MoAb nella cura dell’asma: paradosso o nuova strategia?
Antibodies

Author: Cecilia Mancini
Date: 24/07/2008

Description

<During the last few years, more than 30% of the population has been diagnosed with asthma.
The WHO has recently focused on asthma because of its rapidly increasing prevalence, affecting up to 100 millions of people, and the mortality is about 180000 cases/year.

Asthma

Asthma is a disorder of the conducting airways characterized by TH2-mediated inflammation and enhanced mediator release; the symptoms are variable airflow obstruction highly responsive to inhaled corticosteroids, wheezing, shortness of breath, chest tightness, and coughing,

IgE sensitization to airborne particles is a hallmark of asthma.


Some persons may have an abnormality called atopy, a hereditary predisposition to the development of immediate hypersensitivity reactions against common environmental antigens. These individuals suffer by IgE regulatory defects that allow nonparasitic antigens to stimulate inappropriate IgE production, leading to tissue-damaging type I hypersensitivity.


The term allergen refers specifically to nonparasitic antigens capable of stimulating type I hypersensitive responses in allergic individuals.

Allergens are small proteins or protein-bound substances having a molecular weight between 15,000 and 40,000.

The abnormal IgE response of atopic individuals is at least partly genetic: one locus, on chromosome 5q, is linked to a region that encodes a variety of cytokines, including IL-3, IL-4, IL-5, IL-9, IL-13, and GM-CSF; a second locus, on chromosome 11q, is linked to a region that encodes the β chain of the high-affinity IgE receptor.

The cells that bind IgE are blood basophils and tissue mast cells, and they bind IgE by two different receptors: FcεRI and FcεRII.


The bound is calling cross-linkage.


It is well known that allergens initiate IgE-mediated inflammation by activating mast cells and basophils via binding to IgE and crosslinking of surface high-affinity IgE receptors (FcεRI), causing degranulation within minutes. This process accounts for the early-phase response to allergen. The mast cells and basophils then produce newinflammatory mediators within hours, resulting in influx of additional inflammatory cells and worsening of airway inflammation, which accounts for

the late early-phase response.

In summary, IgE plays a major role in the development of asthma, in airway inflammation, in both intrinsic and extrinsic stable asthma, in asthma exacerbations, and in long-term decline in lung function. Therefore, blocking IgE function was predicted to benefit patients with asthma.

The New Therapy: OMALIZUMAB
Omalizumab (Xolair) is a humanized monoclonal antibody used in the treatment of adolescent and adult patients with moderate to severe allergic asthma

It is a biotechnological product, the first in allergic pathology. It could turn off the pathology from the apical effect. Omalizumab is a murine IgG1, humanized.


How it work? Anti-IgE antibodies bind to the constant region 3 of the IgE heavy chain (CHε3) at the binding sites for the high-affinity (FcεRI), and the low-affinity (FcεRII or CD23) IgE receptors.


This event prevents IgE binding to IgE receptors on basophils and mast cells. Omalizumab prevents IgE-mediated activation of basophils and mast cells, because the bound with anti-IgE have the same binding affinity as does FcεRI.

Omalizumab was approved by the FDA in 2003. Omalizumab has been administered via subcutaneous, that was selected as the most practical for clinical use.

The dose is 0.016 mg/kg per IU/ml of total serum IgE given for each four-week period. It is possible to calculate the appropriate dose based on the patient’s weight and total serum IgE.

Since November 2006, Omalizumab was approved also in Italy, by the AIFA.

Common side effects are pain, induration, erythema, burning sensation, warmth, and localized hive formation, headache, virus and upper respiratory infection… the follow-up are ongoing to study the serious adverse events (clinical trials).>

Comments
2008-07-31T22:29:38 - Cecilia Mancini

1. IgE and receptors
The structure of IgE consists of two identical light (L) chains, polypeptides of about 25KDa
molecular weight, and two identical heavy (H) chains (about 70KDa). Each light chain is bound to a heavy chain by a disulfide bond, and by such noncovalent interactions as salt linkages, hydrogen bonds, and hydrophobic bonds, to form a heterodimer (H-L). Similar noncovalent in-
teractions and disulfide bridges link the two identical heavy and light (H-L) chain combinations to each other to form the basic four-chain (H-L)2 antibody structure, a dimer of dimers.
The first 110 or so amino acids of the amino-terminal region of a light or heavy chain varies greatly among antibodies of different specificity. The carboxyl-terminal domain is designated
CH4/CH4 in IgE. This additional domain (CH4) contributes to an altered conformation of the Fc portion of the molecule that enables it to bind to glyco-protein receptors on the surface of basophils and mast cells.
The antibody and their subclasses can be expressed either as secreted immunoglobulin (sIg) or as membrane bound immunoglobulin (mIg).
Although the half-life of IgE in the serum is only 2–3 days, once IgE has been bound to its receptor on mast cells and basophils, it is stable in that state for a number of weeks.
IgE-BINDING Fc RECEPTORS
The reaginic activity of IgE depends on its ability to bind to a
receptor specific for the Fc region of the heavy chain. Two classes of FcR been identified, designated FcεRI and FcεRII, which are expressed by different cell types and differ by 1000-
fold in their affinity for IgE.
Mast cells and basophils express FcεRI , which binds IgE with a high affinity. The high affinity of this receptor enables it to bind IgE despite the low serum concentration of IgE
Between 40,000 and 90,000 FcεRI molecules have been shown to be present on a human basophil.
The FcεRI receptor contains four polypeptide chains. The external region of the chain contains
two domains of 90 amino acids that are homologous with the immunoglobulin-fold structure and interacts with the CH3/CH3 and CH4/CH4 domains of the IgE molecule via the two Ig-like domains of the α chain.
The other IgE receptor, designated FcεRII or CD23, is specific for the CH3/CH3 domain of IgE and has a lower affinity for IgE. The FcεRII receptor appears to play a variety of roles in regulating the intensity of the IgE response.
When this receptor is blocked with monoclonal antibodies, IgE secretion by B cells is
diminished.
A soluble form of CD23; sCD23 is generated by autoproteolysis of the membrane receptor and has
been shown to enhance IgE production by B cells. Interestingly, atopic individuals have higher levels of CD23 on their lymphocytes and macrophages and higher levels of sCD23 in their serum than do nonatopic individuals.
Recent studies have shown that increased levels of soluble CD23 cause the recruitment of non-sensitised B-cells in the presentation of antigen peptides to allergen specific B-cells, therefore increasing the production of allergen specific IgE.
2. CD23 and tumors
CD23, the low-affinity Fc receptor for IgE, is constitutively expressed on mature, naive B cells, but is lost following B cell activation. Recent studies shown that CD23 expression on B cells decreases in mice plasma cell tumors. In contrast to these findings, they find that IgE-secreting tumors do not cause a loss of CD23 expression on host splenic B cells.
It seems also that plasma cells tumors decrease CD23 mRNA expression in splenic B cells.
Those works are in progress.
3. IgE induce CD23?
It seems that the decrease of IgE, using Monoclonal antibody anti-IgE could also decrease the expression of IgE receptors on mast cells and basophilis surface. This mean that tha CD23 expression is highly influenced by IgE secretion.
These data taken together could mean that high IgE levels protect against plasma cells tumor, in wich there is a decrease of CD23 expression.
Future investigation will be important, because CD23 pathways could be different in asthma and in plasma cells tumor, but there is a risk that a rapid decrease of IgE concentration, due to the use of Monoclonal antibody, can decrease also the CD23 espression, with an increased risk to develop a plasma cells tumor.

2008-07-28T15:17:20 - Gianpiero Pescarmona

IgE e CD23
CD23 e tumori?
IgE inducono CD23?
se si
alti livelli di IgE sono fattori di rischio per tumori con CD23+?

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Omalizumab_fda.pdf31513024/07/2008
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