Development of a Novel Anti-Siglec-15 Antibody for Tumor Immunotherapy.

[PURPOSE] As a novel candidate in cancer immunotherapy, siglec-15-targeting antibodies hold promise for providing alternative therapeutic strategies to tumors unresponsive to programmed death ligand 1 (PD-L1) antibody therapy. To date, pharmacological development targeting siglec-15 has not yet achieved significant breakthroughs or clinical approval. Therefore, this study aims to develop a novel anti-siglec-15 antibody designed to restore tumor immune normalization.

[METHODS] In this study, we constructed a phage immune library derived from lymphoid tissues of lung cancer patients using phage display technology and screened the fully human antibodies against siglec-15 antigen from this library. The antibody affinity was detected by Bio-Layer Interferometry, the binding rate of antibody to positively expressing siglec-15 tumor cells was examined by flow cytometry, and the activity of antibody-mediated killer cells against tumor cells was reflected by Antibody-Dependent Cellular Cytotoxicity (ADCC) action. The blockage of proliferation inhibition caused by siglec-15 antigen by antibodies was investigated by t-lymphocyte proliferation assays, and CD8 T cells were collected from malignant pleural effusion specimens derived from lung cancer patients to determinewhether antibodies could alleviate the immunosuppression present in the tumor microenvironment (TME). The anti-tumor efficacy of the antibody was investigated in vivo by constructing a zebrafish tumor model and a humanized mouse tumor model.

[RESULTS] The antibody demonstrated nanomolar affinity and specificity, enhanced antibody-dependent cellular cytotoxicity (ADCC) against tumor cells, reversed T-cell suppression, and reduced CD8 T-cell exhaustion in vitro analyses. In vivo models confirmed tumor growth inhibition via increased lymphocyte infiltration and activation.

[CONCLUSION] Antibody immune libraries from lymphoid tissues of lung cancer patients can screen specific antibodies against siglec-15 target antigens and exert certain biological functions in vitro and in vivo.