic interaction by binding to the N domain of CEACAM1. Especially the homophilic interaction induced downregulation of ZAP70 phosphorylation in response to TCR stimulation in a CEACAM1 overexpressing Jurkat stable cell line, which was rescued by MG1124 resulting in augmentation of NFAT activity and IL-2 expression. NK cell or cytotoxic T cell-mediated tumor lysis was increased by MG1124 in a CEACAM1 expression-dependent manner. MG1124 inhibited tumor growth in CEACAM1 expressing NSCLC CDX humanized mouse models. In an NSCLC PDX humanized mouse model, MG1124 dose-dependently inhibited tumor growth as monotherapy. Moreover, MG1124 showed synergistic anti-cancer activity with pembrolizumab in NSCLC huPDX models. Pharmacokinetic (PK) analysis in cynomolgus monkeys showed that the half-life (T1/2) of MG1124 was estimated to range from 14 to 17 days, and the peak plasma concentration (Cmax) and overall exposure (AUC) were found to be generally dose proportional. Following this PK study, a toxicity study in cynomolgus monkeys is ongoing.ConclusionsMG1124, a novel anti-CEACAM1 mAb, blocked CEACAM1-mediated negative regulation and restored NK or cytotoxic T cell activities. MG1124 showed effective anti-tumor activity in in vivo mouse models and its combination with PD-1 blockade further enhanced treatment efficacy. The data presented herein support further advancement of MG1124 towards clinical development. MG1124 is a potential therapeutic candidate for immune checkpoint blockade in cancer therapy.ReferencesScott D Gray-Owen, Richard S Blumberg. CEACAM1: contact-dependent control of immunity. Nat Rev Immunol 2006; 6(6): 433–46.Anka Thies. et al., CEACAM1 expression in cutaneous malignant melanoma predicts the development of metastatic disease. J Clin Oncol 2002; 20(10): 2530–6.Sebastian Dango, et al., Elevated expression of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) is associated with increased angiogenic potential in non-small-cell lung cancer. Lung Cancer 2008; 60(3): 426–33.Matthew Dankner, et al., CEACAM1 as a multi-purpose target for cancer immunotherapy. OncoImmunology 2017;6(7):e1328336.