IgE and Anti-IgE Therapy in Asthma and Allergic Disease PDF

PREFACE

This volume chronicles the successes of a true ‘‘bench-to-bedside'' story. The storyline moves logically from the identification of an antiserum precipitating reaginic activity (termed ‘‘IgE'' in part because when injected it caused skin erythema) through well-controlled clinical trials 25 years later demonstrating the safety and efficacy of an anti-IgE monoclonal antibody in allergic disease. Biomedical scientists had labored for three decades to block IgE interaction with immune effector cells expressing IgE receptors. The engineering of a humanized recombinant monoclonal antibody* binding IgE at an epitope shared by IgE receptors FcεRI and FcεRII has provided researchers interested in the immunopathogenesis of asthma with a safe and effective probe uniquely suited to delineate the contribution of IgE. Beyond asthma, anti-IgE will someday also provide invaluable insights into the role of IgE in seasonal and perennial allergic rhinitis, atopic dermatitis, helminth parasitic infections, and allergic bronchopulmonary aspergillosis—to mention only a few disorders discussed in the chapters that follow.

To be sure, technological and conceptual breakthroughs were needed before the fruits of clinical activity in important allergic diseases could be enjoyed and the dream realized. Ko¨hler and Milstein showed us how to immortalize antibodyproducing cells from a mouse spleen and thereby reliably produce large quantities of individual (monoclonal) antibody. In recent years there has been spectacular growth in the use of MAbs to study the role of inflammatory mediators in experimental asthma, and currently there are 10 MAb therapeutics approved by FDA providing important treatments for diseases as varied as Crohn's disease, respiratory syncytial virus infection, and breast cancer. Certainly the early reports (1967–70) describing the role of the new immunoglobulin (IgE) in allergic disease, and later the identification of the domains on IgE responsible for IgE attachment to immune effector cells, were seminal observations. Additionally, the engineering of an IgE-binding MAb that did not crosslink IgE bound to the surface of high-affinity receptor bearing cells, thereby creating a nonanaphylactogenic antibody, was a conceptual breakthrough essential to clinical studies in patients with allergic disease. Ultimately, the ability to ‘‘humanize'' antibodies derived from murine sources has made possible prolonged repeated administration in patients with chronic diseases.

This is an exciting story, but it would not appear before you without the contributions of a great number of professionals whose efforts have directly resulted in this volume in the prestigious Lung Biology in Health and Disease series. We wish, first and foremost, to recognize the chapter authors, selected as recognized international authorities, who have contributed outstanding scholarly reviews. Dr. Lenfant has been an unwavering champion of this volume. His help extends beyond this single volume to his encouragement of a career dedicated to lung research (RBF) supported in the 1980s by the NHLBI Lung Division's Clinical Investigator Award Program. Two Marcel Dekker, Inc., colleagues have made remarkable contributions. Sandra Beberman, Vice President, Medical Division, displayed a saintly level of patience during a prolonged period of writing, and Moraima Suarez, Production Editor, served as a confident guide through the complexities of the production of a textbook of this breadth. We would like to acknowledge the daily unflagging support of our Genentech Executive Assistants, sage partners managing challenging schedules. This volume could not have been completed without the assistance provided by Marilyn Anchick and Bernadette McAllister.

In closing, we wish to acknowledge our patients. Included are the 1.5 million U.S. asthmatics requiring urgent medical care for severe asthma exacerbations, the 500,000 occupying hospital beds, and the 5000 who continue to die annually from reversible obstructive lung disease. Sadly, we recognize that there are far greater numbers of patients who continue to awaken from sleep short of breath and patients who are forced by allergic disease to restrict their activities, narrow their choices, and fall short of their full potential. Finally, we recognize our patients who in the ultimate display of altruism have chosen to volunteer for clinical studies of Xolair. Without such selfless displays of faith and courage there would be no therapeutic advances with which to fill books.

* A word concerning consistency of reference to the monoclonal anti-IgE molecules discussed in this volume: it is the murine antibody MAE11 that was humanized and version 25 (E25 or rhuMAb-E25) was selected for clinical studies. As patient safety was demonstrated and clinical successes mounted, the laboratory designation ‘‘E25'' was assigned new names (omalizumab/Xolair). The term ‘‘anti-IgE'' is intended to refer more broadly or generically to the concept of antibodies binding IgE. Another murine antibody, TESC21, was humanized and in limited early clinical development is referred to as hu56901 (or, in the early literature, as CGP56901).