P-01.05 IOMX-0675, a LILRB1/LILRB2 cross-specific antibody that reprograms the tumor microenvironment to trigger potent anti-tumor activity

<h3>Background</h3> 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 &amp; 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. <h3>Materials and Methods</h3> 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 <i>in vitro</i> differentiated macrophages, dendritic cells and T cells in co-culture assays were investigated by flow cytometry and multiplex immunoassays. <i>In vivo</i> efficacy was tested in a fully engrafted myeloid enhanced humanized mouse xenograft model. <h3>Results</h3> 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 <i>in vitro</i> and in <i>ex vivo</i> 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. <h3>Conclusions</h3> 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 <i>in vitro</i> and <i>in vivo</i>. 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. <b>K. Heinig:</b> A. Employment (full or part-time); Significant; iOmx Therapeutics AG. <b>C.A. Hartl:</b> A. Employment (full or part-time); Significant; iOmx Therapeutics AG. <b>M. Stebegg-Wagner:</b> A. Employment (full or part-time); Significant; iOmx Therapeutics AG. <b>M. Maraslis:</b> A. Employment (full or part-time); Significant; iOmx Therapeutics AG. <b>E. Korotkova:</b> A. Employment (full or part-time); Significant; iOmx Therapeutics AG. <b>C. Ginzel:</b> A. Employment (full or part-time); Significant; iOmx Therapeutics AG. <b>T. Jaquin:</b> A. Employment (full or part-time); Significant; iOmx Therapeutics AG. <b>I.P. Maser:</b> A. Employment (full or part-time); Significant; iOmx Therapeutics AG. <b>B. Langer:</b> A. Employment (full or part-time); Significant; iOmx Therapeutics AG. <b>J. Schilz:</b> A. Employment (full or part-time); Significant; iOmx Therapeutics AG. <b>A. Huth:</b> A. Employment (full or part-time); Significant; iOmx Therapeutics AG. <b>M. Aigner:</b> A. Employment (full or part-time); Significant; iOmx Therapeutics AG. <b>A.N. Marziale:</b> A. Employment (full or part-time); Significant; iOmx Therapeutics AG. <b>S. Bissinger:</b> A. Employment (full or part-time); Significant; iOmx Therapeutics AG.