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A novel Fc-enhanced humanized monoclonal antibody targeting B7-H3 suppresses the growth of ESCC
Huiting Wu1,2, Chang Liu1,2, Qiang Yuan1,2
1Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.
Abstract:
Esophageal squamous cell carcinoma (ESCC) is a prevalent malignant tumor of the digestive tract with a low 5-year survival rate due to the lack of effective treatment methods. Although therapeutic monoclonal antibodies (mAbs) now play an important role in cancer therapy, effective targeted mAbs are still lacking for ESCC. B7-H3 is highly expressed in a variety of tumors and has emerged as a promising therapeutic target. Several mAbs against B7-H3 have advanced to clinical trials, but their development has not yet been pursued for ESCC. Here, we developed a humanized and Fc-engineered anti-B7H3 mAb 24F-Hu-mut2 and systematically evaluated its anti-tumor activity in vitro and in vivo. The 24F-Hu-mut2 was humanized and modified in Fc fragment to obtain stronger antibody-dependent cell-mediated cytotoxicity(ADCC) activity and nanomolar affinity. Furthermore, both of ESCC cell-derived xenograft (CDX) and patient-derived xenograft (PDX) mice models indicated that 24F-Hu-mut2 displayed potent in vivo anti-tumor activity. In addition, a computational docking model showed that the mAb bound to IgC1 and IgC2 domain of B7-H3, which is closer to the cell membrane. Consistently, our ELISA results verified the binding of 24F-Hu-WT and IgC1 and IgC2. Our results indicate that 24F-Hu-mut2 has significant anti-ESCC activity both in vitro and in vivo, and this monoclonal antibody may be a promising antibody against ESCC and other B7-H3 overexpressing tumors.
Insights
A novel humanized anti-B7H3 monoclonal antibody, 24F-Hu-mut2, demonstrates potent anti-tumor activity against esophageal squamous cell carcinoma (ESCC) in preclinical models. This antibody shows promise for treating ESCC and other B7-H3-overexpressing cancers.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Esophageal squamous cell carcinoma (ESCC) has a poor prognosis due to limited effective treatments.
- Therapeutic monoclonal antibodies (mAbs) are crucial in cancer therapy, but targeted options for ESCC are lacking.
- B7-H3 is a promising therapeutic target due to its high expression in various tumors.
Purpose of the Study:
- To develop and evaluate a humanized and Fc-engineered anti-B7H3 mAb (24F-Hu-mut2) for anti-tumor activity against ESCC.
- To assess the in vitro and in vivo efficacy of 24F-Hu-mut2.
- To investigate the binding characteristics of 24F-Hu-mut2 to B7-H3.
Main Methods:
- Humanization and Fc engineering of an anti-B7H3 mAb to enhance antibody-dependent cell-mediated cytotoxicity (ADCC) and affinity.
- In vitro and in vivo evaluation of 24F-Hu-mut2 in ESCC cell-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models.
- Computational docking and ELISA to determine the binding site of the mAb on B7-H3.
Main Results:
- 24F-Hu-mut2 exhibited enhanced ADCC activity and nanomolar affinity.
- Significant in vivo anti-tumor efficacy was observed in both CDX and PDX models.
- Computational and ELISA data confirmed binding to the IgC1 and IgC2 domains of B7-H3, near the cell membrane.
Conclusions:
- 24F-Hu-mut2 demonstrates potent anti-ESCC activity in vitro and in vivo.
- This engineered mAb is a promising therapeutic candidate for ESCC.
- 24F-Hu-mut2 may also be effective against other B7-H3 overexpressing tumors.
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