Abstract A095: IOMX-0675, a cross-specific antibody selectively blocking LILRB1 and LILRB2, robustly repolarizes immunosuppressive myeloid cells and stimulates cytotoxic T cells

Abstract The role of myeloid checkpoints in enabling tumors to evade immune responses has gained increased attention recently. LILRB1 (ILT2) and LILRB2 (ILT4) are immunosuppressive receptors in the leukocyte immunoglobulin-like receptor (LILR) family that bind classical and non-classical MHC-I molecules, such as HLA-G. Myeloid cells in the tumor microenvironment express both LILRB1 and LILRB2, while lymphoid cells only express LILRB1. High levels of LILRB1 and LILRB2 are often seen in patients who do not respond to T cell checkpoint inhibitors, suggesting these receptors may drive tumor resistance. Additionally, HLA-G, a main ligand for LILRB1 and LILRB2, is overexpressed in several solid tumors and linked to poor outcomes. Since it was confirmed that closely related immune-activating LILR members, LILRA1 and LILRA3, are co-expressed with LILRB1 and LILRB2 in certain cancer indications, selective receptor targeting is critical. IOMX-0675, a fully human IgG1 monoclonal antibody developed by iOmx, is engineered for selectivity with an Fc-silenced design. It binds strongly and selectively to the inhibitory LILRB1 and LILRB2 receptors, while binding weakly to immune-activating molecules LILRA1 and LILRA3. Using a high-resolution Fab-based Octet assay, it was confirmed that IOMX-0675 effectively blocks LILRB1 and LILRB2 from binding to HLA-G. In autologous immune cell co-cultures, IOMX-0675 reprograms immunosuppressive macrophages in a dose-dependent manner, restoring lymphoid immune cell function. Even in environments dominated by LILRA1 and LILRA3, IOMX-0675 maintains high selectivity for LILRB1 and LILRB2. This dual-targeting antibody also boosts macrophage phagocytosis and pro-inflammatory cytokine secretion from stimulated PBMCs in whole blood, as demonstrated by flow cytometry and cytokine profiling. In a CD34+ stem cell-engrafted humanized mouse melanoma model, IOMX-0675 showed potent anti-tumor effects and modulated tumor-associated macrophages, echoing in vitro results. In summary, IOMX-0675 is a highly selective antibody that targets both LILRB1 and LILRB2 with minimal affinity for immune-activating LILRA family members. It effectively reprograms immunosuppressive myeloid cells and restores T cell activity in the tumor microenvironment, showing strong results both in vitro and in vivo. This unique binding profile positions IOMX-0675 as a promising dual-targeting myeloid checkpoint inhibitor with best-in-class potential for broad anti-tumor effectiveness across various solid cancers. Citation Format: Christina A. Hartl, Kristina Heinig, Marisa Stebegg-Wagner, Eugenia Korotkova, Michail Maraslis, Carmen Ginzel, Alexander N. Marziale, Stefan Bissinger. IOMX-0675, a cross-specific antibody selectively blocking LILRB1 and LILRB2, robustly repolarizes immunosuppressive myeloid cells and stimulates cytotoxic T cells [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A095.