ADCC in Cancer Therapy

More and more studies have demonstrated the importance of ADCC in tumor clearance, and the main exploration direction is focusing on how to enhance ADCC in the cancer environment. Currently, ADCC is a multi-layered process that involves a network of immune cells, including macrophages, monocytes, dendritic cells (DCs), and granulocytes.

Monoclonal antibody structure and ADCC

Monoclonal antibody (mAbs) immunotherapy is widely used in hematological tumors and solid tumors.

Fig.1 The structure of monoclonal antibody

The Fab region regulates tumor cell surface markers in an agitated or antagonistic manner. The Fc region is recognized by the Fc receptor (FcR) on the cell, through which ADCC function can be stimulated. Case in point: innate lymphocytes recognize tumor-binding antibodies via the IgG-Fc receptor CD16A (FcγRIIIA). Patients with homozygous cancer with the CD16A high-affinity allele have been reported to respond significantly better to monoclonal antibody therapy for various malignancies.

In addition, the therapeutic effect of monoclonal antibodies was positively correlated with the high-affinity binding of CD16A, and NK cells could be enhanced to target tumor antigens by modifying the Fc region of the antibody. Creative Biolabs provides customers with one-stop ADCC customization services, including Fc engineering.

The mechanism of ADCC

The interaction of antibodies and Fc receptors on effector cells is an important condition for ADCC to occur. This interaction is regulated and facilitated by conformational changes in the antibody molecule that occur only after the antibody molecule binds to the corresponding antigen. Binding to multiple antibody molecules on the cell surface of relatively large tumors or viruses, compared to small soluble antigens, promotes physical rearrangement and interaction between Fc receptors presenting on effector cells (Figure 2A). These interactions are often referred to as Fc receptor linkage, agglutination, aggregation, or cross-linking. The leading model for studying "ADCC-like" signaling pathways relies on the hypothesis that the first step in generating an ADCC response is the ligation or cross-linking of Fc receptors on the surface of effector cells, with a large number of "granular" antigens, e.g. with specific antibody-bound virus-infected cells (Figure 2A). Experimentally, to mimic particulate antigen-induced Fc receptor cross-linking, many researchers have incubated NK cells with FcγRIIIA-specific antibodies. This was followed by incubation with secondary antibodies (Figure 2B). Another approach to mimic antigen-induced Fc receptor cross-linking is “reverse ADCC,” an experimental setup in which the polarity of the bridging antibody is reversed (Figure 2C).

Fig.2 Connection of antibodies and Fc.

Currently, monoclonal antibodies using NK-mediated ADCC as a mechanism of action include Herceptin (anti-Her-2/neu), Rituximab (anti-CD20), and Cetuximab (anti-EGFR). In this chapter, Creative Biolabs mainly introduces the application of ADCC-related monoclonal antibodies in various tumor treatments through some published articles. You can view related content by browsing the keywords below:

• Anti-GD2 mAb for Neuroblastoma
• Herceptin/Trastuzumab for HER2-positive Breast Carcinoma
• Cetuximab For EGFR-expressing Metastatic Colorectal Cancer
• Rituximab and Obinutuzumab for B-cell Lymphoma
• Avelumab for Meningioma
• Trastuzumab and Cetuximab for GI-tract Cancer
• Cetuximab plus Avelumab for Non-small Cell Lung Cancer
• Obinutuzumab for Follicular Lymphoma
• Endocytosis Inhibition for Squamous Cell Carcinoma

References

1. Britannica. Monoclonal antibody. "Encyclopedia Britannica." 2023.
2. Manzoor Ahmad Mir. Immunoglobulins, Magic Bullets and Therapeutic Antibodies. 2020, DOI: https://doi.org/10.52305/FGDD2367.