Immunoglobulin E (IgE)

As mentioned above, IgE plays an important role in the asthma inflammatory response pathway, especially for the onset of allergic asthma.

In 2003, Novartis' IgE antibody, omalizumab (trade name Xolair) entered the market as the first antibody drug against asthma, marking the official entry of asthma treatment into the era of antibodies. Omalizumab inhibits the activation of immune cells by neutralizing IgE, reducing the efficiency of T cell antigen presentation, thereby overall reducing the immune response of asthma patients.

The indications for omalizumab are adults and adolescents (over 12 years old) with moderate to severe persistent asthma, and use of inhaled corticosteroids (ICS) cannot be improved, used as an additional drug. Clinical trials have shown that as a high-dose ICS add-on drug, it can significantly reduce the deterioration rate of patients, especially seasonal allergic asthma, and can improve the patient's lung function.

So far, omalizumab has accumulated 500,000 cases worldwide and maintains a good safety and effectiveness record. Since omalizumab is already in its patent sunset, Novartis and other companies are also stepping up the development of new IgE antibodies.

Interleukin 5 (IL-5)

IL-5 can promote the differentiation and maturation of eosinophils, and plays a key role in the pathogenesis of eosinophilic asthma. Therefore, IL-5 has always been the star target of asthma treatment. It is resistant to the treatment of intractability and glucocorticoids. The application of asthma is given high hopes.

At present, two drugs against IL-5 have been approved, namely the GSK mepolizumab (trade name Nucala) approved in 2015, and the 2016 approved Reslizumab (trade name Cinqair) of Teva. Mepolizumab is approved for use in adults and adolescents (over 12 years of age), and reslizumab is only approved for use in adult patients.
Taking the clinical trial of mepolizumab as an example, in patients with eosinophilic asthma (eosinophil count greater than 300 / microliter), mepolizumab significantly reduced the amount of patient's deterioration rate and oral glucocorticoids, and the higher the eosinophil count before the patient is enrolled, the more obvious the effect.

IL-5 acts in conjunction with its receptor, so antibodies against IL-5 receptor (IL-5R) are also used to treat asthma.

Interleukin 4 and 13 (IL-4 / IL-13)

IL-4 and IL-13 are two important cytokines in the pathogenesis of asthma. They can induce B cells to produce more IgE, which promotes increased secretion of respiratory mucus, bronchial fibrosis, and respiratory hypersensitivity. IL-4 and IL-13 have a certain degree of similarity in protein structure, and they can both stimulate downstream molecular pathways by combining the complex formed by IL-4α receptor and IL-13α receptor.
There are currently two phase III clinical trials of antibody drugs against IL-13, but the efficacy has not been fully confirmed.

Lebrikizumab, developed by Roche, has conducted two parallel clinical phase III trials: LAVOLTA1 and LAVOLTA2, but the results of the two trials are not the same. The LAVOLTA1 trial showed that lebrikizumab significantly reduced the exacerbation rate of asthma patients, but the LAVOTA2 trial did not achieve the same effect. Since then, Roche has licensed lebrikizumab to Dermira, which plans to develop it as an atopic dermatitis drug.

AstraZeneca's IL-13 monoclonal antibody tralokinumab also failed to reach its primary endpoint in one of the phase III clinical trials. Pfizer's IL-13 monoclonal antibody anrukinzumab has already undergone a phase II clinical trial in asthma patients, but it has silently disappeared from Pfizer's research and development pipeline. Therefore, the effectiveness of IL-13 antibody in the treatment of asthma needs more accurate clinical trial results to support.

The IL-4 receptor (IL-4R) monoclonal antibody has achieved good results in clinical trials of asthma. In September 2017, Sanofi's IL-4Rα monoclonal antibody dupilumab significantly reduced the patient's deterioration rate and significantly improved the patient's lung function in its uncontrolled persistent asthma phase III clinical trial. In addition, bispecific antibodies that can simultaneously bind IL-4 and IL-13 have also entered early clinical trials.

Other asthma antibody targets

Other molecules in the immune response of asthma also have great potential as therapeutic targets.

This includes targeting inflammatory cytokines of type 2: IL-6, IL-9, IL-17, IL-23, IL-33, OX40 ligand (OX40L) and GM-CSF (granulocyte-macrophage colony stimulating factor, Gramulocyte-macrophase colony-stimulating factor);

Antibodies against cytokine receptors: IL-2Rα, IL-17Rα, and IL-33R.

Some of these monoclonal antibodies have been approved for the treatment of other diseases, such as daclizumab (IL-2Rα monoclonal antibody) has been approved for the treatment of multiple sclerosis (MS), secukinumab (IL-17 monoclonal antibody) and brodalumab (IL-17Rα Monoclonal antibody) is approved for the treatment of moderate to severe plaque psoriasis. These drugs are also undergoing clinical trials for asthma treatment.

Biomarkers: the key to personalized diagnosis and treatment

The treatment and management of severe and uncontrollable asthma has always been challenging, and patients often have great heterogeneity, and the difference between individuals is very large, so personalized treatment combining biomarkers and antibody drugs is imperative.
Currently, commonly used biomarkers for clinical trials include: serum IgE level, fractional exhaled nitric oxide (FeNO), sputum cell count, blood cell count (especially eosinophil count), serum periostein level etc.

In most cases, we need at least two biomarkers to confirm the type of asthma and use appropriate antibody drugs.

Summary

The emergence of antibody drugs partially solves the embarrassment that the drug guidelines are helpless for severe uncontrollable asthma, because antibody drugs can directly regulate the immunity that induces asthma. The types of antibodies currently approved for the treatment of asthma are mainly IgE monoclonal antibodies, IL-5 monoclonal antibodies and IL-5R monoclonal antibodies.

The efficacy of antibody drugs has become increasingly prominent. IgE monoclonal antibodies and IL-5 monoclonal antibodies have been included in the GINA guidelines. As an additional therapy for severe and uncontrollable asthma patients, their market will surely expand further. Of course, the development of some of these targets is relatively bumpy, such as IL-4 / IL-13 antibodies, which have silently disappeared in the research and development pipelines of large companies.

US FDA experts also gave advice on the treatment of asthma with IL-6 antibody (sirukumab) because of concerns about the increased risk of upper respiratory tract infections. On the other hand, some antibodies, such as IL-17 monoclonal antibody and IL-2Rα monoclonal antibody, have been approved for the treatment of other diseases. If they are successful in clinical trials of asthma, their approval will be faster.

We should also note that the current successful antibody drugs are only effective for eosinophilic asthma (mostly type 2 inflammation), and patients need to meet certain biological indicators (such as eosinophil count in the blood greater than 300 per microliter).

For those patients with severe asthma that are not eosinophils, there is no good antibody target. In addition, how to adjust the immune system without increasing the risk of deterioration caused by upper respiratory tract infection is also a problem that needs to be solved in the research and development process.
What is certain is that while the battlefield of cancer antibody drugs is in full swing, the flames of competition in the field of asthma will also become more and more prosperous, and it will become an indispensable place for respiratory medicine.

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