HLA-B27 and HLA-B57 are associated with autoimmunity and long-term viral control and protection against HIV and HCV infection; however, their role in cancer immunity remains unknown. HLA class I molecules interact with innate checkpoint receptors of the LILRA, LILRB and KIR families present in diverse sets of immune cells. Here, we demonstrate that an open format (peptide free conformation) and expression- and stability-optimized HLA-B57-B2m-IgG4_Fc fusion protein (IOS-1002) binds to human leukocyte immunoglobulin-like receptor B1 and B2 (LILRB1 and LILRB2) and to killer immunoglobulin-like receptor 3DL1 (KIR3DL1). In addition, we show that the IgG4 Fc backbone is required for engagement to Fcγ receptors and potent activation of macrophage phagocytosis. IOS-1002 blocks the immunosuppressive ITIM and SHP1/2 phosphatase signaling cascade, reduces the expression of immunosuppressive M2-like polarization markers of macrophages and differentiation of monocytes to myeloid-derived suppressor cells, enhances tumor cell phagocytosis in vitro and potentiates activation of T and NK cells. Lastly, IOS-1002 demonstrates efficacy in an ex vivo patient-derived tumor sample tumoroid model. IOS-1002 is a first-in-class multi-target and multi-functional human-derived HLA molecule that activates anti-tumor immunity and is currently under clinical evaluation.
HLA-B27和HLA-B57与自身免疫及长期病毒控制相关，对HIV和HCV感染具有保护作用，但它们在癌症免疫中的作用尚不明确。HLA I类分子可与多种免疫细胞中存在的LILRA、LILRB和KIR家族天然检查点受体相互作用。本研究证明，一种开放构象（无肽结合状态）且经表达与稳定性优化的HLA-B57-B2m-IgG4_Fc融合蛋白（IOS-1002）能够结合人白细胞免疫球蛋白样受体B1和B2（LILRB1与LILRB2）以及杀伤细胞免疫球蛋白样受体3DL1（KIR3DL1）。此外，研究显示IgG4 Fc骨架结构是实现Fcγ受体结合及有效激活巨噬细胞吞噬功能的关键。IOS-1002可阻断免疫抑制性ITIM结构域及SHP1/2磷酸酶信号级联反应，降低巨噬细胞免疫抑制性M2样极化标志物表达，抑制单核细胞向髓源性抑制细胞分化，在体外增强肿瘤细胞吞噬作用，并有效促进T细胞与NK细胞活化。最后，IOS-1002在离体患者来源肿瘤类器官模型中展现出显著疗效。作为首个多靶点多功能人源化HLA分子，IOS-1002能够激活抗肿瘤免疫反应，目前正处于临床评估阶段。
IOS-1002, a Stabilized HLA-B57 Open Format, Exerts Potent Anti-Tumor Activity
肿瘤(癌症)患者之家