Abstract
Since the approval of the first monoclonal antibody (mAb) in 1986, a huge effort has been made to guarantee safety and efficacy of therapeutic mAbs. As of July 2021, 118 mAbs are approved for the European market for a broad range of clinical indications. In order to ensure clinical efficacy and safety aspects, (pre-)clinical experimental approaches evaluate the respective modes of action (MoA). In addition to antigen-specificity including binding affinity and -avidity, MoA comprise Fc-mediated effector functions such as antibody dependent cellular cytotoxicity (ADCC) and the closely related antibody dependent cellular phagocytosis (ADCP). For this reason, a variety of cell-based assays have been established investigating effector functions of therapeutic mAbs with different effector/target-cell combinations and several readouts including Fcγ receptor (FcγR)-mediated lysis, fluorescence, or luminescence. Optimized FcγR-mediated effector functions regarding clinical safety and efficacy are addressed with modification 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 FcγR-mediated effector functions for the efficacy of therapeutic mAbs.
Highlights
Monoclonal antibodies are immunoglobulins (Ig) which represent a therapeutic tool for malignancies, 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]
The last category comprises the truncation of the Fc domain, which results in monoclonal antibody (mAb) incapable of eliciting Fcγ receptor (FcγR)-mediated downstream events
Aglycosylation of mAbs leads to decreased cytotoxic effector functions and is used when antibody dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) is unwanted in cases where neutralizing and agonistic/antagonistic properties are chosen as modes of action (MoA)
Summary
Monoclonal antibodies (mAbs) are immunoglobulins (Ig) 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]. The human FcRs belong to the Ig superfamily and are type I transmembrane glycoproteins, which bind to the Fc tail of antibodies They comprise receptors for all five antibody classes: FcμR (IgM), FcγR (IgG), FcαR (IgA), FcδR (IgD), and FcεR (IgE) [2,8,9]. Combinations of Fab-mediated antigen-specificity and the activation/inhibition of FcγR-mediated effects result in different MoA such as depletion, agonizing, blocking, as well as the combination of blocking and depletion. This variety enables the development of various treatment options for a wide range of clinical indications. A significant effort has been made to improve therapeutic efficacy and safety via Fc-engineering in order to modify the desired Fc-mediated effector functions of therapeutic mAbs
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
