Antibody Fc

Antibody Fc is the first single text to synthesize the literature on the mechanisms underlying the dramatic variability of antibodies to influence the immune response. The book demonstrates the importance of the Fc domain, including protective mechanisms, effector cell types, genetic data, and variability in Fc domain function. This volume is a critical single-source reference for researchers in vaccine discovery, immunologists, microbiologists, oncologists and protein engineers as well as graduate students in immunology and vaccinology. Antibodies represent the correlate of protection for numerous vaccines and are the most rapidly growing class of drugs, with applications ranging from cancer and infectious disease to autoimmunity. Researchers have long understood the variable domain of antibodies, which are responsible for antigen recognition, and can provide protection by blocking the function of their target antigen. However, recent developments in our understanding of the protection mediated by antibodies have highlighted the critical nature of the antibody constant, or Fc domain, in the biological activity of antibodies. The Fc domain allows antibodies to link the adaptive and innate immune systems, providing specificity to a wide range of innate effector cells. In addition, they provide a feedback loop to regulate the character of the immune response via interactions with B cells and antigen-presenting cells. Clarifies the different mechanisms of IgG activity at the level of the different model systems used, including human genetic, mouse, and in vitro Covers the role of antibodies in cancer, infectious disease, and autoimmunity and in the setting of monoclonal antibody therapy as well as naturally raised antibodies Color illustrations enhance explanations of the immune system

Immunoglobulins are a group of closely related glycoproteins composed of 82 to 96% protein and 4 to 18% carbohydrate. In humans, there are five classes of immunoglobulins, which differ in heavy-chain structure. Immunoglobulin G (IgG) is the major class of immunoglobulins in blood and can be further subdivided in subclasses. The four subclasses of IgG were discovered in the 1960s following extensive studies using specific rabbit antisera against human IgG myeloma proteins.1 They are designated IgG1, IgG2, IgG3, and IgG4, in order of decreasing abundance. Several decades of research has revealed subtle but profound differences among the subclasses. Each subclass has a unique profile with respect to antigen binding, immune complex formation, complement activation, triggering of effector cells, and placental transport (Table 9.1). In addition, IgG antibody responses to different types of antigens or pathogens often lead to marked skewing toward one of the subclasses. On the other hand, selective subclass deficiencies are usually not detrimental to the individual but do sometimes lead to enhanced susceptibility toward specific classes of pathogens. All in all, the acquired variability within the Ig locus seems to have been selected for beneficial changes during evolution for optimizing or fine-tuning the antibody-mediated immune response.

Antibody-dependent cellular cytotoxicity (ADCC), also called antibody-dependent cell-mediated cytotoxicity, is an immune mechanism through which Fc receptor-bearing effector cells can recognize and kill antibody-coated target cells expressing tumor- or pathogen-derived antigens on their surface. Numerous associations between ADCC activity, Fc receptor polymorphisms, and clinical outcomes have been observed in both the settings of vaccination and monoclonal antibody therapy. Here, the effector cells and receptors involved in ADCC are introduced, followed by a description of the four main stages and mechanisms leading to the antibody-dependent effector-mediated killing of the target cell: (1) Recognition of the target cell and Fc receptor cross-linking on the surface of the effector cell; (2) phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) by cellular src kinases within the effector cell; (3) triggering of three main downstream signaling pathways in the effector cell, resulting in cytotoxic granule polarization and release; and (4) killing of the target cell via the predominant perforin/granzyme cell death pathway. Further, a summary and a discussion are presented in relation to case studies in which in vitro ADCC activity correlates with protection against infectious diseases and outcomes in monoclonal antibody therapy of cancer in vivo . The means by which these mechanisms are currently being exploited by recombinant antibody engineering, and a path toward a future in which designed vaccines take advantage of variant ADCC activity are also discussed. Throughout the chapter, attention is drawn to the fact that, while the majority of ADCC studies have been based on research using peripheral blood mononuclear cells in which NK cells have been assumed to be the main effectors, questions remain unanswered about ADCC mediated by non-NK cell populations in peripheral blood and in mucosal compartments.

Diversity of antigen-binding specificity may be considered the hallmark of antibodies; however, the human IgG-Fc region also exhibits binding specificity for multiple ligands. Evolution of the IgG-Fc has resulted in the generation of interaction sites for endogenous (self) ligands that recruit and activate mechanisms facilitating the removal and destruction of antibody–pathogen immune complexes. However, pathogens (bacteria and virus) have co-evolved to elaborate IgG-Fc binding proteins that seek to subvert these protective mechanisms. The four human IgG subclasses exhibit differential binding specificity for these ligands, and the choice of IgG subclass for an antibody therapeutic allows selection for a ligand binding profile appropriate for the intended use. The profile of IgG-Fc ligand binding specificities is being extended through the generation and selection among multiple IgG-Fc mutant proteins. Of particular interest has been the development of mutant aglycosylated antibodies that retain or acquire ligand binding activities. This extends possible production vehicles to include prokaryotic systems, although an increased potential for inducing anti-drug antibodies may be a limiting factor.

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.

This volume explores several aspects of how antibodies mediate their activity in vivo, ranging from cancer immunotherapy to autoimmunity, infection, and vaccination. Divided into seven chapters, it provides in-depth insights into how antibodies and especially the antibody fragment crystallizable (Fc) domain modulate immune responses and antibody activity. The book begins by discussing evolutionary aspects of how the family of Fc receptors that are the key molecules for antibody activity evolved. In turn, it addresses the molecular and cellular pathways underlying IgG activity in cancer immunotherapy, and focuses on how IgG glycosylation regulates IgG and IgE activity in autoimmunity, allergy and infection. In closing, it presents strategies for developing novel antibody-based vaccination approaches. The book is intended for a very broad readership, including graduate students, postdocs and principal investigators with a basic grasp of immunology.