Abstract 5522: BSI-060T, a high affinity, fully human anti-siglec-15 antibody as an alternative immune checkpoint blocker
Authors: Peng Zeyu , Liu Xiaodong F. , Xia Shukai , Liu Jinyu , Li Hongyan , Liu Yuxiang , Davis Hugh M. , Chen Mingjiu , Ma Mark Z. 
Published: June 2022

Background: Siglec-15 is a single-pass type I membrane protein that plays an important role in the immune-suppressive tumor microenvironment (TME). Siglec-15 has low expression levels in most normal human tissues but it is highly expressed in a subset of myeloid cells of the TME and over-expressed in some solid tumors. Siglec-15 on tumor associated macrophages and tumor cells inhibits T cell proliferation and pro-inflammatory cytokine release. Therefore, targeting Siglec-15 may overcome a suppressive TME and enhance the anti-tumor activity of other immune checkpoint inhibitors.

Experimental procedures: Humanized mice were used immunized with recombinant Siglec-15-ECD-Fc. The Biosion proprietary H3 (High-throughput, High-content and High-efficiency) antibody screening platform was used to identify a lead anti-Siglec-15 mAb candidate-BSI-060T. Siglec-15 expression in head and neck, lung and other cancer types was assessed by immunohistochemistry (IHC) in conjunction with PD-L1. The ex vivo release of suppression of T cell activity was determined by stimulating human peripheral blood mononuclear cells with a suboptimal dose of immobilized OKT3 in the presence of recombinant human Siglec-15-Fc with and without BSI-060T. A pharmacokinetic study was carried out in cynomolgus monkeys to determine the exposure of BSI-060T over time. Tumor inhibition of BSI-060T was evaluated in Siglec-15 humanized mice that were inoculated with MC38 cells overexpressing human Siglec-15.

Summary: BSI-060T is a fully human IgG1κ monoclonal antibody that binds to Siglec-15 protein with high affinity and blocks the interaction between Siglec-15 and its putative receptor LRRC4C. BSI-060T shows cross-reactivity to monkey and mouse Siglec-15. In ex vivo T cell response assays, BSI-060T exhibits strong activity on reverting Siglec-15-mediated inhibition of CD8+ and CD4+ T cell proliferation and interferon-γ release. In a humanized Siglec-15 mouse syngeneic tumor model, BSI-060T shows significant inhibition of tumor growth. BSI-060T also exhibits excellent monkey PK. In addition, an IHC assay has been developed and used to identify tumor types overexpressing Siglec-15. This assay will be used for patient recruitment in early clinical development and has the potential to be a companion diagnostic in the future.

Conclusion: BSI-060T exhibits best-in-class biophysical properties and functional characteristics, supporting the initiation of development activities including manufacturing and IND-enabling studies.

Citation Format: Zeyu Peng, Xiaodong F. Liu, Shukai Xia, Jinyu Liu, Hongyan Li, Yuxiang Liu, Hugh M. Davis, Mingjiu Chen, Mark Z. Ma. BSI-060T, a high affinity, fully human anti-siglec-15 antibody as an alternative immune checkpoint blocker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5522.