Fc Mediated Activity Of Antibodies

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.

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

This book focuses on the function of antibodies in vivo. Recent years have seen an exponential growth in knowledge about the molecular and cellular mechanisms of antibody activity. These new results dramatically changed our view of how antibodies function in vivo. The importance of this class of molecules is demonstrated by the heightened susceptibility to infections of humans and mice with an altered capacity to generate pathogen specific antibody responses. Thus, the majority of our currently available vaccines, such as vaccines against influenza, measles and hepatitis focus on the generation of long lasting antibody responses. Recent evidence from a variety of in vivo model systems and from human patient cohorts has highlighted the exclusive role of cellular Fc-receptors for certain immunoglobulin isotypes and subclasses. With the recent discovery of a human Fc-receptor for IgM all different human immunoglobulin isotypes now have a cellular receptor, providing a feedback mechanism and link between antibodies and the cellular components of the immune system. Moreover it has become clear the complement and Fc-receptor system are tightly connected and regulate each other to ensure a well balanced immune response. Among the immunoglobulin isotypes IgG plays a very important protective role against microbial infections and also as a therapeutic agent to kill tumor cells or autoantibody producing B cells in autoimmune disease. Transfer of our knowledge about the crucial function of Fc-receptors has led to the production of a second generation of therapeutic antibodies with enhanced binding to this class of receptors. Binding of antibodies to Fc-receptors leads to the recruitment of the potent pro-inflammatory effector functions of cells from the innate immune system. Hence, Fc-receptors link the innate and adaptive immune system, emphasizing the importance of both arms of the immune system and their crosstalk during anti-microbial immune responses. Besides this pro-inflammatory activity immunoglobulin G (IgG) molecules are long known to also have an anti-inflammatory function. This is demonstrated by the use of high dose intravenous immunoglobulins as a therapeutic agent in many human autoimmune diseases. During the past five years several new insights into the molecular and cellular pathways of this anti-inflammatory activity were gained radically changing our view of IgG function in vivo. Several lines of evidence suggest that the sugar moiety attached to the IgG molecule is responsible for these opposing activities and may be seen as a molecular switch enabling the immune system to change IgG function from a pro- to an anti-inflammatory activity. There is convincing evidence in mice and humans that aberrant IgG glycosylation could be an important new pathway for understanding the impaired antibody activity during autoimmune disease. Besides this tremendous increase in basic knowledge about factors influencing immunoglobulin activity the book will also provide insights into how these new insights might help to generate novel therapeutic approaches to enhance IgG activity for tumor therapy on the one hand, and how to block the self-destructive activity of IgG autoantibodies during autoimmune disease on the other hand.

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.

The field of antibody engineering has become a vital and integral part of making new, improved next generation therapeutic monoclonal antibodies, of which there are currently more than 300 in clinical trials across several therapeutic areas. Therapeutic antibody engineering examines all aspects of engineering monoclonal antibodies and analyses the effect that various genetic engineering approaches will have on future candidates. Chapters in the first part of the book provide an introduction to monoclonal antibodies, their discovery and development and the fundamental technologies used in their production. Following chapters cover a number of specific issues relating to different aspects of antibody engineering, including variable chain engineering, targets and mechanisms of action, classes of antibody and the use of antibody fragments, among many other topics. The last part of the book examines development issues, the interaction of human IgGs with non-human systems, and cell line development, before a conclusion looking at future issues affecting the field of therapeutic antibody engineering. Goes beyond the standard engineering issues covered by most books and delves into structure-function relationships Integration of knowledge across all areas of antibody engineering, development, and marketing Discusses how current and future genetic engineering of cell lines will pave the way for much higher productivity