This study emphasizes the contribution of ADCP through the treatment with -CD20 therapeutic mAbs, since clinically applied pharmaceuticals blocking ADCP (inhibitors for BTK, Pi3J or BCL2) were able to decrease ADCP in this model. strategies such as point mutations, altered glycosylation patterns, combination of different Fc subclasses (cross isotypes), and Fc-truncation of the mAb. These strategies opened the field for a next generation of therapeutic mAbs. In conclusion, it is of major importance to consider FcR-mediated effector functions for the efficacy of therapeutic mAbs. Keywords:therapeutic monoclonal antibodies (mAbs), Fc receptor (FcR), antibody dependent cellular cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), effector function, modes of action (MoA) == 1. Introduction == Monoclonal antibodies (mAbs) are immunoglobulins (Ig) LY315920 (Varespladib) which represent a therapeutic tool for malignancies (hematological or solid), transplant rejection, autoimmune diseases (e.g., rheumatoid arthritis (RA) or multiples sclerosis (MS)) and viral infections (with, e.g., Ebola, influenza, or respiratory syncytial virus (RSV)) [1,2,3,4]. Among the LY315920 (Varespladib) five isotypes of Ig which are IgM, IgG, IgA, IgD, and IgE, IgG is the most abundant isotype within the blood, mainly because of its extremely long serum half-life [5]. Antibodies consist of two heavy chains and two light chains, while each heavy chain associates with a light chain via disulfide bonds and non-covalent interactions to form a heterodimer. Both heterodimers in turn are paired through disulfide bonds between the heavy chains. Each heavy and light chain heterodimer includes the antigen binding fragment (Fab) which is LY315920 (Varespladib) composed of LY315920 (Varespladib) the variable and constant region of the light chain (VL and CL), the variable region of the heavy chain (VH), and the CH1 domain of the constant region of the heavy chain. VL and VH at the tip of the antibody are forming the antigen binding site. C-terminally located to the Fab is the hinge region and the crystallizable fragment (Fc), which includes the CH2 and CH3 domains [6,7]. All mAbs exert their function by direct targeting via their antigen-specific Fab arm. Additionally, Fc:Fc receptor (FcR) interaction can modulate their modes of action (MoA) [2,4,8]. The human FcRs belong to the Ig superfamily and are type I transmembrane glycoproteins, which bind to the Fc tail of NT5E antibodies. They comprise receptors for all five antibody classes: FcR (IgM), FcR (IgG), FcR (IgA), FcR (IgD), and FcR (IgE) [2,8,9]. Hereby, FcRs are of specific therapeutic relevance as all approved mAbs belong to the IgG class [5,7,8]. Humans possess two classes of FcR, the activating and the inhibitory receptors. While activating FcRs transmit their signals via the immunoreceptor tyrosine-based activation motif (ITAM), inhibitory FcRs exert their function through immunoreceptor tyrosine-based inhibitory motifs (ITIM) [2,4,10,11]. The activating FcRs are FcRI (CD64), FcRIIa (CD32a), FcRIIc (CD32c), and FcRIIIa (CD16a), while FcRIIb (CD32b) is the only LY315920 (Varespladib) inhibitory FcR and able to block cellular activation in order to downmodulate immune responses. FcRIIIb (CD16b) is expressed on neutrophils and attached to the cell membrane via a glycophosphadylinositol (GPI) anchor. Despite lacking an intracellular signaling domain and ITAMs, it is capable of promoting neutrophil activation and killing of target cells. Accordingly, FcRIIIb is often considered as activating FcR [2,4,8]. In addition, Brambell et al. discovered an intracellular trafficking receptor for IgG in 1966. This receptor was called the neonatal FcR (FcRn) and represents a non-covalent heterodimer of major histocompatibility complex (MHC) class I like heavy chain and a 2 microglobulin light chain. Due to its ability to bind to the Fc domain of IgG at acidic pH in the endosome, it is capable of protecting IgG from degradation and prolongs their serum half-life [5,12,13]. FcRs can be classified as low affinity receptors, that can bind IgG when multimeric (presented in immune complexes, aggregated, or opsonized), or high affinity receptors, which can bind monomeric Ig [10]. FcRI is the only receptor binding monomeric IgG with a high affinity while all other FcRs bind monomeric IgG with low or intermediate affinity. Thus, the formation of immune complexes allows high avidity Fc binding of multimerized IgG to low or intermediate affinity FcRs. These are in turn crosslinked, leading to cell activation [4]. FcRs are mainly expressed on cells of the innate immune system, such as antigen presenting cells (APC) or natural killer (NK) cells, but can also be found on activated T cells, endothelial cells, microglial cells, osteoclasts, and mesangial cells [8,14,15,16]. An overview of the.