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Enhancing the Anti-tumor Potency of a Novel Siglec-15 Antibody by Engineering its Fc-mediated Effector Functions
Huandi Ding1,2, Bing Yao2,3, Lei Ci4
1State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing.
Abstract:
Siglec-15, an inhibitory immune checkpoint, is an emerging target in cancer immunotherapy. Blocking the function of Siglec-15 is an excellent strategy for cancer treatment and antibody blockade has been used to target Siglec-15. However, whether Fc-mediated effector functions contribute to the therapeutic effect of antibodies remains unclear. Herein, we generated a monoclonal antibody, 1-15D1, which had a high binding affinity with Siglec-15 and strongly activated T-cell immune response in vitro. Subsequently, the Fc-mediated effector functions of 1-15D1 were explored in a Siglec-15 humanized mouse model, and further improvement in antitumor efficacy was observed in the mouse IgG2a isotype group. Thus, we demonstrate that the antitumor effects of 1-15D1 were mediated via multiple factors. In addition to the T-cell immune response, 2 novel mechanisms were explored, including the internalization of the cell surface Siglec-15 and Fc-mediated effector functions. In conclusion, our studies not only provide a potential agent for the improvement of cancer immunotherapy but also suggest that a specific role of Fc-mediated immune regulation may improve the therapeutic potency of Siglec-15 monoclonal antibody.
Insights
Blocking Siglec-15 (sialic acid-binding immunoglobulin-like lectin 15) shows promise in cancer immunotherapy. This study reveals that Fc-mediated effector functions enhance the antitumor efficacy of Siglec-15 antibodies, offering new therapeutic strategies.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Siglec-15 is an inhibitory immune checkpoint and a target for cancer immunotherapy.
- Antibody blockade is a strategy to target Siglec-15, but the role of Fc-mediated effector functions is not fully understood.
Purpose of the Study:
- To investigate the contribution of Fc-mediated effector functions to the therapeutic effect of Siglec-15 antibodies.
- To explore novel mechanisms of Siglec-15 blockade in cancer treatment.
Main Methods:
- Generation of a high-affinity monoclonal antibody (1-15D1) against Siglec-15.
- In vitro activation of T-cell immune response by 1-15D1.
- Evaluation of Fc-mediated effector functions and antitumor efficacy in a Siglec-15 humanized mouse model.
Main Results:
- The monoclonal antibody 1-15D1 demonstrated high binding affinity to Siglec-15 and activated T-cell responses.
- Enhanced antitumor efficacy was observed with the mouse IgG2a isotype, indicating the contribution of Fc-mediated effector functions.
- Siglec-15 internalization was identified as an additional mechanism of action.
Conclusions:
- The antitumor effects of 1-15D1 are multifactorial, involving T-cell activation, Siglec-15 internalization, and Fc-mediated effector functions.
- Fc-mediated immune regulation can improve the therapeutic potency of Siglec-15 monoclonal antibodies.
- This study provides a potential agent for improving cancer immunotherapy and highlights the importance of Fc engineering.
