Anti-IgE

Allergy. Figure 6 Anti IgE antibodies prevent IgE from binding to their receptors on mast cells, and thus from releasing allergic mediators. 

Walker S, Monteil M, Phelan K, Lasserson TJ, Walters EH Anti-IgE for chronic asthma Cochrane Database Syst Rev 2003 CD003559. 

Conroy MC, Adkinson NF Jr, Lichtenstein LM SO Measurement of IgE on human basophils relation to serum IgE and anti-IgE-induced histamine release. J Immunol 1977 118 1317-1321. 

Recent evidence from our laboratory shows that the supernatants of HHMC activated by anti-IgE can convert a synthetic substrate of big endothelin to endothelin 1. The latter observation is particularly important because endothelin 1 is a potent bronchoconstrictor in allergic subjects [30]. 

Fig. 2. Effects of increasing concentrations of anti-igE on histamine secretion from eieven preparations of HHMC from patients undergoing heart transpiantation. Each point represents the mean SEM. 

In rare cases, initiation of specific immunotherapy with insect venom leads to recurrent anaphylaxis, even with antihistamine premedication. In those cases, comedication with omalizumab (anti-IgE) has been reported to induce tolerance. In a case of recurrent anaphylaxis to induction of specific immunotherapy, the injection of 300 mg of omalizumab between 4 days and 1 h reportedly led to tolerance [42]. This approach also appears worthy of consideration in patients with both idiopathic recurrent anaphylaxis and mastocytosis who do not respond to standard antimediator therapy, as has been described in 2 atopic patients with ISM [43]. Most patients with mastocytosis and idiopathic anaphylaxis, however, are sufficiently controlled by standard antimediator therapy with antihistamines with or without low-dose corticosteroids. 

The principle underlying the BAT is that the attachment of the antigen to the IgE present on the surface of the basophil leads to the activation of the basophil and the release of its mediators (histamine, leukotrienes, prostaglandins, etc.) and the expression on its membrane of molecules such as CD63, CD203c or others which are markers of basophil activation. The basophils are identified with monoclonal antibodies marked with fluorochromes and anti-IgE and anti-CD63 receptors [for a complete review, we suggest readers read references 19-22]. 

Omalizumab is a recombinant humanized monoclonal anti-IgE antibody that inhibits binding of IgE to receptors on mast cells and basophils, resulting in the inhibition of mediator release and attenuation of the early- and late-phase allergic response. It may be a treatment option for moderate to severe persistent asthmatics 12 years of age or older whose asthma is not controlled by inhaled corticosteroids and who have a positive skin test or in vitro reactivity to perennial allergens.37 Omalizumab significantly decreases inhaled corticosteroid use, number and length of exacerbations, and increases asthma-related quality of life.37... 

Omalizumab (Xolair) is an anti-IgE antibody approved for the treatment of allergic asthma not well controlled by oral or inhaled corticosteroids. The dosage is determined by the patient s baseline total serum IgE (international units/mL) and body weight (kg). Doses range from 150 to 375 mg given subcutaneously at either 2- or 4-week intervals. 

Acid acetone extracts of human and rodent leukocytes (RBL-cells) have been found to contain immunoreactive SOM (iSOM) and immunoreactive SP (iSP) as determined by radioimmunoassay [144], Quantities of the peptides varied from 325 pg iSOM/107 cells for human monocytes and 272 pg iSOM/107 cells for RBL-cells to 4.4 pg iSOM/107 cells for human T cells. iSP was highest in murine bone marrow-derived mast cells (64 pg iSP/107 cells) and RBL-cells (23 pg iSP/107 cells) and lowest in human T and B lymphocytes (2.5 and 1.2 pg iSP/107 cells, respectively). Interestingly, the murine bone marrow-derived mast cells had the highest ratio of iSP to iSOM. Preliminary chromatographic results show a large and a small SOM (SOM-28 and SOM-14, respectively). SOM-14 (3 x 10 9 M) has been shown to inhibit histamine release and LTC4 generation from murine bone marrow-derived mast cells stimulated by anti-IgE serum [144]. 

Interleukin-1 (IL-1) produced by monocytes and several other cell types [70, 146] has a wide array of biological properties, including T cell activation and inflammatory interactions with muscle, liver, fibroblasts, brain and bone [70, 146], IL-1, both natural and recombinant, has been shown to release histamine from human basophils and from human adenoidal mast cells [70,146,151] and this release was abolished by an IL-1 antibody. However, the average release produced by 10 units of IL-1 was less than 20% and there was considerable variability between populations of basophils in the extent of histamine release. Moreover, the secretory response elicited was quite slow (within 15 min) compared with that of other peptides [151]. Desensitization of the basophils by anti-IgE serum had no effect on the subsequent IL-1 response, suggesting different mechanisms of action [ 151], as has been the case with other peptides. Interestingly, the portion of the IL-1 molecule that is responsible for its immu-nostimulatory activity appears to be separate from that portion responsible for its proinflammatory effects [152]. However, that portion of the molecule responsible for eliciting basophil and mast-cell histamine release has not as yet been defined. 

Defining the biochemical mechanisms that couple stimulation at the cell surface to secretion by exocytosis is a major focus in biological research. In the mast cell, the steps by which immunologic secretagogues (for example, specific antigen, anti-IgE antibodies) activate a secretory response have been extensively studied and there are several reviews covering this area [ 12-14, 16, 121, 177],... 

Xolair Qmalizumab Genentech, Novartis, and Tanox (Houston, TX), Anti-IgE AUergic asthma 2003... 

Hamilton RG, Lichtenstein LM Down-regulation of FceRI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol 1997 158 ... 

WARNING Rqx>rts of anaphylaxis 2—24 h after administration, even in previously treated pts Uses Mod-sevCTe asthma in >/=12 y w/ reactivity to an all gen when Sxs inadequately controlled w/ inhaled st oids Action Anti-IgE Ab Dose 150-375 mg SQ q2-4wk (dose/frequency based on SCTum IgE level BW, see package insert) Caution (B, /-] Contra Component aU gy, acute bronchospasm Disp Inj SE Site Rxn, sinusitis, HA, anaphylaxis rqwrted in 3 pts Interactions May X effectiveness OF vaccines and T tox OF hve vaccines may T natalizumab Infxn tox EMS Not for acute asthma, use inhaled J-agonists allergic Rxns are common OD Unlikely to cause hfe-threatening Sxs, exc t for aU gic Rxn... 

As a result, treatment of patients in the basic group, using biospecific hemosorption with anti-IgE sorbent decreased the IgE level in plasma by 50%. This decrease correlated with significant improvement of clinical symptoms and laboratory indices of patients. Patients in the control group had no significant clinical or laboratory signs of improvement. 

In summary, it can be concluded that the developed biospecific anti-IgE hemosorbent may be widely used to treat patients with severe forms of allergic and combined bronchial asthma, as well as in situations where high IgE level plays a critical role and its reduction may benefit a patient. 

N. Dasovich, T.D. Sweeney, S.J. Shire, C.C. Hsn, and Y.E Maa, Effect of mannitol crystallization on the stability and aerosol performance of a spray-dried pharmaceutical protein, recombinant humanized anti-IgE monoclonal antibody. J Pharm Sci, 1998. 87(11) 1406-11. 

This chapter presents the basic pharmacology of the methylxanthines, cromolyn, leukotriene pathway inhibitors, and monoclonal anti-IgE antibody—agents whose medical use is almost exclusively for pulmonary disease. The other classes of drugs previously... 

OTHER DRUGS IN THE TREATMENT OF ASTHMA Anti-IgE Monoclonal Antibodies... 

Treatment with omalizumab, the monoclonal humanized anti-IgE antibody, is reserved for patients with chronic severe asthma inadequately controlled by high-dose inhaled corticosteroid plus long-acting B-agonist combination treatment (eg, fluticasone 500 meg plus salmeterol 50 meg inhaled twice daily). This treatment reduces lymphocytic, eosinophilic bronchial inflammation and effectively reduces the frequency and severity of exacerbations. It is reserved for patients with demonstrated IgE-mediated sensitivity (by positive skin test or radioallergosorbent test [RAST] to common allergens) and an IgE level within a range that can be reduced sufficiently by twice-weekly subcutaneous injections. 

Walker S et al Anti-IgE for chronic asthma in adults and children. Cochrane Database Syst Rev 2006 2 CD003559. 

Omalizumab is an anti-IgE recombinant humanized monoclonal antibody that is approved for the treatment of allergic asthma in adult and adolescent patients whose symptoms are refractory to inhaled corticosteroids (see Chapter 20). The antibody blocks the binding of IgE to the high-affinity Fes receptor on basophils and mast cells, which suppresses IgE-mediated release of type I allergy mediators such as histamine and leukotrienes. Total serum IgE levels may remain elevated in patients for up to 1 year after administration of this antibody. 

Immunosuppressive therapy is utilized in chronic severe asthma, where cyclosporine is often effective and sirolimus is another alternative. Omalizumab (anti-IgE antibody) has recently been approved for the treatment of severe asthma (see previous section). Tacrolimus is currently under clinical investigation for the management of autoimmune chronic active hepatitis and of multiple sclerosis, where IFN-3 has a definitive role. 

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