Anti‐IgE Antibodies for the Treatment of IgE‐Mediated Allergic Diseases
Introduction
A therapeutic anti‐IgE antibody is a monoclonal antibody (MAb) designed to target IgE and IgE‐expressing B cells without the complication of its cross‐linking IgE bound by the high‐affinity IgE.Fc receptors (also called type I IgE.Fc receptors, FcɛRI) on basophils and mast cells. Such an antibody is distinctively different from a common anti‐IgE antibody, which can bind to and cross‐link IgE‐FcɛRI and hence sensitize the effector cells bearing them to discharge various pharmacological mediators. In this chapter, a therapeutic anti‐IgE antibody designed above is referred to as “anti‐IgE,” as has been used routinely in the allergy and asthma fields.
Historically, research on IgE has arrived at an interesting juncture. IgE was discovered in 1967 by Johansson (Johansson, 1967) and Ishizakas (Ishizaka and Ishizaka, 1967), and 20 years later in early 1987, the anti‐IgE concept was invented by one of the authors (Chang) of this chapter. In 2007, it will be 20 years since the anti‐IgE concept was proposed and research on developing the first antibody prototype initiated (Chang et al., 1990). Today, various immunoassys relating to IgE are now essential tools in the care of allergic diseases, and the initial application of the anti‐IgE therapy for treating moderate‐to‐severe allergic asthma has been approved by health agencies in many countries—it has been used to treat more than 60,000 patients with difficult‐to‐treat allergic asthma.
The diagram in Fig. 1 summarizes the main events in developing the anti‐IgE program. Initially, CGP51901 (a chimeric anti‐IgE derived from mouse MAb TESC‐21; Davis et al., 1993), which was studied in a Phase I and II clinical trial (Corne 1997, Racine‐Poon 1997), and CGP56901 (or TNX‐901, a humanized anti‐IgE based on TESC‐21; Kolbinger et al., 1993) were developed in one corporate program. Later, omalizumab (a humanized anti‐IgE, also referred to as E25) emerged in another corporate program (Presta et al., 1993). In 1996, the two programs were combined and omalizumab was chosen for further development on the basis of its superior manufacturing process. TNX‐901, which was shown to be safe and efficacious in a Phase II trial on allergic rhinitis (using CGP51901) and in a Phase II trial on peanut allergy (Leung et al., 2003), should serve as a backup drug candidate.
Among the key events in the clinical development of the anti‐IgE concept are that omalizumab was approved by the United States in 2003 and by the European Union in 2005 for use in treating patients with moderate‐to‐severe allergic asthma. Omalizumab has now been studied in nearly 30 Phase II and III human trials in various allergic diseases and conditions (3 Anti‐IgE Is Approved for Treating Moderate‐to‐Severe Asthma, 4 Studies on Other Allergic Diseases, 5 The Potential of Using Anti‐IgE to Assist Allergen‐Based Immunotherapy).
For most clinicians treating allergic diseases, omalizumab would appear as a very different drug among the battery of drugs for treating allergic diseases. An anti‐IgE is a protein, a macromolecular (∼150,000 Da) biological substance; it is a humanized IgG (γ1,κ) antibody or a recombinant antibody, which has been substantially improved by genetic engineering methodologies for in vivo use in human patients. In overall structure, chemical and physical properties (such as kinetic properties), and ability to mediate a wide spectrum of Fc‐related immune mechanisms, a recombinant, humanized anti‐IgE IgG1 is similar to an authentic human IgG1. Only the three short complementarity‐determining regions (CDRs) in the VH domain and the three CDRs in the Vκ domain from the parental mouse antibody are retained; nearly the entire four framework segments in each of the VH and the Vκ are derived from sequence‐matched human VH and Vκ; the entire CH1, CH2, and CH3 domains of the heavy chain are from human γ1 and the Cκ domain of the light chain is from human κ (Kolbinger 1993, Presta 1993). A striking feature of omalizumab and TNX‐901 is that, like a human IgG1, they circulate in the treated patients with a half‐life of about 21 days.
Omalizumab is presently provided by the manufacturers in a dry powder formulation, which requires the reconstitution with water to resume a solution form for subcutaneous injection (Strunk and Bloomberg, 2006). Other formulations such as a solution in prefilled syringes for easier administration are under development. Unlike other small molecular compounds synthesized in organic chemical plants, omalizumab is produced by a host Chinese hamster ovary (CHO) cell line in 12,000‐ or 15,000‐liter bioreactor tanks. CHO cell line has become a standard for producing protein pharmaceuticals for human applications (Wurm, 2004). In our case, the CHO cell line was engineered by transfecting with the recombinant “humanized” genes coding the improved γ1 and κ chains. The CHO cells express the exogenously introduced antibody genes and produce the humanized antibody in very high yields.
IgE is well known for its roles in mediating type I hypersensitivity reaction (Gould 2003, Janeway 2005). Through the work of many researchers in the last few decades and the clinical studies of anti‐IgE more recently, IgE is now known to play important roles in many allergic diseases. Allergic diseases are generally defined as significant pathological changes that are caused by excessive reactions of the immune system to innocuous substances which the patients are exposed to. While allergic reactions to some substances involves nearly entirely type II, III, or IV hypersensitivity reactions (Janeway et al., 2005), most allergic reactions to inhaled or ingested protein substances involves at least partly type I hypersensitivity reaction and IgE (Oettgen and Geha, 1999). The main allergic diseases or conditions that involve IgE by some extent include allergic asthma (Menz 1998, Oettgen 2001), allergic rhinitis (Bodtger 2006, Tschopp 1998) and conjunctivitis (Mimura et al., 2004), allergic or anaphylactic reactions to certain foods (such as peanuts, tree nuts, shell fish, and so on; Sabra et al., 2003), allergic reactions to certain drugs (such as protamin and heparin; Sicherer 2005, Weiss 1989), allergic reactions to insect bites (especially wasp and fire ant stings; King 2000, Schafer 1996), atopic dermatitis (Leung, 1993), allergic reactions to natural rubber latex (Ebo and Stevens, 2002), allergic reactions to certain raw materials (such as papain, subtilisin, yeasts, and so on) (Baur 1979, Lemiere 1996) or products in factories (Bernstein, 1997), and allergic reactions to other less common harmless substances.
Many of the allergic diseases mentioned above affect ever‐increasing population in most regions of the world (Isolauri et al., 2004). The prevalence is related to economical development (Section 7.1) (Gold and Wright, 2005) and in developed countries the aggregate rates of cases of allergic diseases that are serious enough to seek doctors' help are more than 10% generally and maybe 20−30% in some regions. These diseases affect the health and the quality of life (sleep, school, work, family, and so on) of millions of patients and consume large amounts of healthcare resources.
An earlier review (Chang, 2000) by the lead author of this chapter presented an overview of the rationale and pharmacological basis of the anti‐IgE therapy. Since then, a lot of progress relating to anti‐IgE has been made. A large number of review articles have been published on anti‐IgE, especially reviews summarizing the clinical trials on allergic asthma and discussing the utility of this treatment modality in managing asthma (Busse 2001, Holgate 2005a, Lanier 2003, Milgrom 2004, Strunk 2006). In this chapter, we will focus on aspects of the anti‐IgE concept and development, which have been largely left out by most previous anti‐IgE reviews. We will discuss the rationale behind the anti‐IgE invention, the clinical development of anti‐IgE on various disease indications, and present a comprehensive analysis on the multiple intricate immunoregulatory pharmacological effects of anti‐IgE. We will also discuss the development of other approaches that target IgE and IgE‐expressing B cells.
Section snippets
IgE Isotype‐Specific Control and IgE Targeting
The idea of isotype‐specific suppression of antibodies had already been pursued academically (Bich‐Thuy 1984, Hoover 1983) by researchers before the anti‐IgE approach was conceptualized. In the field of IgE suppression, a group led by Haba and Nisonoff investigated the potential of inducing intolerance to IgE in mice by administering IgE within a few days after birth when the mice did not produce any IgE. This could suppress the production of IgE even when the mice grew to adulthood. After the
Anti‐IgE Is Approved for Treating Moderate‐to‐Severe Asthma
In 1994−1995, the first Phase II trial of anti‐IgE was performed with CGP51901 at three medical centers in Central Texas on patients with severe allergic rhinitis caused by mountain cedar pollens. The patients were randomized in four groups and given weekly injections of placebo or CGP51901 at 15‐, 30‐, or 60‐mg dose. The results revealed a robustly clear dose response, showing that the antibody was safe and efficacious in alleviating nasal and ocular allergic symptoms (results not published;
Studies on Other Allergic Diseases
Among the large populations of patients affected by allergic rhinitis, food allergy (especially peanut allergy), or atopic dermatitis are severe cases, which cannot be adequately treated with currently available drugs and are in need of better medicine. There are smaller patient populations who are affected by sensitivity to occupation‐related materials, such as natural rubber latex, papain, yeast, and so on, to certain drugs, or to insect stings. While it is clear that IgE is involved in the
The Potential of Using Anti‐IgE to Assist Allergen‐Based Immunotherapy
In economically advanced countries in North America and Western Europe, allergy is a well‐defined medical specialty serving substantial medical needs. In this specialty, vast amounts of research and development have been carried out and clinical tools accumulated. Undoubtedly, the most significant body of knowledge base in the allergy specialty is the know‐how on immunotherapy. Since immunotherapy was introduced by Noon nearly a century ago (in 1911), a sea of experience has been organized for
Stages Along IgE‐Mediated Allergic Pathway
Omalizumab has already been approved in many countries for treating allergic asthma and has potential for broad use in treating severe allergic rhinitis and several other IgE‐mediated allergic diseases. In order to understand how anti‐IgE renders its pharmacological mechanisms to achieve the effects of alleviating allergic symptoms, it is important to dissect the IgE‐mediated allergic pathway and analyze the intricate interactions among its elements and related factors. Figure 5 shows that the
Neutralization of Free IgE
Because IgE is a key molecule in the IgE‐mediated allergic pathway, neutralizing IgE and decreasing its synthesis would seem to be a logical approach to mitigate the IgE‐mediated allergic pathway. In applying anti‐IgE to neutralize the activity of IgE in the blood and interstitial space in a patient, a question stands out: to how low should the free IgE be brought down? In a few early clinical trials, answers in terms of the percentages of the baseline levels of plasma IgE were provided.
The Dynamical Relationship Between Free IgE and FcɛRI
The above analysis that IgE must be reduced to >99% in order for FcɛRI on mast cells and basophils to become significantly unoccupied is based on steady state kinetic properties, reflecting the concentration of IgE and the density of FcɛRI and the interaction between them. However, on the surface of living mast cells and basophils, the presence of IgE‐unoccupied and ‐occupied FcɛRI is highly dynamic and regulated, and not merely dictated by the chemical kinetics between IgE and FcɛRI.
As
Potential Beneficial Effects of IgE:Anti‐IgE Immune Complexes
The precipitous drop of FcɛRI on basophils and mast cells has provided a plausible, convincing explanation for the pharmacological effect of anti‐IgE in improving IgE‐mediated allergic symptoms. Indeed, as basophils and mast cells are rendered insensitive to allergen stimulation, the discharge of mediators by these cells on exposure to allergens will be retarded and hence manifestation of allergic symptoms greatly diminished. Can this FcɛRI downregulation effect provides the whole explanation
Can Anti‐IgE Modulate IgE‐Committed B Lymphoblasts and Memory B Cell?
One of the most intriguing issues that remain to be addressed definitively is whether anti‐IgE can modulate mIgE‐expressing B cells. This question is of great interest, because if anti‐IgE can inhibit mIgE‐committed B memory cells or B lymphoblasts, the generation of allergen‐specific IgE that is induced by the new exposure to allergens should be intercepted, resulting in a profound attenuation of the allergic pathway. Several lines of in vitro and animal model studies amply support that
Anti‐IgE Should Neutralize the Cytokinergic Properties of IgE
IgE is one of the five classes of antibodies. Its overall structure is very similar to that of antibodies from other classes and its antigen‐binding domains are from the pool of variable regions shared by other classes of antibodies. Its production is induced by exposure to antigens, albeit preferentially by parasitic worms (Capron et al., 1987) and a wide range of environmental antigens. The immunological mechanisms of IgE leading to the protective and pathological effects are initiated and
Can Anti‐IgE Attain a Long‐Term Remission State?
The value and impact of the anti‐IgE therapy will be greatly expanded, if it can achieve a long‐term remission state at least in some of the treated patients. The clinical trials performed so far have not incorporated a study segment to address this aspect for a few considerations. A major concern among officials at governmental regulatory agencies and researchers developing the anti‐IgE program during the early phase of the clinical development of anti‐IgE was that the effect of anti‐IgE in
Is Immune Defense Function Compromised?
It is a rational assumption that the IgE antibody class had evolved in a branch of the vertebrate species for immune defense (Warr et al., 1995). While there is not a large body of evidence in the literature supporting IgE's roles in immune defense, a significant number of papers suffice to indicate that IgE contributes in part to the defense of various infectious agents, especially parasitic worms, in many animal species. Because immunity against infectious agents is critical for the survival
Approaches for Attenuating IgE‐Mediated Allergic Pathway
Various therapeutic approaches have been developed to modulate the immune system to inhibit IgE synthesis, to inhibit TH2 response, or to drive a shift from TH2 to TH1 response (Stokes and Casale, 2004). These include anti‐IL‐4, anti‐IL‐5, and IL‐4 and IL‐5 receptor antagonists (Barnes 2002, Kips 2001, Yamagata 2006). These immune modulators appear to be very attractive agents for attenuating the IgE‐mediated pathway and of the TH2 arm. However, the results from clinical studies are not
Concluding Remarks
The clinical utility of omalizumab for pediatric asthma, allergic rhinitis, peanut allergy, atopic dermatitis, and others, and for combining with SIT and RIT will probably take another 5–10 years to develop for most regions of the world. The therapeutic efficacy exhibited by omalizumab and TNX‐901 in about 30 Phase II and III clinical trials amply demonstrates that IgE plays significant roles in the pathogenesis of not only allergic rhinitis but also allergic asthma, peanut allergy, and
Acknowledgments
Supported by grant no. 94–2320‐B007–004 from the National Science Council, Taiwan.
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