**5. Omalizumab (anti-IgE monoclonal antibody)**

Several therapeutic anti-IgE antibodies, able to reduce free IgE levels and to block the binding of IgE to FcRI without cross-linking IgE and triggering degranulation of IgEsensitized cells have been developed. At present omalizumab is the only monoclonal antibody (mAb) - based drug approved for the treatment of asthma. A new mAb specific for human IgE has been shown to possess a unique set of binding specificities. This mAb, 8D6, binds to a conformational epitope on the CH3 domain of human IgE and can compete with omalizumab for binding to IgE. Like omalizumab, it does not bind to IgE already bound to the high-affinity IgE Fc receptor (FcɛRI) on basophils and mast cells. It also does not cause activation and degranulation of IgE-pulsed, human FcɛRI-expressing rat basophilic leukemic cells (RBL SX-38). This mAb can inhibit IgE binding to recombinant α chain of human FcɛRI in ELISA and to human FcɛRI-expressing RBL SX38 cells in fluorescence flow cytometric analysis. However, unlike omalizumab, 8D6 can bind to IgE already bound by the low-affinity IgE Fc receptors (FcɛRII, or CD23). Since earlier investigators have shown that anti-CD23 mAbs can inhibit the synthesis of IgE in lymphocyte culture in vitro and can down-regulate IgE production in treated patients, 8D6 may offer pharmacological mechanisms in addition to those mediated by omalizumab, for controlling IgE in patients with allergic diseases. (Shiung et al, 2001).

Chu et al, have explored the effects of IgE sequestration versus IgE suppression by comparing omalizumab to FcγRIIb-optimized anti-IgE antibodies in humanized mouse models of immunoglobulin production. By using a murine anti-IgE antibody as a template, the authors humanized, increased IgE binding, and modified its Fc domain to increase affinity for FcγRIIb. Relative to omalizumab, this new mab, XmAb7195, has a 5-fold higher affinity for human IgE and more than 400-fold higher affinity for FcγRIIb. In addition to sequestering soluble IgE, XmAb7195 inhibited plasma cell differentiation and consequent human IgE production through coengagement of IgE B-cell receptor with FcγRIIb. In peripheral blood mononuclear cells-engrafted mice, XmAb7195 reduced total human IgE (but not IgG or IgM) levels by up to 40-fold relative to omalizumab (Chu et al, 2012).

Omalizumab represents an important clinical advance in the management of allergic diseases and can be considered to be safe in children with seasonal allergic rhinitis

Treatment of Allergic Rhinitis: Anticholinergics, Glucocorticotherapy,

Study Patients and type of AR

ragweed AR

birch and grass pollen AR

Further analyses during grass pollen season after previous

Cauwenberge, 2005)

study (Van

asthma and persistent AR

ragweed AR

Nayak et al, 2003 287 patients with

Bez et al, 2004 225 children with

Vignola et al, 2004 405 patients with

Casale et al, 2006 159 patients with

RRQoL = rhinitis-related quality of life.

immunotherapy" in allergic rhinitis.

**6. Allergen-specific Immunotherapy** 

phospholipase A2 pathway (Figure 1).

Rolinck-Werninghaus et al, 2004

Leukotriene Antagonists, Omalizumab and Specific-Allergen Immunotherapy 97

retreatment with omalizumab

Four treatment groups: -grass IT + omalizumab -grass IT + placebo -birch IT + omalizumab -birch IT + placebo

Four treatment groups: -birch IT + placebo -birch IT + omalizumab -grass IT + placebo -grass IT + omalizumab

comparison

omalizumab-placebo

Four treatment groups: -omalizumab + placebo -omalizumab + RIT -placebo + placebo -placebo + RIT

ECP = eosinophilic cationic protein; NSSS = nasal symptom severity scores; RIT = rush immunotherapy;

Two stages have been defined in AR immune pathophysiology. The first stage is named sensitization phase reaction, and is initiated by preferential activation and polarization of the immune response to environmental antigens, that culminates with a generation of a predominant Th2 immune response and production of IgE antibodies; the second stage, named effector phase reaction, is initiated with a second encounter with antigen (Ag) leading to activation of effector mechanisms, such as degranulation of granulocytes and release of histamine (Robles-Contreras et al, 2011). Allergen-induced cell degranulation is the key event in allergic inflammation and leads to early-phase symptoms. Early phase reaction (EPR) has been studied extensively in both humans and animals; EPR is initiated with a second encounter with the antigen by IgE previously attached to IgE receptors (FcεRI, FcεRII or CD23). Cross-linking of IgE receptors induces: a) release of preformed mediators such as histamine, proteases and chemotactic factors; b) activation of transcription factors and cytokine gene expression, and c) production of prostaglandins and leukotrienes by

Table 1. Clinical studies with "omalizumab" and combination "omalizumab-specific

Type of study Comments

Decrease in serum free IgE levels.

omalizumab: no pollen-induced increase in ECP and decrease in tryptase in nasal secretions; significantly lower tryptase levels in the omalizumab group.

Significantly diminished rescue medication use and reduction in the number of symptomatic days with omalizumab monotherapy.

omalizumab + IT combination on symptom severity compared to IT

Combination of IT and

Superior efficacy of the

or omalizumab alone.

patients

Significant improvement in RRQoL in the omalizumab-treated

Significant improvement in severity scores during the ragweed season with omalizumab + IT compared to IT alone

undergoing specific immunotherapy simultaneously (Kamin et al, 2010). Rush IT (RIT) carries a greater risk of acute allergic reactions (including anaphylaxis) than standard subcutaneous IT. In RIT, the accelerated dosing schedule can cause early increases in total and specific IgE concentrations that could predispose individuals to allergic reactions. The effect of omalizumab on the safety and efficacy of RIT was studied in adult patients with ragweed-AR. (Table 1).


undergoing specific immunotherapy simultaneously (Kamin et al, 2010). Rush IT (RIT) carries a greater risk of acute allergic reactions (including anaphylaxis) than standard subcutaneous IT. In RIT, the accelerated dosing schedule can cause early increases in total and specific IgE concentrations that could predispose individuals to allergic reactions. The effect of omalizumab on the safety and efficacy of RIT was studied in adult patients with

comparison

comparison

comparison

omalizumab-placebo

omalizumab-placebo

omalizumab-placebo

Four treatment groups: -grass IT + omalizumab -grass IT + placebo -birch IT + omalizumab -birch IT + placebo

Four treatment groups: -grass IT + omalizumab -grass IT + placebo -birch IT + omalizumab -birch IT + placebo

comparison

omalizumab-placebo

Type of study Comments

Decrease dose-dependent in serum free IgE correlation between symptoms and IgE levels

Decrease serum free IgE levels with omalizumab association between free IgE levels and clinical outcome mean daily NSSS, concomitant medication use, RRQoL was significantly better with omalizumab

Significant association between IgE reduction, nasal symptoms and rescue medication use; significantly lower NSSS, lower need for rescue medication, better RRQoL scores, 75% reduction in days missed from work in patients receiving 300 mg

Symptom load was significantly reduced in both omalizumab groups compared to placebo. In vitro sulfidoleukotriene release was significantly lower with IT + omalizumab compared to IT + placebo, parallel to the reduction in symptoms and the use of rescue medication.

Significant reduction in symptom load and rescue medication use in the omalizumab + IT group compared to IT alone.

Omalizumab reduced symptom load regardless of IT and had a protective effect independent of the type of allergen and additional

Significantly lower NSSS and rescue antihistamines; improved RRQoL in the omalizumab group patient evaluation of efficacy significantly favored omalizumab.

clinical benefit to IT.

omalizumab

ragweed-AR. (Table 1).

Study Patients and type of AR

ragweed AR

birch pollen AR

ragweed AR

and grass pollen AR

birch and grass pollen AR

289 patients with perennial AR

Casale et al, 1997 240 patients with

Ädelroth et al, 2000 251 patients with

Casale et al, 2001 536 patients with

Kopp et al, 2002 92 children with birch

Kuehr et al, 2002 221 children with

Chervinsky et al,

2003


ECP = eosinophilic cationic protein; NSSS = nasal symptom severity scores; RIT = rush immunotherapy; RRQoL = rhinitis-related quality of life.

Table 1. Clinical studies with "omalizumab" and combination "omalizumab-specific immunotherapy" in allergic rhinitis.
