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The following is a summary of “Engineering Dimeric EGFR-directed IgA Antibodies Reveals a Central Role of CD147 during Neutrophil-mediated Tumor Cell Killing of Head and Neck Squamous Cancer Cells,” published in the May 2024 issue of Allergy & Immunology by Zwick, et al.
Human IgA Abs antibodies engage neutrophils for cancer immunotherapy more effectively than IgG Abs. Prior studies have shown that engineering approaches can enhance the biochemical and functional properties of these antibodies.
For a study, researchers sought to develop and evaluate a novel engineered IgA2 antibody against the epidermal growth factor receptor (EGFR) by using protein engineering and polymerization techniques to improve its functional properties.
An IgA2 antibody was generated through protein engineering and polymerization, resulting in a molecule with covalently linked light (L) and heavy (H) chains and effective polymerization via the joining chain. The engineered dimer’s functional performance was assessed against its monomeric variant, focusing on Fab-mediated mechanisms of action and binding to the Fc receptor. The study evaluated the antibody’s capacity to engage neutrophils for antibody-dependent cell-mediated cytotoxicity (ADCC) of adherent cancer cells, using various cancer cell lines, including A431 vulva carcinoma and both HPV-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) cell lines.
The engineered IgA2 dimer outperformed its monomeric counterpart in terms of Fab-mediated functions and Fc receptor binding. The ability to engage neutrophils for ADCC of target cancer cells was cell-line dependent. The dimer showed long-term efficacy against A431 vulva carcinoma cells but was ineffective against HPV-negative HNSCC cell lines. However, it triggered neutrophil-mediated cytotoxicity against HPV-positive HNSCC cell lines. The short-term ADCC efficacy correlated with EGFR expression on target cells and the capacity of cancer cell-conditioned media to increase CD147 levels on neutrophils. Notably, HPV-positive HNSCC cell lines released higher levels of soluble CD147 and induced less membranous CD147 on neutrophils compared to HPV-negative cells. Meanwhile, membranous CD147 on neutrophils might hinder proper IgA–Fc receptor binding, soluble CD147 enhanced IgA–neutrophil-mediated ADCC in a dose-dependent manner.
Engineered IgA antibodies and utilizing impedance-based ADCC assays provided significant insights into target-effector cell interactions. The CD147 emerged as a critical parameter for neutrophil-mediated cytotoxicity, highlighting its potential role in enhancing IgA-based cancer immunotherapy.
