P-01.05 IOMX-0675, a LILRB1/LILRB2 cross-specific antibody that reprograms the tumor microenvironment to trigger potent anti-tumor activity
Year: 2025
Type: conference-abstract
Abstract: Background 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. The frequently observed upregulation of LILRB1 & LILRB2 in patients non-responsive to T cell immune 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. Materials and Methods Target expression levels were confirmed by RNAseq analysis. Selective binding properties and IOMX-0675-mediated blocking of LILRB1 and LILRB2 interaction with HLA-G, its primary ligand expressed on tumor cells, were shown by Fab-based Octet assays. Treatment-induced effects on phagocytosis, cellular phenotype and cytokine profile of in vitro differentiated macrophages, dendritic cells and T cells in co-culture assays were investigated by flow cytometry and multiplex immunoassays. In vivo efficacy was tested in a fully engrafted myeloid enhanced humanized mouse xenograft model. Results IOMX-0675, identified through iOmx’s proprietary phage display library, exhibits a highly differentiated binding profile with selective, high-affinity binding to LILRB1 and LILRB2, while showing only weak affinity to the closely related immune-activating LILR family members LILRA1 and LILRA3. In autologous macrophage T cell co-culture assays, IOMX-0675 effectively reprograms immunosuppressive macrophages in a dose-dependent manner, restoring lymphoid immune cell function. Importantly, even in environments dominated by LILRA1 and LILRA3, IOMX-0675 retains its pharmacodynamic activity. IOMX-0675 enhances phagocytic activity, stimulates pro-inflammatory functions and drives robust pro-inflammatory cytokine secretion in both in vitro and in ex vivo stimulated PBMCs and enhances anti-PD-1 therapeutic efficacy in mixed lymphocyte reactions. 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. Conclusions 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. K. Heinig: A. Employment (full or part-time); Significant; iOmx Therapeutics AG. C.A. Hartl: A. Employment (full or part-time); Significant; iOmx Therapeutics AG. M. Stebegg-Wagner: A. Employment (full or part-time); Significant; iOmx Therapeutics AG. M. Maraslis: A. Employment (full or part-time); Significant; iOmx Therapeutics AG. E. Korotkova: A. Employment (full or part-time); Significant; iOmx Therapeutics AG. C. Ginzel: A. Employment (full or part-time); Significant; iOmx Therapeutics AG. T. Jaquin: A. Employment (full or part-time); Significant; iOmx Therapeutics AG. I.P. Maser: A. Employment (full or part-time); Significant; iOmx Therapeutics AG. B. Langer: A. Employment (full or part-time); Significant; iOmx Therapeutics AG. J. Schilz: A. Employment (full or part-time); Significant; iOmx Therapeutics AG. A. Huth: A. Employment (full or part-time); Significant; iOmx Therapeutics AG. M. Aigner: A. Employment (full or part-time); Significant; iOmx Therapeutics AG. A.N. Marziale: A. Employment (full or part-time); Significant; iOmx Therapeutics AG. S. Bissinger: A. Employment (full or part-time); Significant; iOmx Therapeutics AG.
Source: Poster presentations
Authors: K Heinig, CA Hartl, M Stebegg-Wagner, M Maraslis, E Korotkova, C Ginzel, T Jaquin, IP Maser, B Langer, J Schilz, A Huth, M Aigner, AN Marziale, S Bissinger
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4408813291