Abstract A045: PSB120, a LILRB2 specific antibody enhances sensitivity to Gemcitabine through an HLA-G independent mechanism

Abstract The suppressive micro-environment within tumors is partly caused by infiltrating macrophages. Expression of HLA-G on tumor cells and its receptor LILRB2 on tumor macrophages are associated with poor prognosis in cancer patients. Anti LILRB2 antibodies have been developed to block HLA-G and LILRB2 interaction and to promote M1 macrophage differentiation. Whether anti LILRB2 antibody can exert its effect through an HLA-G independent mechanism has not been investigated. Here, we describe PSB120, a fully humanized anti LILRB2 antibody with high affinity to LILRB2 without cross-reactivity to other members of LILR family. PSB120 blocks HLA-G binding with high efficiency. In vitro, PSB120 changes macrophage differentiation by significantly enhancing M1 phenotypes and down-regulating several M2 phenotypes, including enhanced TNF production, down-regulation of CD163 and CD14, and reduced capability of efferocytosis. Interestingly, these activities were observed in both HLA-G blockers and non-blockers, suggesting an HLA-G independent mechanism. We further determined the in vivo efficacy of PSB120 in LILRB2-B3 transgenic mice using syngeneic tumor models. We found PSB120 can be combined with anti-mPD1 to synergistically inhibit the growth of wild type MC38 tumor cells. The synergistic effect of PSB120 is inversely correlated with its Fc receptor binding activity: antibody without FcR binding showed significant activity, whereas those with IgG4 Fc or enhanced Fc binding showed no activity. Furthermore, PSB120 can significantly enhance the activity of Gemcitabine in both MC38 and LLC tumor models in LILRB2-B3 transgenic mice. Since neither MC38 nor LLC tumor cells express HLA-G, these results demonstrated the HLA-G independent mechanism of PSB120. In summary, these findings uncovered an HLA-G independent function of anti LILRB2 antibodies and suggested the potential to broaden their applications in immunotherapy. Citation Format: YuFeng Peng, Annum Munir, Meijuan Zhang. PSB120, a LILRB2 specific antibody enhances sensitivity to Gemcitabine through an HLA-G independent mechanism [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A045.