Cancer Research | Fc-Engineered Glycomodified Antibody Enhances Immune Effector Cell Activation and Inhibits Breast Cancer Progression

This study designed an antibody with Fc domain engineering and glycosylation modification, which significantly enhances the binding ability to FcγRIIIa-expressing immune effector cells, thereby improving the anti-tumor activity of NK cells and macrophages. The antibody demonstrates superior anti-tumor efficacy in both HER2+ and FRα+ breast cancer models.

 

Literature Overview
This article, 'An Fc-Engineered Glycomodified Antibody Supports Proinflammatory Activation of Immune Effector Cells and Restricts Progression of Breast Cancer', published in the journal Cancer Research, reviews and summarizes the enhancement of antibody binding capacity to FcγRIIIa through Fc domain engineering, thereby increasing the anti-tumor activity of immune effector cells. The study evaluated the expression profiles of FcγRs in HER2+ and triple-negative breast cancer (TNBC) using scRNA-seq and spatial transcriptomic analyses, and validated their role in the design of anti-HER2 and anti-FRα antibodies. The paragraph is coherent and logically structured, ending with a Chinese period.

Background Knowledge
Breast cancer is one of the most common cancers globally, with HER2+ and triple-negative breast cancer (TNBC) having higher risks of recurrence and treatment resistance. Traditional anti-HER2 antibodies, such as trastuzumab, show certain efficacy in treating HER2+ breast cancer, but approximately 70% of patients develop resistance within a year. TNBC has limited treatment options due to the lack of clear molecular targets. In recent years, immunotherapy has become a research hotspot, particularly focusing on Fcγ receptors (FcγR), which play a crucial role in antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). However, effectively enhancing antibody binding to FcγRIIIa, especially in individuals carrying low-affinity alleles (such as FcγRIIIa-F158), remains an unmet clinical need. This study develops Fc-engineered antibodies targeting HER2 and FRα by combining glycoengineering and Fc point mutations to enhance immune effector cell activation, and validates their anti-tumor efficacy in mouse models.

 

 

Research Methods and Experiments
The research team evaluated the expression patterns of FcγRs in the tumor microenvironment of HER2+ and TNBC patients using scRNA-seq and NanoString analyses, and validated the co-expression of FcγRs and FRα by integrating spatial transcriptomic data. Based on these findings, they designed four anti-HER2 antibody variants (IgG1-WT, IgG1-GM, IgG1-DE, IgG1-DE/GM) and isotype-matched anti-FRα antibodies. These antibodies were analyzed for binding affinity to different FcγR alleles using surface plasmon resonance (SPR), and their ability to activate NK cells and macrophages was assessed in vitro. Additionally, in mouse models, these antibodies were evaluated for their ability to inhibit the growth of HER2+ and FRα+ tumors in vivo, and their impact on immune cell infiltration within the tumor microenvironment was analyzed.

Key Conclusions and Perspectives

• FcγRIIIa is broadly expressed in the tumor microenvironment of HER2+ and TNBC patients and remains expressed even after the development of treatment resistance.
• Double modifications through glycoengineering and Fc point mutations significantly enhance the binding affinity to FcγRIIIa, particularly for the low-affinity allele FcγRIIIa-F158.
• The Fc-engineered antibodies significantly enhance NK cell ADCC activity and macrophage proinflammatory polarization in vitro.
• In mouse models, these antibodies effectively inhibit the growth of HER2+ and FRα+ tumors at lower doses and promote the infiltration of FcγRIIIa+ cells into the tumor.
• The study demonstrates that an antibody engineering strategy enhancing FcγRIIIa binding can improve the therapeutic efficacy for breast cancer with treatment resistance.

Research Significance and Prospects
This study provides a novel antibody engineering strategy for HER2+ and TNBC patients by enhancing the binding ability of antibodies to FcγRIIIa and improving the activation efficiency of immune effector cells. The approach shows significant efficacy in preclinical models, offering a theoretical basis and technical roadmap for the development of antibody therapies targeting drug-resistant breast cancer. Future studies may focus on further optimizing the antibody structure and validating its safety and efficacy in clinical trials.

 

 

Conclusion
This study validated the key role of FcγRIIIa in anti-HER2 and anti-FRα antibody-mediated immunotherapy by integrating gene expression analysis, antibody engineering, and mouse tumor models. The research identified a substantial presence of FcγRIIIa+ NK cells and M1 macrophages in the tumor microenvironment of HER2+ and TNBC patients, which remained in the tumor even after the development of treatment resistance. The dual modifications via glycoengineering and point mutations significantly enhanced the binding affinity of the antibodies to FcγRIIIa, thereby increasing anti-tumor immune cell activity in both in vitro and in vivo experiments. This study provides theoretical and experimental support for the application of FcγR-optimized antibodies in breast cancer immunotherapy, potentially offering new treatment options for patients with drug-resistant breast cancer.

 

Alicia M Chenoweth, Anthony Cheung, Jitesh Chauhan, Andrew NJ Tutt, and Sophia N Karagiannis. An Fc-Engineered Glycomodified Antibody Supports Proinflammatory Activation of Immune Effector Cells and Restricts Progression of Breast Cancer. Cancer Research.