Natural Killer Cell Mediated Antibody-Dependent Cellular Cytotoxicity in Tumor Immunotherapy with Therapeutic Antibodies

Abstract

In the last decade several therapeutic antibodies have been Federal Drug Administration (FDA) and European Medicines Agency (EMEA) approved. Although their mechanisms of action in vivo is not fully elucidated, antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer (NK) cells is presumed to be a key effector function. A substantial role of ADCC has been demonstrated in vitro and in mouse tumor models. However, a direct in vivo effect of ADCC in tumor reactivity in humans remains to be shown. Several studies revealed a predictive value of FcγRIIIa-V158F polymorphism in monoclonal antibody treatment, indicating a potential effect of ADCC on outcome for certain indications. Furthermore, the use of therapeutic antibodies after allogeneic hematopoietic stem cell transplantation is an interesting option. Studying the role of the FcγRIIIa-V158F polymorphism and the influence of Killer-cell Immunoglobuline-like Receptor (KIR) receptor ligand incompatibility on ADCC in this approach may contribute to future transplantation strategies. Despite the success of approved second-generation antibodies in the treatment of several malignancies, efforts are made to further augment ADCC in vivo by antibody engineering. Here, we review currently used therapeutic antibodies for which ADCC has been suggested as effector function.

The therapeutic potential of natural killer cells to target medulloblastoma

“…They can directly lyse infected or transformed cells without specific immunization [7]. They can also recognize the Fc part of antibodies via the low-affinity FccRIIIA (CD16) receptor and perform antibodydependent cellular cytotoxicity (ADCC) [8,9]. In addition, NK cells express a large number of receptors that trigger NK cytolytic activity on recognition of specific ligands on target cells [10,11].…”

Antibody and Antibody Mimetic Immunotherapeutics

“…As a result of this biological shell game, antibodies evade degradation by serum and lysosomal proteases [5,6]. A region found within Fc is also necessary to induce activation immunotherapeutic mechanisms, such as antibody-dependent cellular cytotoxicity (ADCC) [7,8] or complement-dependent cytotoxicity (CDC) [9,10]. Specifically, Fc γ-receptors on the surface of immune effector cells, such as natural killer cells and macrophages, recognize Fc in antibodies that are bound to disease-relevant receptors on the surface of targeted cells (via interactions involving CDRs within the Fab fragment).…”

Immunotherapy in Colorectal Cancer

“…NK cells recognize tumor cells via cellular stress or DNA damage signals [22] . Activated NK cells directly kill target tumor cells through several mechanisms, including [23] : (1) cytoplasmic granules such as perforin and granzyme B [24] ; (2) tumor necrosis factor-related apoptosis-inducing ligand and Fas ligand (FasL) [25,26] ; (3) effector molecules such as IFN-γ and nitric oxide (NO) [24,27] ; and (4) antibody-dependent cellular cytotoxicity (ADCC) [28] . NK cell activators (IL-2, IL-12, IL-15, and IL-18), have also been validated in preclinical cancer models [23] .…”