Engineering Anti-Tumor Monoclonal Antibodies and Fc Receptors to Enhance ADCC by Human NK Cells

SIMPLE SUMMARY: Human natural killer (NK) cells can be targeted to tumor antigens by their IgG Fc receptors that interact with the Fc regions of antibodies that recognize surface proteins on cancer cells. Therapeutic antibodies specific to cancer cell antigens are used to treat various malignancies. NK cells in turn kill antibody-bound tumor cells through a process known as antibody-dependent cell-mediated cytotoxicity (ADCC). The ADCC response of NK cells can be modulated by changes in the antibody or Fc receptor. In this review, we detail the functions of Fc receptors in human NK cells and expand upon current research illustrating how engineering monoclonal antibodies and Fc receptors enhance NK cell-mediated ADCC for the treatment of cancer. ABSTRACT: Tumor-targeting monoclonal antibodies (mAbs) are the most widely used and characterized immunotherapy for hematologic and solid tumors. The significance of this therapy is their direct and indirect effects on tumor cells, facilitated by the antibody’s antigen-binding fragment (Fab) and fragment crystallizable region (Fc region), respectively. The Fab can modulate the function of cell surface markers on tumor cells in an agonistic or antagonistic manner, whereas the Fc region can be recognized by an Fc receptor (FcR) on leukocytes through which various effector functions, including antibody-dependent cell-mediated cytotoxicity (ADCC), can be elicited. This process is a key cytolytic mechanism of natural killer (NK) cells. These innate lymphocytes in the human body recognize tumor-bound antibodies exclusively by the IgG Fc receptor CD16A (FcγRIIIA). Two allelic versions of CD16A bind IgG with either lower or higher affinity. Cancer patients homozygous for the higher affinity allele of CD16A have been reported to respond significantly better to mAb therapies for various malignancies. These studies revealed that mAb therapy efficacy positively correlates with higher affinity binding to CD16A. Approaches to enhance tumor antigen targeting by NK cells by modifying the Fc portion of antibodies or the FcR on NK cells are the focus of this review.