SIGLEC15 (Sialic acid-binding immunoglobulin-like lectin 15) belongs to the Siglec family of sialic acid-binding, immunoglobu-lin-like proteins. SIGLEC15 is an effective immunosuppressive molecule which is highly expressed on M2 macrophages but can be upregulated in many human cancers. The SIGLEC15 signaling pathway is non-redundant to the PD-L1 pathway in cancer, and thesurface expression of SIGLEC15 is generally non-overlapping with PD-L1 expression on tumors. SIGLEC15 engages a putative responder protein expressed on the surface of effector cells, such as CD8 T cells, inducing suppression of anti-tumor immune re- sponses. Blocking of SIGLEC15 amplifies anti-tumor immunity in the tumor microenvironment and inhibits tumor growth. This opens a road for anti-SIGLEC15 antibody therapeutics which may provide a solution for patients with SIGLEC15-positive and PD-L1-negative tumors, a patient population less likely to respond to a PD-1/PD-L1 directed therapy. Biocytogen has generated a humanized SIGLEC15 mouse model to address the need for in vitro functional validation and in vivo efficacy evaluation of SI- GLEC15-targeting strategies. In these mice, genomic DNA spanning exons 2~4 of mouse Siglec15 gene encoding the extracellular domain, was replaced by its human counterpart. Following the humanization procedure, human SIGLEC15 could be detected on bone marrow derived macrophages (BMDM). Basal leukocyte subpopulations, including T/B/NK cells, DC, granulocytes, and monocytes/macrophages, were similar between humanized and wild-type mice. In addition, Biocytogen has generated a human- ized MC38 cell line, in which the mouse Siglec15 gene was replaced with the full-length human coding sequence. The successful humanization of M38 was confirmed by RT-PCR and flow cytometry. Using the hMC38 tumor model, we showed modest efficacy of the anti-SIGLEC15 antibodies in inhibiting tumor growth in vivo. Combined SIGLEC15 and PD-1/PD-L1 blockade showed greater tumor inhibition than monotherapies. In summary, SIGLEC15 humanized mice can be employed for in vivo efficacy evaluation of anti-SIGLEC15 antibodies in immune normalization approaches for cancer treatment. Besides the tumor models (B16F10 and other tumors underway), we are also actively exploring the feasibility of the SIGLEC15 humanized mice as a pre-clinical model for osteoporosis in a light of recent discovery of SIGLEC15’s role in osteoclast differentiation.