By Dr. Larry Chiaramonte
The sophistication of the immune system makes the Pentagon look like amateurs. Like the military, it isn’t infallible. At times, as with allergy and autoimmune diseases, there is collateral damage where the system affects our bodies adversely. As an allergist, for many years, I have tried to mitigate the damage using the tools at hand—antihistamines, steroids, immunotherapy. But all the while I have known that if the immune system is more intricate and wondrous than we understood, so the malfunctions were beyond the therapies we had available to deal with them. Now, however, we know much more about the immune system than we ever did before, and we are beginning to see corresponding therapies. It’s a very exciting time.
The most important factor in manipulating the system for our benefit is to manage the communication and control. The first one of any consequence was omalizumab [Xolair] which blocks the attachment of IgE to the mast cell is the only biological therapy available to treat asthma at present. It is a “monoclonal antibody”. It binds to allergic IgE antibodies in a way that makes them unable to attach to high-affinity receptors on mast cells and basophils. They become fuses that cannot be mounted on bombs and are eliminated from the blood rapidly. More of these “mAbs”* to immune communicators are in the pipeline.
As we learned a long time ago, IgE was not the magic bullet for diagnosing allergies and we have also learned that anti-IgE is not the magic bullet for treating them. So we have had to look at other mechanisms. We have discovered is a class of cytokines (proteins) called Interleukins. These act as the chemical communicators between the cells of the immune system. They are a large group (IL-1 to IL-35) produced mainly by Leukocytes. Monoclonal antibodies to block the effects of three big ones [IL-4, IL-5 and IL-13] have recently been produced and used in the treatment of asthma and atopic disease.
Interleukin-5 [IL-5] effects eosinophil growth and differentiation, migration, activation, effector function, and survival. Eosinophils are the effector cell in allergic inflammation that produces cellular death. IL-5 results largely from a Th2-type [allergic IgE} lymphocyte response.
There are three new monoclonal antibodies to block the effects of interleukin IL-5 They are:
Mepolizumab Anti IL-5 made by GlaxoSmithKline administered subcutaneously at the dose of 100 mg once every 4 weeks.
Reslizumab Anti IL5 made by Teva dose 0.3 mg/kg-0.3 mg/kg, administered intravenously (iv) once every 4 weeks, for a total of 4 doses.
Benralizumab anti-IL-5 receptor made by AstraZeneca.
Interleukin 4 (IL4) induces differentiation of naive helper T cells (Th0 cells) to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4 in a positive feedback loop.
IL-4 induces B-cell class switching to IgE, decreases the production of Th1 cells, IFN-gamma (which readers of Henry’s book on Dr. Xiu-Min Li will recognize as something that rises when patients achieve tolerance to their allergens). Overproduction of IL-4 is associated with allergies. Along with other Th2 cytokines, it is involved in the airway inflammation observed in the lungs of patients with allergic asthma.
Interleukin-13, [IL-13] induces changes in parasitized organs that are required to expel the offending organisms or their products. and also induces many features of allergic lung disease (IL-4 contributes to these physiological changes, but is less important than IL-13).
There are three new monoclonal antibodies to block the effects of interleukins IL-4 and/or Il-13. They are:
Lebriizumab Anti-IL-13, made by Genentech–high pretreatment levels of serum periostin best.
Dupilumab Made by Sanofi, this antibody blocks signaling of shared IL-4 receptors with IL13.
Tralokinumab Blocks IL-13 [mostly] made by MedImmune. an arm of AstraZeneca.
Six new agents are in the pipeline, but which one is best for what patient? Finding out is easier said than done. In general, FDA-approved mAbs have emerged between 10 and 12 years after the date that the new technologies on which they were based were reported in the scientific literature. At least when they age whiskey that long the distillers know how it will taste and more or less how people will use it. Which one will get approved first? What will be the route, dose, frequency, length, and cost? What will the side effects, good and bad be as it reaches a wider population? Good side effects are called off-label uses. Bad ones end up as black box warnings.
New Biomarker for Asthma
Asthma is a heterogeneous disease with multiple, overlapping phenotypes. More of these observed differences seem to emerge all the time. One of the longstanding phenotypes is called eosinophilic asthma, after the white blood cell that accumulates in the lungs as it does at other sites which are subject to chronic inflammation. The eosinophil is the marker for classic allergic asthma, which responds to the go-to treatment inhaled corticosteroids, or ICS. But it’s a hard thing to study. Getting a sputum eosinophil sample is obnoxious, especially for children. So plenty of patients who have asthma symptoms but who have something called neutrophil-dominant asthma that doesn’t respond to steroids will get ICS anyway. One biomarker measures the exhaled nitric oxide, an inflammation byproduct, in expelled breath, but we need more in order to better characterize the disease phenotypes and to identify the responders to specific targeted therapies.
One promising example is periostin, which can be found in the blood. This is an extracellular matrix protein that is induced by interleukin IL-4 and IL-13 in airway epithelial cells and lung fibroblasts.
Periostin has proven to be an important biomarker of TH2-associated airway inflammation and a potential predictor of airway eosinophilia. If we can predict response to treatment with inhaled corticosteroids accurately using this marker, we can eliminate their use among people who will not benefit from them and focus on therapies for them. Furthermore, recent asthma clinical trials have established that serum periostin may have value in predicting the response to targeted therapy with biologic agents such as lebrikizumab and omalizumab.
My great hope is that in years to come, my younger colleagues will achieve much greater rates of relief for their patients than we have done in the past. These new technologies are really exciting. Unfortunately, there are many caveats. One is that doctors in practice are not always quick to adopt new treatments that they didn’t learn about in their fellowships. Another is cost. Xolair is hugely expensive. Will other mAbs follow that path? Will they only be available in the form of sometimes painful shots and like Xolair result in allergic reactions of their own? Will doctors punt their administration to infusion centers, which can get away with charging the insurance companies much more than individual practitioners can get for the same treatment?
Get out your crystal ball.
*[Standard nomenclature for mAbs identifies their source with the last 4 or 5 letters: -omab, murine: -ximab, chimeric: -zumab, humanized: and –umab, human. The middle part of the name reflects the disease indication for which the mAb was initially]
IL-5 from Wikipedia