Abstract 6435: BCG008, a human Siglec-15 blocking antibody, displays potent anti-tumor activity in Siglec-15-humanized mice

Abstract Sialic acid-binding Ig-like lectin 15, or Siglec-15, is identified as a critical immune suppressor. Siglec-15 expression is normally limited to certain myeloid cells, but it can be upregulated in a variety of tumors and on tumor-infiltrating myeloid cells. Siglec-15 significantly inhibits antigen-specific T cell responses both in vitro and in vivo. Conversely, genetic ablation of Siglec-15 promotes anti-tumor responses. Therefore, a Siglec-15-targeting blocking antibody could represent a novel class of anti-tumor immunotherapy. BCG008, a fully human monoclonal antibody antagonist of Siglec-15, was generated from RenMab™ mice, which contain the entire human immunoglobulin variable domain. Compared to a reference Siglec-15 blocking antibody (5G12), BCG008 exhibited higher affinity for human and cynomolgus monkey Siglec-15 and targeted distinct binding epitopes. In in vitro studies, BCG008 significantly abrogated Siglec-15-mediated T cell suppression in a dose-dependent manner, as measured by CD4+ and CD8+ T cell proliferation. Subsequently, the efficacy and safety of BCG008 was evaluated in syngeneic tumor models in Siglec15-humanized mice. BCG008 monotherapy significantly inhibited tumor growth, and the effect of the tumor inhibition was potentiated when administered in combination with other immune-checkpoint inhibitors, including anti-PD-L1 antibodies. In safety evaluation, BCG008 was well-tolerated in the tumor-bearing mice; no adverse effects were observed even at high doses (e.g. 30 mg/kg). Taken together, these results demonstrate that BCG008 is a novel anti-human Siglec-15 blocking antibody with favorable efficacy and safety profiles that can provide potential benefits for future cancer immunotherapy. Citation Format: Yongfei Yang, Aidong Qu, Fengping Yao, Pan Song, Hongyuan Liang, Maopeng Tian, Fang Yang, Zhaoxue Yu, Xu Zhou, Xiuling Li. BCG008, a human Siglec-15 blocking antibody, displays potent anti-tumor activity in Siglec-15-humanized mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6435.