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Monoclonal anti-IgE antibody E25 therapy for asthma
Res. Immunol.
© INSTITUTPASTEUR/ELsEVIER
Paris 1998
1998, 149, 189-192
Monoclonal anti-IgE antibody E25 therapy for asthma H.A. Boushey and J.W. Fahy Asthma Clinical Research Center, University of California San Francisco, 505 Parnassus Avenue, M-1429, Box 0130, San Francisco, CA 94143-0130 (USA)
IgE is believed to play a pivotal role in the pathophysiology of asthma [1, 2]. The interaction of antigen with IgE bound to high affinity FceSR1 receptors on mast cells provokes the release of preformed mediators, such as histamine and tryptase, and the synthesis and release of protaglandins, leukotrienes and cytokines [3]. Antigen also interacts with IgE bound to FceSR1 on other inflammatory cells, like eosinophils, macrophages, B lymphocytes, and dendritic cells [4] and also with IgE that binds to the lower-affinity FceSR2 receptor also found on various inflammatory cells [5]. The cellular mechanisms of inflammation activated by antigen challenge may thus involve stimulation of changes in function and the release of mediators from a variety of different cells. The mediators released by mast cells are thought to cause the airway mucosal oedema and contraction of smooth muscle responsible for the bronchoconstriction that appears within ten minutes and usually resolves within sixty minutes after antigen challenge [3]. Less certain are the mediators responsible for the airway oedema, smooth muscle contraction, and infiltration with inflammatory cells that characterize the late asthmatic response [6].
Development of anti-IgE antibodies Because of IgE's apparently central role in the pathogenesis of asthma and other atopic diseases, anti-IgE antibodies have been developed for therapeutic testing [7]. These efforts were at
Received April 1, 1998.
first frustrated by antibody recognition of cellbound IgE, leading to mast cell activation. This was overcome by the development of a murine monoclonal antibody with the novel feature that it recognizes the specific Fc portion of circulating IgE that binds to its receptors [8] and thus does not complex with basophil or mast-cell-bound IgE. In murine studies, this antibody was shown also to reduce circulating levels of IgE, to reduce cutaneous sensitivity to allergen injection and to inhibit IgE production after antigen challenge. A humanized variant of this antibody, rhu-mAb-E25, made by engrafting the critical amino acids responsible for binding to IgE onto a consensus human IgG1 framework, has been shown not to provoke histamine release from IgE-sensitized mast cells [9] but to inhibit passive sensitization of human lung tissue 10 and allergen-induced IgE synthesis by cultured peripheral blood mononuclear leukocytes from atopic volunteers [8]. Chronic administration of rhu-mAb-E25 to human volunteers with perennial symptoms of rhinits and positive skin tests to house dust mite has been shown to cause not only a reduction in serum IgE levels, but also to have the potentially beneficial additional action of downregulating the density of FcESR1 receptors on circulating basophils [11].
Clinical studies of anti-lgE antibody therapy Once preliminary studies had shown that administration of rhu-mAb-E25 caused a dose-depen-
190
H.A. B O U S H E Y A N D J.V. F A H Y
dent reduction in free circulating IgE without any evidence of anaphylaxis or of immune-complexmediated toxicity, clinical trials of its efficacy in treating allergic diseases of the airways were undertaken. The first large clinical trial examined the effects of repeated dosing with rhu-mAb-E25 over 12 weeks in 240 patients with allergic rhinitis [ 12]. The results showed that symptoms of rhinitis correlated with antigen-specific IgE levels and also that rhu-mAb-E25 was well tolerated and reduced serum-free IgE levels in a dose-dependent manner. Because the doses were not adjusted individually for baseline IgE levels, however, only 11 of the 181 subjects randomized to active treatment had a fall in IgE levels to below the limit of detection (< 24 ng/mL). This may account for the failure of the rhu-mAb-E25 treatment given in this study to significantly affect symptoms of rhinitis. Indeed, it is likely that the levels of IgE must be lowered by > 9 9 % , for the density of Fc~SR1 receptors on basophils is around 10 4_105 per cell, and the number of IgE antibodies that must be activated to provoke half maximal histamine release is only 102-103 per cell 13. As a first step in determining whether doses of rhu-mAb-E25 calculated to reduce serum IgE to undetectable levels might represent a useful therapy for allergic asthma, Boulet and his colleagues in Canada, and we in San Francisco, undertook concurrent clinical studies. Boulet et al. examined changes in the early reaction to antigen challenge given after 4, 8, and 11 weeks of regular treatment with rhu-mAb-E25, given in doses adjusted for baseline IgE levels, in 11 asthmatic subjects [14]. We examined changes in the early- and late-phase reactions to inhaled allergen in allergic asthmatic subjects given 9 weeks of treatment with rhu-mAb-E25, again in doses adjusted to cause reduction of serum IgE to undetectable levels [15]. In both studies, treatment with rhu-mAb-E25 was well tolerated and reduced serum IgE to undetectable levels in most (but not all) subjects. In both studies, the treatment attenuated the early response to antigen challenge. Boulet et al. showed the median allergen PC 15 to increase by 2.3, 2.2, and 2.7, doubling doses at roughly 4-week intervals in 11 treated subjects. We similarly found that 9 weeks of rhu-mAb-E25 treatment
increased the dose of allergen needed to provoke an early asthmatic response and reduced the mean fall in FEV1 during the early response in 9 subjects. We also found that the treatment reduced the late response by more than 60%. That the increase in bronchial reactivity and the influx of eosinophils into the airway mucosa associated with the late phase response may also have been attenuated was suggested by reductions in the fall in PC20Meth. and in the rise in sputum eosinophil counts and ECP concentrations obtained the morning after antigen challenge. rhu-mAb-E25's attenuation of the late-phase response confirms that IgE-mediated events are important in its pathogenesis. It is not possible, however, even to specify the cellular source of the mediators responsible, for macrophages and eosinophils, as well as mast cells, to express Fc~SR1 receptors on their surface. It may also be noteworthy, of course, that neither the early nor the late response were completely attenuated. One possible explanation is that cells already armed with IgE rnay persist in the airways for long periods after free serum IgE has been reduced to undetectable levels (the 56th day, on average). Indeed, our finding that rhu-mAb-E25 treatment had no effect on cutaneous reactivity to antigen may indicate that cutaneous mast cells have a longer half life than airway mucosal mast cells, are less accessible to intravenously infused antibody, or differ in some other way. There are, of course, many other possible explanations for rhu-mAb-E25's failure to completely inhibit the early and late responses to antigen challenge, including the possibility that non-IgE-bearing cells, such as lymphocytes, may also be directly activated by inhaled allergen to initiate proinflammatory events, as has been suggested by studies of murine models of allergic sensitization of the airways [ 16]. The effectiveness of rhu-mAb-E25 in inhibiting both early and late responses to allergen challenge suggests potential promise as a therapeutic agent. Inhibition of bronchial responses to allergen, especially the late response, has been found to be generally predictive of therapeutic efficacy in the chronic treatment of asthma [17]. That this is also true for rhu-mAb-E25 was recently e~tablished in a randomized, placebo-
A B S T R A C T : N E W T H E R A P Y IN A L L E R G I C DISEASES
controlled, multi-centre US study of its efficacy in 317 patients with moderate to severe allergic asthma requiring inhaled and/or oral corticosteroids [18]. Two doses of rhu-mAb-E25 were studied, a low dose of 0.006 or a high dose of 0.014 mg/kg/IU/ml given intravenously at twoweek intervals for 12 weeks. E25 treatment was associated with a 99 % mean fall in serum free IgE in both treatment groups and with significantly greater improvement in symptoms (42 % improvement in symptom score) than was seen with placebo treatment. Peak flow and frequency of "as needed" [3-agonists also fell significantly in the high-dose group. The reported success of anti-IgE antibody treatment of asthma raises questions as to possible long-term consequences of treatment, like whether the applicability of this treatment to large populations will be limited by impairment of host defence against parasitic infection. Limited work done in Schistosoma mansoni-infected mice has so far provided inconsistent results: one study has reported that anti-IgE antibody treatment decreased worm burden and egg production [19], and another has reported that IgE knockout mice have increased worm burdens after experimental innoculation [20].
Murine studies of the role of FceSR1 and FcESR2 receptors The finding that treatment with a monoclonal antibody directed against the Fc portion of IgE inhibits the late response to antigen challenge only confirms that IgE-dependent mechanisms are involved in the pathogenesis of the late response. The studies done so far in humans do not allow inferences as to the cells or even the IgE receptors most involved, for the anti-IgE antibodies inhibit binding of IgE to both it high affinity and low affinity receptors, and both types of receptor are found on inflammatory cells. Studies of this question in mice have surprisingly suggested that it may be the activation of Fc~SR2-dependent pathways that is most important in causing the eosinophilic inflammation of the airways thought to underlie the late response [16]. In BALB/c mice immunized intraperitoneally with house dust mite
191
antigen and subsequently challenged with the antigen by aerosol, Coyle and coworkers showed an influx of eosinophils into lung lavage fluid and an increase in interleukin-4 and -5 production by lung lymphocytes. Treatment with an anti-IgE antibody reduced serum IgE and blocked both the influx of eosinophils and the increases in IL4 and IL5 secretion, confirming IgE's importance for allergen-induced secretion of Th2 cytokines and the recruitment of eosinophils after antigen provocation. Mast-cell-deficient mice, however, responded to sensitization and challenge just as did control mice, suggesting that IgE-dependent mast cell degranulation is not critical for the recruitment of eosinophils into the lungs. In contrast, mice treated with an antibody against CD23 (FceSR2 receptor) and CD23 knockout mice showed marked reductions in lung eosinophilia after antigen challenge. Coyle et al. interpret these findings as suggesting that anti-IgE suppresses eosinophil infiltration and Th2 cytokine production by inhibiting IgE-CD23-facilitated antigen presentation to T cells in the airways [21]. In summary, IgE represents a logical target for the treatment of allergic diseases, and inhibiting IgE with a non-anaphylactogenic monoclonal antibody has been shown to be feasible, and an anti-IgE humanized monoclonal antibody has been developed for clinical study. Treatment with this antibody attenuates the early and late phase responses to inhaled allergen challenge in allergic asthmatics and has been shown to be effective as regular therapy in patients with moderate to severe corticosteroid-dependent allergic asthma. The mechanism of this protective effect is unclear, but murine studies suggests that inhibition of antigen IgE complex binding to low affinity FceSR2 receptors may be most important, perhaps by inhibiting IgE focusing of antigen presentation to T lymphocytes, thus preventing initiation of an augmented Th2 cytokinemediated inflammatory cascade. The development of a selective, apparently safe anti-IgE monoclonal antibody holds great promise both as a novel treatment for asthma and allergic rhinitis and as a research tool for defining the role of IgE in health and disease.
192
H.A. B O U S H E Y A N D J.V. F A H Y
References [1] Ishizaka, T. & Ishizaka, K.(1975), Biology of immunoglobulin E. Prog. Allergy, 19, 60-121. [2] Burrows, B., Martinez, F.D., Halonen, M., Barbee, R. & Cline, M.G. (1989), Association of asthma with serum IgE levels and skin-test reactivity to allergens. N. Engl. J. Med., 320, 271-277. [3] Holgate, S.T., Robinson, C. & Church, M.K. (1993), Mediators of immediate hypersensitivity. In: Allergy Principles and Practice, Vol. 4th. Middleston, E., Reed, C.E., Regis, E.F., Adkinson, N.F., Yuninger, J.W. & Busse, W.W. St. Louis, Mosby, (pp. 267-301). [4] Rajakulasingam, K., Durham, SR., O'Brien, F. et al. (1997), Enhanced expression of high-affinity IgE receptor (FceRI) a chain in human allergen-induced rhinitis with co-localization to mast cells, macrophages, eosinophils, and dendritic cells. J. Allergy Clin. Immunol., 100, 78-86. [5] Sutton, B.J. & Gould, H.J. (1993), The human IgE network. Nature, 366, 421-428. [6] Zweiman, B. (1993), The late phase response: Role of IgE, its receptor, and cytokines. Curr. Opin. ImmunoL, 5, 950-955. [7] Davis, F.M., Gossett, L.A., Pinkston, K.L. et al. (1993), Can anti-IgE be used to treat allergy? Springer Semin. Immunopathol., 15, 51-73. [8] Shields, R.L., Whether, W.R., Zioncheck, K. et al. (1995), Inhibition of allergic reactions with antibodies to IgE. Int. Arch. Allergy lmmunol., 107, 308-312. [9] Presta, L.G., Lahr, S.J., Shields, R.L. et al. (1993), Humanization of an antibody directed against IgE. J. lmmunol., 151, 2623-2632. [10] Saban, R., Haak-Frendscho, M., Zine, M. et al. (1994), Human FceRl-IgG and humanized anti-IgE monoclonal antibody MaE11 block passive sensitization of human and rhesus monkey lung. J. Allergy Clin. ImmunoL, 94, 836-843. [11] MacGlashan, D.W., Bochner, B.S., Adelman, D.C. et al. (1997), Down-regulation of FceRI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J. lmmunol., 158, 1438-1445. [12] Casale, T.B., Bernstein, I.L., Busse, W.W. et al. (1997), Use of an anti-IgE humanized monoclonal antibody in ragweed-induced allergic rhinitis. J. Allergy Clin. lmmunoL, 100, 110-121.
[13] MacGlashan, D.W., Peters, S.P., Warner, J. & Lichtenstein, L.M. (1986), Characteristics of human basophil sulfidopeptide leukotriene release: releasability defined as the ability of the basophil to respond to dimeric cross-links. J. Immunol., 136, 2231. [14] Boulet, L.-P., Chapman, K.R., Cote, J. et al. (1997), Inhibitory effects of an anti-IgE antibody E25 on allergen-induced early asthmatic response. Am. J. Respir. Crit. Care Med., 155, 1835-1840. [15] Fahy, J.V., Fleming, H.E., Wong, H.H. et al. (1997), The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects. Am. J. Respir. Crit. Care Med., 155, 1828-1834. [16] Coyle, A.J., Wagner, K., Bertrand, C., Tsuyuki, S., Bews, J. & Heusser, C. (1996), Central role of immunoglobulin (Ig) E in the induction of lung eosinophil infiltration and T helper 2 cell cytokine production: inhibition by a non-anaphylactogenic anti-IgE antibody. J. Exp. Med., 183, 1303-1310. [17] Cockcroft, D.W. & Murdock, K.Y. (1987), Comparative effects of inhaled salbutamol, sodium cromoglycate, and beclomethasone dipropionate on allergeninduced early asthmatic responses, and increased bronchial responsiveness to histamine. J. Allergy Clin. Immunol., 79, 734-740. [18] Fick, R.B., Simon, S.J., Su, J.Q., Zeiger, R. & E25 Study Group. (1998), Anti-IgE (rhuMAb) treatment of the symptoms of moderate-severe allergic asthma. Ann. Allergy Asthma Immunol., Abstract, (in press). [19] Amiri, P., Haak-Frendscho, M., Robbins, K., McKerrow, J.H., Stewart, T. & Jardieu, P. (1994), Antiimmunoglobulin E treatment decreases worm burden and egg production in schistosoma mansoni-infected normal and interferon knockout mice. J. Exp. Med., 180, 43-51. [20] King, C.L, Xianli, J., Malhotra, I., Liu, S., Mahmoud, A.A.F. & Oettgen, H.C. (1997), Mice with a targeted deletion of the IgE gene have increased worm burdens and reduced granulomatous inflammation following primary infection with schistosoma mansoni. J. ImmunoL, 158, 294-300. [21] Pirron, U., Schlunck, T., Prinz, J.C. & Rieber EP. (1990), IgE-dependent antigen focusing by human B lymphocytes is mediated by the low affinity receptor for IgE. Eur. J. ImmunoL, 20, 1547-1551.
© INSTITUTPASTEUR/ELsEVIER
Paris 1998
1998, 149, 189-192
Monoclonal anti-IgE antibody E25 therapy for asthma H.A. Boushey and J.W. Fahy Asthma Clinical Research Center, University of California San Francisco, 505 Parnassus Avenue, M-1429, Box 0130, San Francisco, CA 94143-0130 (USA)
IgE is believed to play a pivotal role in the pathophysiology of asthma [1, 2]. The interaction of antigen with IgE bound to high affinity FceSR1 receptors on mast cells provokes the release of preformed mediators, such as histamine and tryptase, and the synthesis and release of protaglandins, leukotrienes and cytokines [3]. Antigen also interacts with IgE bound to FceSR1 on other inflammatory cells, like eosinophils, macrophages, B lymphocytes, and dendritic cells [4] and also with IgE that binds to the lower-affinity FceSR2 receptor also found on various inflammatory cells [5]. The cellular mechanisms of inflammation activated by antigen challenge may thus involve stimulation of changes in function and the release of mediators from a variety of different cells. The mediators released by mast cells are thought to cause the airway mucosal oedema and contraction of smooth muscle responsible for the bronchoconstriction that appears within ten minutes and usually resolves within sixty minutes after antigen challenge [3]. Less certain are the mediators responsible for the airway oedema, smooth muscle contraction, and infiltration with inflammatory cells that characterize the late asthmatic response [6].
Development of anti-IgE antibodies Because of IgE's apparently central role in the pathogenesis of asthma and other atopic diseases, anti-IgE antibodies have been developed for therapeutic testing [7]. These efforts were at
Received April 1, 1998.
first frustrated by antibody recognition of cellbound IgE, leading to mast cell activation. This was overcome by the development of a murine monoclonal antibody with the novel feature that it recognizes the specific Fc portion of circulating IgE that binds to its receptors [8] and thus does not complex with basophil or mast-cell-bound IgE. In murine studies, this antibody was shown also to reduce circulating levels of IgE, to reduce cutaneous sensitivity to allergen injection and to inhibit IgE production after antigen challenge. A humanized variant of this antibody, rhu-mAb-E25, made by engrafting the critical amino acids responsible for binding to IgE onto a consensus human IgG1 framework, has been shown not to provoke histamine release from IgE-sensitized mast cells [9] but to inhibit passive sensitization of human lung tissue 10 and allergen-induced IgE synthesis by cultured peripheral blood mononuclear leukocytes from atopic volunteers [8]. Chronic administration of rhu-mAb-E25 to human volunteers with perennial symptoms of rhinits and positive skin tests to house dust mite has been shown to cause not only a reduction in serum IgE levels, but also to have the potentially beneficial additional action of downregulating the density of FcESR1 receptors on circulating basophils [11].
Clinical studies of anti-lgE antibody therapy Once preliminary studies had shown that administration of rhu-mAb-E25 caused a dose-depen-
190
H.A. B O U S H E Y A N D J.V. F A H Y
dent reduction in free circulating IgE without any evidence of anaphylaxis or of immune-complexmediated toxicity, clinical trials of its efficacy in treating allergic diseases of the airways were undertaken. The first large clinical trial examined the effects of repeated dosing with rhu-mAb-E25 over 12 weeks in 240 patients with allergic rhinitis [ 12]. The results showed that symptoms of rhinitis correlated with antigen-specific IgE levels and also that rhu-mAb-E25 was well tolerated and reduced serum-free IgE levels in a dose-dependent manner. Because the doses were not adjusted individually for baseline IgE levels, however, only 11 of the 181 subjects randomized to active treatment had a fall in IgE levels to below the limit of detection (< 24 ng/mL). This may account for the failure of the rhu-mAb-E25 treatment given in this study to significantly affect symptoms of rhinitis. Indeed, it is likely that the levels of IgE must be lowered by > 9 9 % , for the density of Fc~SR1 receptors on basophils is around 10 4_105 per cell, and the number of IgE antibodies that must be activated to provoke half maximal histamine release is only 102-103 per cell 13. As a first step in determining whether doses of rhu-mAb-E25 calculated to reduce serum IgE to undetectable levels might represent a useful therapy for allergic asthma, Boulet and his colleagues in Canada, and we in San Francisco, undertook concurrent clinical studies. Boulet et al. examined changes in the early reaction to antigen challenge given after 4, 8, and 11 weeks of regular treatment with rhu-mAb-E25, given in doses adjusted for baseline IgE levels, in 11 asthmatic subjects [14]. We examined changes in the early- and late-phase reactions to inhaled allergen in allergic asthmatic subjects given 9 weeks of treatment with rhu-mAb-E25, again in doses adjusted to cause reduction of serum IgE to undetectable levels [15]. In both studies, treatment with rhu-mAb-E25 was well tolerated and reduced serum IgE to undetectable levels in most (but not all) subjects. In both studies, the treatment attenuated the early response to antigen challenge. Boulet et al. showed the median allergen PC 15 to increase by 2.3, 2.2, and 2.7, doubling doses at roughly 4-week intervals in 11 treated subjects. We similarly found that 9 weeks of rhu-mAb-E25 treatment
increased the dose of allergen needed to provoke an early asthmatic response and reduced the mean fall in FEV1 during the early response in 9 subjects. We also found that the treatment reduced the late response by more than 60%. That the increase in bronchial reactivity and the influx of eosinophils into the airway mucosa associated with the late phase response may also have been attenuated was suggested by reductions in the fall in PC20Meth. and in the rise in sputum eosinophil counts and ECP concentrations obtained the morning after antigen challenge. rhu-mAb-E25's attenuation of the late-phase response confirms that IgE-mediated events are important in its pathogenesis. It is not possible, however, even to specify the cellular source of the mediators responsible, for macrophages and eosinophils, as well as mast cells, to express Fc~SR1 receptors on their surface. It may also be noteworthy, of course, that neither the early nor the late response were completely attenuated. One possible explanation is that cells already armed with IgE rnay persist in the airways for long periods after free serum IgE has been reduced to undetectable levels (the 56th day, on average). Indeed, our finding that rhu-mAb-E25 treatment had no effect on cutaneous reactivity to antigen may indicate that cutaneous mast cells have a longer half life than airway mucosal mast cells, are less accessible to intravenously infused antibody, or differ in some other way. There are, of course, many other possible explanations for rhu-mAb-E25's failure to completely inhibit the early and late responses to antigen challenge, including the possibility that non-IgE-bearing cells, such as lymphocytes, may also be directly activated by inhaled allergen to initiate proinflammatory events, as has been suggested by studies of murine models of allergic sensitization of the airways [ 16]. The effectiveness of rhu-mAb-E25 in inhibiting both early and late responses to allergen challenge suggests potential promise as a therapeutic agent. Inhibition of bronchial responses to allergen, especially the late response, has been found to be generally predictive of therapeutic efficacy in the chronic treatment of asthma [17]. That this is also true for rhu-mAb-E25 was recently e~tablished in a randomized, placebo-
A B S T R A C T : N E W T H E R A P Y IN A L L E R G I C DISEASES
controlled, multi-centre US study of its efficacy in 317 patients with moderate to severe allergic asthma requiring inhaled and/or oral corticosteroids [18]. Two doses of rhu-mAb-E25 were studied, a low dose of 0.006 or a high dose of 0.014 mg/kg/IU/ml given intravenously at twoweek intervals for 12 weeks. E25 treatment was associated with a 99 % mean fall in serum free IgE in both treatment groups and with significantly greater improvement in symptoms (42 % improvement in symptom score) than was seen with placebo treatment. Peak flow and frequency of "as needed" [3-agonists also fell significantly in the high-dose group. The reported success of anti-IgE antibody treatment of asthma raises questions as to possible long-term consequences of treatment, like whether the applicability of this treatment to large populations will be limited by impairment of host defence against parasitic infection. Limited work done in Schistosoma mansoni-infected mice has so far provided inconsistent results: one study has reported that anti-IgE antibody treatment decreased worm burden and egg production [19], and another has reported that IgE knockout mice have increased worm burdens after experimental innoculation [20].
Murine studies of the role of FceSR1 and FcESR2 receptors The finding that treatment with a monoclonal antibody directed against the Fc portion of IgE inhibits the late response to antigen challenge only confirms that IgE-dependent mechanisms are involved in the pathogenesis of the late response. The studies done so far in humans do not allow inferences as to the cells or even the IgE receptors most involved, for the anti-IgE antibodies inhibit binding of IgE to both it high affinity and low affinity receptors, and both types of receptor are found on inflammatory cells. Studies of this question in mice have surprisingly suggested that it may be the activation of Fc~SR2-dependent pathways that is most important in causing the eosinophilic inflammation of the airways thought to underlie the late response [16]. In BALB/c mice immunized intraperitoneally with house dust mite
191
antigen and subsequently challenged with the antigen by aerosol, Coyle and coworkers showed an influx of eosinophils into lung lavage fluid and an increase in interleukin-4 and -5 production by lung lymphocytes. Treatment with an anti-IgE antibody reduced serum IgE and blocked both the influx of eosinophils and the increases in IL4 and IL5 secretion, confirming IgE's importance for allergen-induced secretion of Th2 cytokines and the recruitment of eosinophils after antigen provocation. Mast-cell-deficient mice, however, responded to sensitization and challenge just as did control mice, suggesting that IgE-dependent mast cell degranulation is not critical for the recruitment of eosinophils into the lungs. In contrast, mice treated with an antibody against CD23 (FceSR2 receptor) and CD23 knockout mice showed marked reductions in lung eosinophilia after antigen challenge. Coyle et al. interpret these findings as suggesting that anti-IgE suppresses eosinophil infiltration and Th2 cytokine production by inhibiting IgE-CD23-facilitated antigen presentation to T cells in the airways [21]. In summary, IgE represents a logical target for the treatment of allergic diseases, and inhibiting IgE with a non-anaphylactogenic monoclonal antibody has been shown to be feasible, and an anti-IgE humanized monoclonal antibody has been developed for clinical study. Treatment with this antibody attenuates the early and late phase responses to inhaled allergen challenge in allergic asthmatics and has been shown to be effective as regular therapy in patients with moderate to severe corticosteroid-dependent allergic asthma. The mechanism of this protective effect is unclear, but murine studies suggests that inhibition of antigen IgE complex binding to low affinity FceSR2 receptors may be most important, perhaps by inhibiting IgE focusing of antigen presentation to T lymphocytes, thus preventing initiation of an augmented Th2 cytokinemediated inflammatory cascade. The development of a selective, apparently safe anti-IgE monoclonal antibody holds great promise both as a novel treatment for asthma and allergic rhinitis and as a research tool for defining the role of IgE in health and disease.
192
H.A. B O U S H E Y A N D J.V. F A H Y
References [1] Ishizaka, T. & Ishizaka, K.(1975), Biology of immunoglobulin E. Prog. Allergy, 19, 60-121. [2] Burrows, B., Martinez, F.D., Halonen, M., Barbee, R. & Cline, M.G. (1989), Association of asthma with serum IgE levels and skin-test reactivity to allergens. N. Engl. J. Med., 320, 271-277. [3] Holgate, S.T., Robinson, C. & Church, M.K. (1993), Mediators of immediate hypersensitivity. In: Allergy Principles and Practice, Vol. 4th. Middleston, E., Reed, C.E., Regis, E.F., Adkinson, N.F., Yuninger, J.W. & Busse, W.W. St. Louis, Mosby, (pp. 267-301). [4] Rajakulasingam, K., Durham, SR., O'Brien, F. et al. (1997), Enhanced expression of high-affinity IgE receptor (FceRI) a chain in human allergen-induced rhinitis with co-localization to mast cells, macrophages, eosinophils, and dendritic cells. J. Allergy Clin. Immunol., 100, 78-86. [5] Sutton, B.J. & Gould, H.J. (1993), The human IgE network. Nature, 366, 421-428. [6] Zweiman, B. (1993), The late phase response: Role of IgE, its receptor, and cytokines. Curr. Opin. ImmunoL, 5, 950-955. [7] Davis, F.M., Gossett, L.A., Pinkston, K.L. et al. (1993), Can anti-IgE be used to treat allergy? Springer Semin. Immunopathol., 15, 51-73. [8] Shields, R.L., Whether, W.R., Zioncheck, K. et al. (1995), Inhibition of allergic reactions with antibodies to IgE. Int. Arch. Allergy lmmunol., 107, 308-312. [9] Presta, L.G., Lahr, S.J., Shields, R.L. et al. (1993), Humanization of an antibody directed against IgE. J. lmmunol., 151, 2623-2632. [10] Saban, R., Haak-Frendscho, M., Zine, M. et al. (1994), Human FceRl-IgG and humanized anti-IgE monoclonal antibody MaE11 block passive sensitization of human and rhesus monkey lung. J. Allergy Clin. ImmunoL, 94, 836-843. [11] MacGlashan, D.W., Bochner, B.S., Adelman, D.C. et al. (1997), Down-regulation of FceRI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J. lmmunol., 158, 1438-1445. [12] Casale, T.B., Bernstein, I.L., Busse, W.W. et al. (1997), Use of an anti-IgE humanized monoclonal antibody in ragweed-induced allergic rhinitis. J. Allergy Clin. lmmunoL, 100, 110-121.
[13] MacGlashan, D.W., Peters, S.P., Warner, J. & Lichtenstein, L.M. (1986), Characteristics of human basophil sulfidopeptide leukotriene release: releasability defined as the ability of the basophil to respond to dimeric cross-links. J. Immunol., 136, 2231. [14] Boulet, L.-P., Chapman, K.R., Cote, J. et al. (1997), Inhibitory effects of an anti-IgE antibody E25 on allergen-induced early asthmatic response. Am. J. Respir. Crit. Care Med., 155, 1835-1840. [15] Fahy, J.V., Fleming, H.E., Wong, H.H. et al. (1997), The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects. Am. J. Respir. Crit. Care Med., 155, 1828-1834. [16] Coyle, A.J., Wagner, K., Bertrand, C., Tsuyuki, S., Bews, J. & Heusser, C. (1996), Central role of immunoglobulin (Ig) E in the induction of lung eosinophil infiltration and T helper 2 cell cytokine production: inhibition by a non-anaphylactogenic anti-IgE antibody. J. Exp. Med., 183, 1303-1310. [17] Cockcroft, D.W. & Murdock, K.Y. (1987), Comparative effects of inhaled salbutamol, sodium cromoglycate, and beclomethasone dipropionate on allergeninduced early asthmatic responses, and increased bronchial responsiveness to histamine. J. Allergy Clin. Immunol., 79, 734-740. [18] Fick, R.B., Simon, S.J., Su, J.Q., Zeiger, R. & E25 Study Group. (1998), Anti-IgE (rhuMAb) treatment of the symptoms of moderate-severe allergic asthma. Ann. Allergy Asthma Immunol., Abstract, (in press). [19] Amiri, P., Haak-Frendscho, M., Robbins, K., McKerrow, J.H., Stewart, T. & Jardieu, P. (1994), Antiimmunoglobulin E treatment decreases worm burden and egg production in schistosoma mansoni-infected normal and interferon knockout mice. J. Exp. Med., 180, 43-51. [20] King, C.L, Xianli, J., Malhotra, I., Liu, S., Mahmoud, A.A.F. & Oettgen, H.C. (1997), Mice with a targeted deletion of the IgE gene have increased worm burdens and reduced granulomatous inflammation following primary infection with schistosoma mansoni. J. ImmunoL, 158, 294-300. [21] Pirron, U., Schlunck, T., Prinz, J.C. & Rieber EP. (1990), IgE-dependent antigen focusing by human B lymphocytes is mediated by the low affinity receptor for IgE. Eur. J. ImmunoL, 20, 1547-1551.