Life Sciences: Omalizumab / Xolair

OMALIZUMAB/XOLAIR
Name
Institution Affiliation
Course
Date of Submission
Omalizumab/ Xolair
Executive Summary
Omalizumab has proved to be the first biological medicinal procedure that has been used to treat asthmatic patients. Its development and consequent use was as a result of numerous scientific research and analysis. To determine its efficiency, a number of clinical trials were done involving many test subjects. The research was successful hence Omalizumab was put into use. However, its cost is relatively high and therefore it is only available to the few who can afford it (Busse et al., 2009). Many people in developing countries pass on due to severe allergic asthma due to the fact that they cannot afford Omalizumab to help cure their ailment.
Overview of article:
1. Introduction,
Concept Overview,
Asthma Overview
Description of Omalizumab
2. Review case study
a) Critical evaluation
b) Discovery of drug
c) Production process
d) Clinical trials
e) Registration of omalizumab
f) Cost
g) Sales
3. Conclusion
4. References
1. Introduction
Omalizumab is a humanized IgG monoclonal antibody (mAb). It is an immunoglobulin (Ig) used to counter attack allergies by cutting down the number of allergens in the body. IN essence, it slows down the reaction of the body to allergens that result to severe allergicasthma. In most cases, it is used in moderate or severe allergic asthma patients (Corren et al., 2011). It has passed its clinical trial and it now trades as Xolair.
Overview of Concept
In most cases, Omalizumab works by binding itself to immunoglobin (lg) E, an antibody that is involved in dealing with allergic reactions in the body and is approximately 149 kilodaltons in weight.Any allergic reaction will be characterized by an increase in the lgE production by the body (Humbert et al., 2011). In the end, the lgE therefore is prevented from attaching itself to other cells in the body that may cause allergic reactions. The attachment nature of Omalizumab helps to reduce the effect of responses to lgE without degranulation of the basophile that usually take place with the connection the lgE that is bound to the basophile.
Asthma Overview
Asthma has been a major disease for a long time thereby creating a heavy burden on numerous health care systems in the world.. Asthma is mainly characterized by atopy which has an etiologic role. It is estimated that about 60% of asthma cases and development are atopy related. Asthma is also believed to be causedby environmental and genetic factors.Pollution, chemicals and exposure to viruses as just examples of environmental factors that speed up asthma acquisition (Elvin et al., 2013). The chronic inflammation of the airwaves is what leads to contraction of the smooth muscles hence resulting to an asthmatic condition. People have different levels or stages of asthma, majorly moderate and severe or persistent asthma. The numbers of asthmatic patients have continued to increase due to these factors at an alarming rate. Some victims of asthma experience other health related diseases like anxiety disorders and gastro-esophageal reflux disease (GERD).
The Immunoglobulin E (IgE) is important to our body. They are the basic indicators of any allergic response by the body. EachlgE has a reaction to specific allergens introduced into the body. An allergic response by the lgEis characterized by production of inflammatory mediators like histamine. In most cases,lgEattaches to allergen s and cause the production of mediators from mast cells. A cascade of allergic reaction only starts to take place when lgE bind to the mast cells. Allergic cascade has three steps (Elvin et al., 2013). The first one being sensitization to an allergen where the body has been exposed for the first time. The second stage involves the stages that take place after the exposure. This may involve binding and cross linking of the lgE. The last stage involves severe symptoms of the reaction being seen.
Figure 1: Allergic cascade overview. (Shier, Butler,& Lewis, 2001)
Figure 2: Mechanism of Omalizumab interruption of allergic cascade(Shier, Butler,& Lewis, 2001)
Description of Omalizumab
Omalizumab is a type of antibody which is monoclonal in nature that can be identified through conventional hybridization techniques of somatic cells. MAE11, a marine monoclonal anti-human IgE, has been identified through this process. MAE11`s paratope happened to have been directed toward the binding site where Fc-epsilon-RI on mast cells and basophils. According to Oba et al. (2011), in a process that involved a form of transplantation of thecomplementarily-determining regions, MAE11 was humanized onto a human IgG1 antibody framework…" In order to achieve a properly maintained spatial arrangement of the CDR, there are additional MAE11 that had to be introduced into the antibody that is humanized. This process resulted in a humanized monoclonal antihuman IgE antibody, rhuMAb-E25 which contained approximately 5% nonhuman amino-acid residues. The rhuMAb-E25 adapted the name of Omalizumab later on.
Figure 3.Omalizumab is represented in this figure. The complementarily-determining regions are represented by the dark black areas of the portion Fab that has been transplanted from MAE11 (the murine monoclonal antibody) (Youssef et al., 2010)
2. Review of Study
a) Critical evaluation of the findings of the Study
Omalizumab is not cost effective to the average man especially to the patients who suffered from severe asthmatic conditions. Patients have to use up to $ 1, 300 per month in the medication process of treating asthma using Omalizumab. This includes laboratory testing, high drug costs, numerous hospitalization and frequent emergency departmental visits. Moreover, theconsequent use of Omalizumab has a number of side effects. Furthermore, not all patients respond positively with the use of the drug. A number of patients have experienced a severe, life threatening allergic reaction. Some cases were immediately after the injection whereas others were after a couple of hours. Bleeding, numbness, unusual swellings of the face throat or lips, breathing difficulties and skin rash are just a few side effects of Omalizumab (Djukanović et al, 2013). On the other hand, the administration of Omalizumab to patients may lead hypersensitivity reactions including life threatening anaphylaxis which occurs after any dose of the drug, hypotension, bronchospasm, urticaria and syncope. Use of the drug can lead to increased cardiovascular side effects. This can be in the form of pulmonary hypertension, failure of the cardiac muscles, ischemic heart diseases and cerebrovascular disorders. Other side effects include a 20% chance of respiratory tract infection, 16% chance of sinusitis infection and 11% chance of being infected by pharyngitis.
b) Discovery of Omalizumab-
Even though some sources that that the first discovery of lg E was in 1968 by Japan scientists, Teruko and Kimishige Ishizaka, it is evident that the first role of lgE was known in the early 1920s. It was discovered much later than the other immmunoglobin subclasses. It was in 1921 that scientists, Prausnitz and Kustner discovered the existence of a substance that that played a role in hypersensitivity reactions (Birch et al., 2012). It was years later, in 1968 that it was specifically identified as a subclass of immunoglobulin. After asserting that it was indeed an immunoglobin subclass, the World Health Organization (WHO) officially announced its presence. This antibody is a monomer in the immunoglobin structure with five domains. Furthermore, it contains the ε heavy chain. Its presence is majorly in the plasma and has a concentration of less than 1 µg/mL. Its half- life is only 2 days in the serum.
Figure 4: Structure of the lgE antibody.
IgE was discovered for its role in reactions that were as a result of allergies. When exposed to allergens, people develop certain symptoms thereby leading to the production oflgE that are specific to that type of allergen. This therefore evokes a reaction cascade. lgE evolved when people started to investigate about its main role in the human body. It was later found out that it major role is protection from parasitic infections. Moreover, its discovery led to the consequent analysis of its association with allergic diseases like asthma, food allergy, and allergic rhinitis.
Treatments of allergic diseases were done by molecular engineers. The different molecules which were bioengineered were involved in the pathogenesis of instantaneous allergic reactions.This led to a consequent production of therapies to counter the allergic reactions. An example of a treatment that was to counter the allergic reactions was the anti-adhesion molecules which was developed but was a failure.
The development of antibodies to heal allergic diseases experienced a lot of challenges like massive parasitic infections. Despite the challenge of humanization involved, the production of a humanized anti- lgE was made possible by the use of hybridoma methods. This was done by sampling animals for testing. Monkeys and mice were majorly used during this research. The animals were injected with human lgE and their B lymphocytes collected.
c) Production Processes
Genetic development- To begin with, there was a selection of a mouse monoclonal antibody. It was imperative to identify an antibody among a pool of hybridomas with desired characteristics on the lgE molecule. The key amino acids were replaced in the human lgG1 with those of the chosen antibody for humanization to be achieved. This was mainly in the regions that were complementary. The higher the affinity for free lgE and inability to bind to their cell receptor the better chance for selection. This was to make sure that the antibody was not in a position of binding with the lgE cell thereby preventing histamine release. The hosting of the antibody expression was by a parent line called Chinese Hamster Ovary (CHO).In addition, standard electroporation methods were used for transfection of the plasmid holding the antibody. On higher scale production, a better performing clone was chosen. They are also used to screen Omalizumab.
Cell banking- The cells used during the genetic makeup had to be preserved for future use. The Master Cell Bank (MCB) and Working Cell Bank (WCB) are usually prepared. Recombinant human insulin protein is used in these banks. Moreover, the banks are equipped with standard cryopreservation techniques (Pawankar et al., 2009). The MCB is used to generate Working Cell Banks (WCBs), which provide supply cells for manufacture, to continually produce the product in the future. Omalizumab protein uniqueness determine the greatest cell age.
Production- Production of Omalizumab is in a batch-fed suspension cell culture. During this process, cells are culture in three stages namely, Seed train stage(which provides a continuous cells source) , Inoculum train stage and Production stage(Pelaia, 2011).The seed train is initiated by thawing an ampoule from the Working Cell Bank (WCB). The expansion of the culture is under pressure in spinner vessels or bioreactors. The seed train is maintained by continuoussub cultivation. A portion of seed train cell number is used to provide inocula for the production cultures of theOmalizumab. In production stage, the cells are initiated by being transferred to the bioreactor that contains non- selective medium of serum.
Purification- This state is characterized by 3 consequential chromatographic steps. The first being affinity chromatography then followed by cation exchange chromatography. The last stage is anion exchange chromatography. The eluate is obtained from the last stage. The eluate is then concentrated through diafiltration and ultrafiltration before being formed in bulk.
d) Clinical Trials
Early Clinical Trials- Early trials majored on the ability of Omalizumab to soothe the asthmatic response to an inhaled aeroallergen difficulty. The evidence shows that the subjects who suffered the mild asthma that is stable who were tested showed a positive result to the prick test and to at least one aeroallergen which was followed by a response to another aeroallergen. challenge. Patients were selected at random and studied for 8- 10 weeks when they were under Omalizumab or placebo (Sullivan et al., 2009). On comparison to the recipients of placebo, it was revealed that each asthmatic response phase was reduced on the introduction of Omalizumab to the body during the period following aeroallergen challenge.
In the challenges involving methacholines, there were no responses observed and there is evidence of an expiratory forced within the first second(FEV1) in the absence of bronchodilator, symptoms, or aeroallergen challenge. Since the patients had already been put under control at the baseline, this was however expected. When the FEV1measurements had been carried out to almost 7 hours after the challenge it showed a distinct fall of the procedure that failed to achieve the exact results. May it be noted that at the end of this therapy the percentage of the eosinophils had come to a significant level that turned out to be lower in as much as the magnitude was not exactly different from the Omalizumab and the placebo recipients.
Trial`s on adolescents - Among patients who were adults and adolescents who were already allergic due to asthma, a second phase of study was conducted and provided an early large-scale. The number of patients selected for the study totaled to 320 and each had either moderate to severe cases of asthma that is persistent in nature. In this trial, the use of randomized placebo, with the implementation of a higher dozes of Omalizumab or alternatively a small doze of Omalizumab according to Pelaia (2001). As revealed in the study, the patients had to exude the characteristics of a skin prick test that is positive to either two or more FEV...