Fc Mediated Antibody Functions And Fc Receptor Polymorphism

Fcγ receptors (FcγR) mediate many effector functions of antibody and are critical for defense against pathogens, including bacteria, viruses, and parasites. A number of single nucleotide polymorphisms have been identified in both activating and inhibitory FcγR genes that affect either the binding affinity for IgG or receptor function. Reviewing the available evidence from murine knockout mice, in vitro studies utilizing human cells, and genetic studies in humans, the current view on the role of FcγR polymorphisms in susceptibility to infection will be summarized here. Genetic studies have often yielded conflicting results, which may be due to small sample size or the inherent difficulties associated with genotyping the FCGR locus, or they may reflect differences in the functional importance of interactions between FcγR and its ligands (IgG versus CRP) in differing clinical manifestations of infectious disease. The engagement of the inhibitory FcγR limits the proinflammatory response initiated by FcγR ligation. FCGR polymorphisms that favor activating FcγR may result in excessive inflammation that is deleterious to the host, despite its efficacy in eliminating the pathogen. Overall, pathogen encounter is likely to be the main factor driving the retention of FCGR polymorphisms within the gene pool. Evidence suggests that potent infections, such as malaria, have exerted a significant evolutionary pressure on the maintenance and prevalence of FcγR polymorphisms in different populations.

Molecular mechanisms of antibody-mediated Fc receptor activation have long been an interest in both Fc receptor biology and antibody therapeutics. The structural efforts to elucidate antibody recognition by Fc receptors have led to the generation of several crystal structures of antibody Fc fragments complexed with Fc receptors. Collectively, these structures revealed a conserved receptor binding mode for IgG and IgE, distinct from those for the neonatal Fc receptor (FcRn), protein A, and protein G. Fcγ receptor recognition in the lower hinge region allows enhanced antigen recognition through dimeric Fabs but obligates immune-complex formation for receptor activation. It also provides the basis for Fcγ receptors to differentiate among IgG subclasses. More recently, pentraxins have also been shown to bind and activate Fc receptors, and structural efforts to elucidate pentraxin Fcγ receptor recognition have revealed surprising similarities between pentraxins and immunoglobulins in Fc receptor recognition. This review summarizes the structural findings that formed the basis of modern antibody–Fc receptor biology and recent advances of shared Fc receptor recognition by innate pentraxins.

In the past decade, we have experienced an explosion of new information about cancer therapeutic targets. Many of the targets have been validated by the discovery and approval of new medicines which have been approved for the treatment of cancer. On the heels of these successes, innumerable new targets and new potential therapeutics are being developed by many different groups including government agencies, pharmaceutical companies, biotechnology companies, academic institutions, and individual investigators. Understanding the expanding "universe" of cancer therapies is therefore becoming impossible and no single source exists which serves as a reference for the involved parties. Further, the interested parties have vastly different areas of expertise, from focused laboratory based science, to clinical research, to corporate and regulatory oversight. The text would be updated every two years, more often depending on pace of change, interest and sales. While useful online, this reference book would likely be kept in hard copy as well.

This volume provides a state-of-the-art update on Fc Receptors (FcRs). It is divided into five parts. Part I, Old and New FcRs, deals with the long-sought-after FcμR and the recently discovered FCRL family and TRIM21. Part II, FcR Signaling, presents a computational model of FcεRI signaling, novel calcium channels, and the lipid phosphatase SHIP1. Part III, FcR Biology, addresses major physiological functions of FcRs, their glycosylation, how they induce and regulate both adaptive immune responses and inflammation, especially in vivo, FcR humanized mice, and the multifaceted properties of FcRn. Part IV, FcRs and Disease, discusses FcR polymorphism, FcRs in rheumatoid arthritis and whether their FcRs make macaques good models for studying HIV infection. In Part V, FcRs and Therapeutic Antibodies, the roles of various FcRs, including FcγRIIB and FcαRI, in the immunotherapy of cancer and autoimmune diseases using monoclonal antibodies and IVIg are highlighted. All 18 chapters were written by respected experts in their fields, offering an invaluable reference source for scientists and clinicians interested in FcRs and how to better master antibodies for therapeutic purposes.

Historically, lack of specificity for cancer cells has been a major problem in cancer treatment; however, the development of monoclonal antibodies (mAbs), which combine high specificity with multiple mechanisms of action (MoAs), started a revolution in anti-cancer treatment options which continues to date. As of January 2013, 15 major antibody products were being marketed for cancer treatment in various countries around the globe, 10 of which are unmodified mAbs, which generally have multiple potential MoAs and may act via direct, Fab-domain-related effects or indirect, Fc-domain-related effects. Fc-domain-related effects consist of immune-mediated effector functions, which include complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). ADCC and ADCP depend on the engagement of Fcγ-receptors (FcγR) on immune effector cells by Fc-domains clustered due to antibody–antigen binding. Similarly, CDC depends on the engagement of proteins of the complement system by clustered antibody Fc domains. In this chapter, preclinical and clinical studies with approved anti-cancer mAbs are reviewed, with an emphasis on the role of FcγR-mediated effector functions. The importance of therapeutic antibody–FcγR interactions for human treatment can be deduced from correlations of clinical responses with FcγR polymorphisms, results supported by a wealth of preclinical and in vitro studies.