Monoclonal antibody immunotherapy is widely used in hematological tumors and solid tumors. They are composed of antigen-binding fragments (Fabs) and fragment crystal regions (Fc regions) that have direct and indirect effects on tumor cells. The ADCC effect is generated by the Fc region, which is also a key killing mechanism for NK cells.
Human natural killer cells (NKs) can target tumor antigens through their IgG-Fc receptors, interacting with antibody Fc regions to recognize cancer cell surface proteins. At present, many monoclonal antibodies (mAbs) have been studied to treat various malignancies. This article focuses on how monoclonal antibodies mediate ADCC function in human NK cells.
Innate lymphocytes in these people can only recognize antibodies that bind to tumors through the IgG-Fc receptor CD16A (FcγRIIIA). The two alleles of CD16A bind to IgG with lower or higher affinity. Studies have shown that the therapeutic effect of monoclonal antibodies is positively correlated with the high-affinity binding of CD16A, and NK cells can be enhanced to target tumor antigens by modifying the Fc part of the antibody.
ADCC plays a major role in the treatment of monoclonal antibody. This effect is mainly mediated by NKs, which are lymphocytes of the natural immune system that seek out transformed and virus-infected cells in the body. CD16A mediates the ADCC of NK cells. CD16A-expressing NK cells are the major subpopulation (approximately 90%) in peripheral blood and are the main cell population that enhances endogenous NK cell-mediated ADCC action. The mechanism of improving NK cell-mediated ADCC has been shown to improve therapeutic outcomes that rely on this process to clear tumors.
Fig.1 NK cell and ADCC.1,2
NK Cells and ADCC
In monoclonal antibody therapy, NKs are the driving immune cells that mediate the anti-tumor ADCC effect. NK cells do not express T cell receptors. A small percentage of circulating NK cells express high levels of CD56, called CD56bright, which are considered immature NK cells that primarily release pro-inflammatory cytokines when stimulated. NK cells kill target cells in two ways. One is through native cytotoxicity, where mature NK cells directly attach to and kill target cells using activated receptors. The second is through the ADCC effect, that is, in the presence of IgG antibodies bound on the cell surface, NK cells indirectly recognize target cells through FcR. This is triggered by the formation of lysis synapses between NK cells and target cells. F-actin in NK cells accumulates at synapses, lyses the granules polarizing along the center of the microtubule tissue to the cells of interest, and subsequently expels perforin and granzyme B.
As one of the modern biopharmaceuticals, the development of mAbs continues to grow every year. At the same time, tolerance to mAbs therapy has emerged, and in-depth studies of drug mechanisms can help reveal the mechanism of tolerance. Studies have shown that the tolerability of mAb therapy can be solved by Fab and Fc region engineering. For the Fc region, various types of Fc engineering are involved to alter glycosylation and amino acid residues to enhance ADCC. Another approach is to indirectly optimize the efficacy of monoclonal antibodies using enhanced FcγRs engineered NK cells
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