Abstract 2237: IOMX-0675, a LILRB1/LILRB2 cross-specific antibody that repolarizes the tumor microenvironment to drive potent anti-tumor activity

Abstract IOMX-0675 is a monoclonal immunoglobulin G1 (IgG1) antibody targeting LILRB1 (ILT2) and LILRB2 (ILT4), key immunosuppressive receptors of the leukocyte immunoglobulin-like receptor (LILR) family, that play a pivotal role in tumor immune evasion. LILRB1 and LILRB2 recognize both classical and non-classical MHC-I molecules and are highly expressed on tumor-infiltrating myeloid cells, with LILRB1 also found on lymphoid cells. Their frequently observed upregulation in patients non-responsive to T cell checkpoint blockade, implicate a role in driving tumor resistance. Expression profiling revealed co-expression of immune-activating LILR members, LILRA1 and LILRA3, with LILRB1 and LILRB2 in specific cancer indications, underscoring the importance of selective receptor targeting to achieve effective therapeutic outcomes. IOMX-0675, identified through iOmx’s proprietary phage display library, exhibits a highly differentiated binding profile with selective, high-affinity binding to the inhibitory receptors LILRB1 and LILRB2, while showing only weak affinity to the closely related immune-activating LILR family members LILRA1 and LILRA3. In autologous immune cell co-cultures, IOMX-0675 effectively reprograms immunosuppressive macrophages in a dose-dependent manner, restoring lymphoid immune cell function. Importantly, IOMX-0675 retains its high selectivity for LILRB1 and LILRB2 and its pharmacodynamic activity, even in environments dominated by LILRA1 and LILRA3. IOMX-0675 enhances phagocytic activity, stimulates pro-inflammatory functions across various macrophage subtypes and drives robust pro-inflammatory cytokine secretion in stimulated PBMCs, both in vitro and in ex vivo whole blood assays. In a CD34+ stem cell-engrafted humanized mouse melanoma model, IOMX-0675 exhibited potent anti-tumor activity and repolarized tumor-associated macrophages, closely aligning with in vitro findings and underscoring its therapeutic promise. In summary, we developed IOMX-0675, a highly selective cross-specific antibody that effectively antagonizes both LILRB1 and LILRB2 while exhibiting negligible binding to immune-activating LILR family members. IOMX-0675 demonstrates robust reprogramming of the immunosuppressive myeloid compartment and restores cytotoxic T cell activity within the tumor microenvironment, both in vitro and in vivo. Its differentiated binding profile positions IOMX-0675 as a best-in-class therapeutic candidate with the potential to maximize anti-tumor efficacy and address significant unmet medical needs for patients. Citation Format: Kristina Heinig, Christina A. Hartl, Marisa Stebegg-Wagner, Eugenia Korotkova, Michail Maraslis, Carmen Ginzel, Thomas Jaquin, Bettina Langer, Jonas Schilz, Alina Huth, Maximilian Aigner, Alexander N. Marziale, Stefan Bissinger. IOMX-0675, a LILRB1/LILRB2 cross-specific antibody that repolarizes the tumor microenvironment to drive potent anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2237.