Background: Myeloid immune suppression in the tumor microenvironment is known to contribute to tumor immune evasion. ILT2 (aka LILRB1) and ILT4 (aka LILRB2) are distinct ITIM-containing immunosuppressive receptors that recognize shared MHC-I ligands. Both ILT2 and ILT4 are highly expressed on tumor infiltrating myeloid cells, while ILT2 is also expressed on tumor-associated T and NK cells. Furthermore, both ILT2 and ILT4 are upregulated in patients who do not respond to T cell checkpoint inhibitor therapy, implicating these receptors as potential resistance mechanisms. Given their regulation in human cancers and their potential to mediate immune suppression in a broad range of tumor-associated immune cells, ILT2 and ILT4 may represent promising targets for cancer immunotherapy. The complementary nature of ILT2 and ILT4 activities suggests a dual antagonist strategy is warranted. To this end, we have developed NGM707. NGM707 is a humanized monoclonal antibody with specificity for both ILT2 and ILT4, blocking their interaction with both classical MHC-I (HLA-A, HLA-B, HLA-C) as well as the non-classical MHC-I molecule HLA-G. We present here preclinical data on the pharmacology of NGM707.
Methods: NGM707 was evaluated for ILT2 and ILT4 specificity, ligand blocking and functional activity. Activity was assessed on various myeloid cell subsets, including monocyte-derived macrophages, myeloid-derived suppressor cells (MDSC) and dendritic cells. ILT2 blockade by NGM707 was also assessed on NK cells and T cells.
Results: In vitro and biochemical pharmacology studies demonstrated that NGM707 bound potently to human ILT2 (1.03 nM KD) and ILT4 (0.205 nM KD). NGM707 binding to ILT2 and ILT4 blocked interaction with their ligands, including classical MHC-I and non-classical MHC-I (HLA-G). Functional studies demonstrated that NGM707-mediated ILT2 and ILT4 blockade reprogrammed suppressive myeloid cells and enhanced their activity, including stimulation of allogeneic T cell responses. NGM707-mediated ILT2 blockade also enhanced NK- and CD8 T cell-mediated killing of tumor cells. NGM707 in combination with an anti-PD-1 antibody additively enhanced macrophage-mediated allogeneic stimulation of CD4 T cells, suggesting combined treatment with NGM707 and an anti-PD-1 antibody can lead to complementary immune-modulatory activities.
Conclusions: NGM707 is a novel dual antagonist antibody targeting both ILT2 and ILT4. The preclinical data presented indicate that by blocking ILT4, NGM707 can reprogram suppressive myeloid cells to a stimulatory state, and that by blocking ILT2, NGM707 can stimulate the activation of both myeloid and lymphoid cells. These data support the clinical evaluation of NGM707 as a therapeutic for patients with solid tumor malignancies.
Citation Format: Kalyani Mondal, Christina Song, Jane Tian, Carmence Ho, Lee B. Rivera, Jiawei Huang, Peirong Chen, Suzanne Crawley, Vicky Y. Lin, Jonathan Sitrin, Julie M. Roda, David Shen, Hui Tian, Yan Wang, Alan Kutach, Jeong Kim, James Sissons, Daniel D. Kaplan, Geoffrey W. Stone. Preclinical evaluation of NGM707, a novel anti-ILT2/anti-ILT4 dual antagonist monoclonal antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB156.