Considerations of Antibody Geometric Constraints on NK Cell Antibody Dependent Cellular Cytotoxicity

Abstract

It has been well-established that antibody isotype, glycosylation, and epitope all play roles in the process of antibody dependent cellular cytotoxicity (ADCC). For natural killer (NK) cells, these phenotypes are linked to cellular activation through interaction with the IgG receptor FcγRIIIa, a single pass transmembrane receptor that participates in cytoplasmic signaling complexes. Therefore, it has been hypothesized that there may be underlying spatial and geometric principles that guide proper assembly of an activation complex within the NK cell immune synapse. Further, synergy of antibody phenotypic properties as well as allosteric changes upon antigen binding may also play an as-of-yet unknown role in ADCC. Understanding these facets, however, remains hampered by difficulties associated with studying immune synapse dynamics using classical approaches. In this review, I will discuss relevant NK cell biology related to ADCC, including the structural biology of Fc gamma receptors, and how the dynamics of the NK cell immune synapse are being studied using innovative microscopy techniques. I will provide examples from the literature demonstrating the effects of spatial and geometric constraints on the T cell receptor complex and how this relates to intracellular signaling and the molecular nature of lymphocyte activation complexes, including those of NK cells. Finally, I will examine how the integration of high-throughput and "omics" technologies will influence basic NK cell biology research moving forward. Overall, the goal of this review is to lay a basis for understanding the development of drugs and therapeutic antibodies aimed at augmenting appropriate NK cell ADCC activity in patients being treated for a wide range of illnesses.

Design of a Trispecific Checkpoint Inhibitor and Natural Killer Cell Engager Based on a 2 + 1 Common Light Chain Antibody Architecture

“…One the other hand, a competent or a (glyco-)engineered Fc in combination with a 1 + 1 bsAb can effectively engage NK cells (90). Still, NK cell activity is also dependent on the distance between the target and the effector cell (91)(92)(93). Therefore, depending on the epitope of a tumor-specific Fab, an adjacent anti-CD16a Fab arm engaging NK cells might mediate a more favorable target:effector cell distance compared to the an Fc.…”

Defucosylation of Tumor-Specific Humanized Anti-MUC1 Monoclonal Antibody Enhances NK Cell-Mediated Anti-Tumor Cell Cytotoxicity

“…Monoclonal antibodies recognizing tumor antigens can induce ADCC through the binding of the antibody Fc tail to the FcγRIIIa (CD16) molecules on NK cells [ 6 ]. Therefore, we asked whether the humanized CIM-301 anti-MUC1 antibodies can indeed bind to NK cells (gating strategy in Figure S1A ) by detecting labeled antibodies bound to the Fc portion of the anti-MUC1 antibody ( Figure 2 A).…”

“…The antigen-binding fragment determines the specificity of mAb. The Fc portion of the mAb bind on the Fc receptor expressed on the effector immune cells, including natural killer (NK) cells, macrophages, and dendritic cells [ 6 ].…”

“…Moreover, human NK cells express the FcγRIIIa receptor (also known as CD16a), which recognizes the Fc fragment of IgG. This induces NK cell-mediated eradication of IgG-opsonized abnormal cells via the secretion of their cytotoxic granules in a process called antibody-dependent cellular cytotoxicity (ADCC) [ 6 ]. Modulation of glycosylation of the antibody’s Fc tail influences the interaction with the FcγRIIIa receptor and can modulate this NK cell effector function.…”

On Origin and Evolution of the Antibody Molecule

“…The interaction between IgG and Fcγ receptors occurs at the hinge region and the N-terminus of CH2 and is dependent on glycans bound to Asn 297, which stabilize an asymmetrical conformation of Fc; the stoichiometry of the binding is 1:1, differently from Fcα, which binds dimeric IgA [ 97 ].…”