Fc-Engineered Antibodies with Enhanced Fc-Effector Function for the Treatment of B-Cell Malignancies

SIMPLE SUMMARY: Monoclonal antibody (mAb) therapy has been an important addition to the therapeutic arsenal in B-cell malignancies. MAbs can induce cytotoxicity against B-cell malignancies by antibody effector functions mediated via their fragment crystallizable (Fc) region. In order to enhance the anti-tumor potential of antibodies, various Fc-engineering strategies have been developed. In this review we summarize the well-established as well as recently developed Fc-engineering strategies which are aimed to increase Fc-effector function and to enhance the anti-tumor potency of mAbs. In addition, the increased number of Fc-engineered mAbs in (pre-)clinical development asks for a clear overview describing the specific type of Fc-engineering, their antigen and disease target, and the current developmental stage, which we aimed to provide in this review. ABSTRACT: Monoclonal antibody (mAb) therapy has rapidly changed the field of cancer therapy. In 1997, the CD20-targeting mAb rituximab was the first mAb to be approved by the U.S. Food and Drug Administration (FDA) for treatment of cancer. Within two decades, dozens of mAbs entered the clinic for treatment of several hematological cancers and solid tumors, and numerous more are under clinical investigation. The success of mAbs as cancer therapeutics lies in their ability to induce various cytotoxic machineries against specific targets. These cytotoxic machineries include antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC), which are all mediated via the fragment crystallizable (Fc) domain of mAbs. In this review article, we will outline the novel approaches of engineering these Fc domains of mAbs to enhance their Fc-effector function and thereby their anti-tumor potency, with specific focus to summarize their (pre-) clinical status for the treatment of B-cell malignancies, including chronic lymphocytic leukemia (CLL), B-cell non-Hodgkin lymphoma (B-NHL), and multiple myeloma (MM).