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Development of a Novel Anti-Siglec-15 Antibody for Tumor Immunotherapy
1Public Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.
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.
Insights
Researchers developed a novel anti-siglec-15 antibody from lung cancer patients
Area of Science:
- Immunotherapy
- Oncology
- Antibody Engineering
Background:
- Siglec-15 (sialic acid-binding immunoglobulin-like lectin 15) is a novel target in cancer immunotherapy.
- Existing therapies like programmed death ligand 1 (PD-L1) antibodies are ineffective for some tumors.
- Development of siglec-15-targeting antibodies offers alternative therapeutic strategies.
Purpose of the Study:
- To develop a novel fully human antibody targeting siglec-15.
- To restore tumor immune normalization in cancer immunotherapy.
- To address limitations in current siglec-15 pharmacological development.
Main Methods:
- Phage display technology was used to screen antibodies from a library derived from lung cancer patients.
- Antibody characterization included affinity (Bio-Layer Interferometry), binding (flow cytometry), and functional assays (ADCC, T-cell proliferation).
- In vivo efficacy was evaluated using zebrafish and humanized mouse tumor models.
Main Results:
- The developed antibody exhibited nanomolar affinity and specificity for siglec-15.
- In vitro studies showed enhanced ADCC, reversed T-cell suppression, and reduced CD8+ T-cell exhaustion.
- In vivo models demonstrated significant tumor growth inhibition with increased lymphocyte infiltration and activation.
Conclusions:
- Fully human antibodies against siglec-15 can be effectively screened using immune libraries from cancer patients.
- The novel anti-siglec-15 antibody demonstrates potent anti-tumor activity through immune modulation.
- This antibody holds promise for treating tumors unresponsive to PD-L1 blockade.
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