Development of a novel humanized anti-TSLP monoclonal antibody, QX008N, and exploration of combination therapy of anti-TSLP antibody and anti-IL-4R antibody.

BACKGROUND: Severe asthma is a complex and chronic respiratory disease, and current conventional treatments are not effective in controlling the patients' condition. Thymic stromal lymphopoietin (TSLP) is a key regulatory factor in the initiation and maintenance of asthma. Thus, blocking TSLP during allergic inflammation emerges as a promising therapeutic approach; however, novel anti-TSLP therapies remain to be developed. Furthermore, the importance of other signaling molecules, such as IL-4 and IL-13, should be considered. Moreover, to the best of our knowledge, the inhibitory effect of binding upstream and downstream signaling molecules has not been assessed. PURPOSE: This study aimed to develop a novel, humanized anti-TSLP antibody and explore the enhancement in its efficacy when combined with anti-IL-4R antibodies to treat asthma. RESULTS: QX008N, derived from a rabbit antibody platform, exhibits a high affinity for TSLP and superior efficacy in blocking TSLP-induced signaling pathways and inflammation in vitro compared with Tezepelumab. In a cynomolgus monkey asthma model, QX008N ameliorated lung function and reduced the levels of eosinophils and IgE. Moreover, the coadministration of QX008N with anti-IL-4R antibodies enhanced the inhibition of inflammatory mediator production triggered via costimulation in vitro. In mouse asthma models, the simultaneous blockade of TSLP and IL-4R using anti-TL4R and anti-TSLP surrogates surpassed the efficacy of monotherapy. To the best of our knowledge, the therapeutic effect of a combination of anti-TSLP and IL-4R antibodies in an asthma model has not yet been reported. CONCLUSION: These results furnish comprehensive preclinical evidence for QX008N as an innovative anti-TSLP therapeutic agent and provide a preliminary rationale for the development of combination therapies that simultaneously target the TSLP and IL-4R signaling pathways.

Spotlight on a Short-Time Treatment with the IL-4/IL-13 Receptor Blocker in Patients with CRSwNP: microRNAs Modulations and Preliminary Clinical Evidence.

Already used for the treatment of some allergic and inflammatory diseases, such as asthma or atopic dermatitis, dupilumab has also been approved as add-on therapy for patients with CRSwNP, and it could represent the keystone to reducing the remission time as well as to improve healing and quality of life. On the other hand, the role of miRNAs as potential biomarkers of immune modulation is emerging. We analyzed the effects of a short-time treatment with dupilumab in patients with CRSwNP, analyzing the immune response modification as well as miRNAs modulations. First, in this early observation stage, all patients experienced remarkable improvement and were clinically stable. Indeed, we observed a significant decrease in CD4+ T cells and a significant reduction in total IgE (p < 0.05) and serum IL-8 levels (p < 0.01), indicating a reduction in the general inflammatory condition. In addition, we analyzed a panel of about 200 circulating miRNAs. After treatment, we noted a significant downregulation of hsa-mir-25-3p (p-value = 0.02415) and hsa-mir-185-5p (p-value = 0.04547), two miRNAs involved in the proliferation, inflammation, and dug-resistance, in accordance with the clinical status of patients. All these preliminary data aimed to identify new biomarkers of prognosis, identifiable with non-invasive procedures for patients. Further, these patients are still under observation, and others with different levels of responsiveness to treatment need to be enrolled to increase the statistical data.

Efficacy and Safety of Itepekimab in Patients with Moderate-to-Severe Asthma.

BACKGROUND: Monoclonal antibodies targeting IgE, interleukin-4 and -13, and interleukin-5 are effective in treating severe type 2 asthma, but new targets are needed. Itepekimab is a new monoclonal antibody against the upstream alarmin interleukin-33. The efficacy and safety of itepekimab as monotherapy, as well as in combination with dupilumab, in patients with asthma are unclear. METHODS: In a phase 2 trial, we randomly assigned, in a 1:1:1:1 ratio, adults with moderate-to-severe asthma receiving inhaled glucocorticoids plus long-acting beta-agonists (LABAs) to receive subcutaneous itepekimab (at a dose of 300 mg), itepekimab plus dupilumab (both at 300 mg; combination therapy), dupilumab (300 mg), or placebo every 2 weeks for 12 weeks. After randomization, LABA was discontinued at week 4, and inhaled glucocorticoids were tapered over weeks 6 through 9. The primary end point was an event indicating a loss of asthma control, assessed in the itepekimab group and the combination group, as compared with the placebo group. Secondary and other end points included lung function, asthma control, quality of life, type 2 biomarkers, and safety. RESULTS: A total of 296 patients underwent randomization. By 12 weeks, an event indicating a loss of asthma control occurred in 22% of the patients in the itepekimab group, 27% of those in the combination group, and 19% of those in the dupilumab group, as compared with 41% of those in the placebo group; the corresponding odds ratios as compared with placebo were as follows: in the itepekimab group, 0.42 (95% confidence interval [CI], 0.20 to 0.88; P = 0.02); in the combination group, 0.52 (95% CI, 0.26 to 1.06; P = 0.07); and in the dupilumab group, 0.33 (95% CI, 0.15 to 0.70). As compared with placebo, the forced expiratory volume in 1 second before bronchodilator use increased with the itepekimab and dupilumab monotherapies but not with the combination therapy. Itepekimab treatment improved asthma control and quality of life, as compared with placebo, and led to a greater reduction in the mean blood eosinophil count. The incidence of adverse events was similar in all four trial groups. CONCLUSIONS: Interleukin-33 blockade with itepekimab led to a lower incidence of events indicating a loss of asthma control than placebo and improved lung function in patients with moderate-to-severe asthma. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03387852.).

Interleukin-4 Receptor Inhibition Targeting Metastasis Independent of Macrophages.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma occurring in children and carries a dismal prognosis when metastatic disease is detected. Our previous work has suggested the cytokine receptor IL4Rα may play a role in contributing to metastasis in the alveolar subtype of rhabdomyosarcoma (aRMS), and thus could present a therapeutic target. The IL4 signaling axis has been characterized in various adult cancers as well; however, pediatric trials often follow similar adult trials and the role of the IL4Rα receptor has not been explored in the context of a mediator of metastasis in adult disease. Here, we demonstrate that the impact of IL4Rα blockade in an orthotopic allograft model of aRMS is not mediated by a macrophage response. We further examine the effect of IL4 blockade in adult colon, breast, and prostate cancers and find that inhibition of IL4Rα signaling modulates in vitro cell viability of HCT-116 colon carcinoma cells; however, this finding did not translate to an autocrine-related in vivo difference in tumor burden or lung metastasis. Our results suggest that if humanized IL4 mouse host strains are not available (or not ideal due to the need for immunosuppressing the host innate immune response for xenograft systems), then genetically-engineered mice and mouse allograft studies may be the best indicator of therapeutic targeting efficacy.

A non-canonical type 2 immune response coordinates tuberculous granuloma formation and epithelialization.

The central pathogen-immune interface in tuberculosis is the granuloma, a complex host immune structure that dictates infection trajectory and physiology. Granuloma macrophages undergo a dramatic transition in which entire epithelial modules are induced and define granuloma architecture. In tuberculosis, relatively little is known about the host signals that trigger this transition. Using the zebrafish-Mycobacterium marinum model, we identify the basis of granuloma macrophage transformation. Single-cell RNA-sequencing analysis of zebrafish granulomas and analysis of Mycobacterium tuberculosis-infected macaques reveal that, even in the presence of robust type 1 immune responses, countervailing type 2 signals associate with macrophage epithelialization. We find that type 2 immune signaling, mediated via stat6, is absolutely required for epithelialization and granuloma formation. In mixed chimeras, stat6 acts cell autonomously within macrophages, where it is required for epithelioid transformation and incorporation into necrotic granulomas. These findings establish the signaling pathway that produces the hallmark structure of mycobacterial infection.

IL-13 antagonists in the treatment of atopic dermatitis.

Atopic dermatitis (AD) is a prevalent inflammatory skin disease. IL-13 contributes significantly to the pathogenesis of AD in several ways, and beneficial results have been demonstrated with anti-IL-13 therapies. Currently, the only monoclonal antibody (mAb) approved for AD treatment is dupilumab, an antagonist of the IL-4 receptor alpha (IL-4Rα) subunit common to IL-4 and IL-13 receptors, but clinical trials evaluating anti-IL-13 mAbs are providing promising results. The topics of this review will be mAbs targeting IL-13 for the treatment of AD such as dupilumab, tralokinumab and lebrikizumab, small molecules targeting the IL-13 pathway, and a brief explanation of therapies targeting IL-13 for the treatment of other skin diseases.

Dupilumab shows long-term effectiveness in a large cohort of treatment-refractory atopic dermatitis patients in daily practice: 52-Week results from the Dutch BioDay registry.

BACKGROUND: Real-life data on long-term effectiveness and safety of dupilumab in atopic dermatitis patients are limited. OBJECTIVE: To study 52-week effectiveness and safety of dupilumab in a prospective multicenter cohort of adult patients with treatment-refractory atopic dermatitis. METHODS: Patients treated with dupilumab and participating in the Dutch BioDay registry were included. Clinical effectiveness and safety were evaluated. RESULTS: Two hundred ten atopic dermatitis patients were included. Mean percentage change in Eczema Area and Severity Index score after 16 weeks was -70.0% (standard deviation 33.2%) and further decreased to -76.6% (standard deviation 30.6%) by week 52. A greater than or equal to 75% improvement in the score was achieved by 59.9% of individuals by week 16 and by 70.3% by week 52. The most reported adverse effect was conjunctivitis (34%). Limited patients (17; 8.1%) discontinued dupilumab treatment. LIMITATIONS: Because of the lack of a control group and observational design, factors of bias may have been induced. CONCLUSION: Treatment with dupilumab resulted in a rapid improvement in clinical outcome measures, and effectiveness further improved during the 52-week follow-up period.

IL-4 induces M2 macrophages to produce sustained analgesia via opioids.

IL-4 is a pleiotropic antiinflammatory cytokine, which can be neuroprotective after nervous system injury. The beneficial actions of IL-4 are thought to result from the blunting of action of inflammatory mediators, such as proinflammatory cytokines. Here, we demonstrate that IL-4 induces M2 macrophages to continuously produce opioid peptides and ameliorate pain. IL-4 application at injured nerves in mice shifted F4/80+ macrophages from the proinflammatory M1 to the antiinflammatory M2 phenotype, which synthesized opioid peptides (Met-enkephalin, ß-endorphin, and dynorphin A 1-17). These effects were accompanied by a long-lasting attenuation of neuropathy-induced mechanical hypersensitivity, beyond the IL-4 treatment. This IL-4-induced analgesia was decreased by opioid peptide antibodies and opioid receptor (δ, µ, κ) antagonists applied at injured nerves, which confirms the involvement of the local opioid system. The participation of M2 macrophages was supported by analgesia in recipient mice injected at injured nerves with F4/80+ macrophages from IL-4-treated donors. Together, IL-4-induced M2 macrophages at injured nerves produced opioid peptides, which activated peripheral opioid receptors to diminish pain. Fostering the opioid-mediated actions of intrinsic M2 macrophages may be a strategy to tackle pathological pain.

Anti-IL-4/IL-13 for the treatment of asthma: the story so far.

Introduction: Severe asthma is a global health concern with high morbidity and mortality. Understanding of its complex pathophysiology continues to increase, providing specific immune targets for therapeutic intervention.Areas covered: In this review, we focus on the role of IL-4 and IL-13 in severe asthma and on the biologic therapies developed to target them, particularly dupilumab, a monoclonal antibody against the IL-4 receptor α subunit and IL-4/IL-13 receptor complex. A literature search was undertaken for all studies of monoclonal antibodies against IL-4 and IL-13.Expert Opinion: Dupilumab decreases the rate of severe asthma exacerbations and improves symptoms, lung function, and quality of life. Importantly, these effects are also observed during reduction of maintenance oral corticosteroid doses. Those with the highest T2 biomarkers derive the greatest benefit and the presence of atopic dermatitis or chronic rhinosinusitis with or without nasal polyposis may recommend dupilumab as the preferred biologic treatment for a patient.

IL-4Rα Blockade by Dupilumab Decreases Staphylococcus aureus Colonization and Increases Microbial Diversity in Atopic Dermatitis.

Dupilumab is a fully human antibody to interleukin-4 receptor α that improves the signs and symptoms of moderate to severe atopic dermatitis (AD). To determine the effects of dupilumab on Staphylococcus aureus colonization and microbial diversity on the skin, bacterial DNA was analyzed from swabs collected from lesional and nonlesional skin in a double-blind, placebo-controlled study of 54 patients with moderate to severe AD randomized (1:1) and treated with either dupilumab (200 mg weekly) or placebo for 16 weeks. Microbial diversity and relative abundance of Staphylococcus were assessed by DNA sequencing of 16S ribosomal RNA, and absolute S. aureus abundance was measured by quantitative PCR. Before treatment, lesional skin had lower microbial diversity and higher overall abundance of S. aureus than nonlesional skin. During dupilumab treatment, microbial diversity increased and the abundance of S. aureus decreased. Pronounced changes were seen in nonlesional and lesional skin. Decreased S. aureus abundance during dupilumab treatment correlated with clinical improvement of AD and biomarkers of type 2 immunity. We conclude that clinical improvement of AD that is mediated by interleukin-4 receptor α inhibition and the subsequent suppression of type 2 inflammation is correlated with increased microbial diversity and reduced abundance of S. aureus.

Atopic Dermatitis: Collegium Internationale Allergologicum (CIA) Update 2019.

Atopic dermatitis (AD) is a chronic inflammatory skin disease presenting with recurrent eczematous lesions and intense pruritus. It is common and affects both children and adults, often beginning in infancy. Due to the unpredictable disease course, its visible skin lesions, itching and scratching followed by sleeplessness, other associated atopic diseases, and behavioral and psychiatric disorders, AD is an immense burden for patients and caregivers. AD is determined by a genetic predisposition characterized by an impaired skin barrier and a T-helper-2-predominant inflammation. Restoration of the skin barrier is the main approach for treating and preventing AD. In order to cope with acute flares, usually topical corticosteroids (TCS) are applied, while topical calcineurin inhibitors (TCI) are used mainly for maintenance therapy. There is a small group of patients who are refractory to TCS and TCI and require systemic immunosuppressive drugs such as ciclosporin. Novel, targeted therapies are under clinical investigation, among which an anti-IL-4/IL-13 receptor antibody has recently been approved in several countries. As we learn to understand the pathomechanisms of AD, the characteristics of the different patient subgroups, and the effectiveness of various targeted therapies, a personalized treatment ensuring the best efficacy and safety and, probably, a disease-modifying effect will result.

Characterization of cryptic allosteric site at IL-4Rα: New paradigm towards IL-4/IL-4R inhibition.

Interleukin-4(IL-4), an anti-inflammatory cytokine, plays significant role in pathogenesis of various diseases such as asthma, tumors, and HIV infections. These responses are mediated by expression of IL-4R (receptor) on various hematopoietic and non-hematopoietic cells surfaces. To date, the X-ray crystal structure of unbound (i.e. free) IL-4R is not reported which hampers active research on the molecular interaction mechanism between IL-4 and IL-4R. To investigate the missing gaps about stable binding mode of IL-4 and drug-ability of IL-4R active site, modelling and molecular dynamics (MD) simulation of IL-4/IL-4R complex was performed. Drug-ability of the target protein changed after modelling the loop region near C-terminal of IL-4R protein. This led to the identification of a novel druggable site other than the reported interfacial site. Our analysis showed that the modelled residues Ser111 and Ser164-Lys167 are part of newly discovered allosteric site, which underwent major fluctuation after association with its ligand protein (IL-4). The results indicated possible role of this cryptic allosteric site in IL-4/IL-4R signaling pathway that might help us to block IL-4/IL-4R association to prevent various allergic and malignant diseases.

Novel systemic drugs in treatment of atopic dermatitis: results from phase II and phase III studies published in 2017/2018.

PURPOSE OF REVIEW: The present review will give an update of recently published clinical studies on novel systemic treatment approaches in atopic dermatitis. RECENT FINDINGS: Until 2017 immunosuppressive drugs such as cyclosporine had to be used in atopic dermatitis when the disease could not sufficiently be treated with topical drugs. Several new substances specifically targeting inflammation in atopic dermatitis are currently studied. In 2017, dupilumab was approved in the United States and in Europe for first-line biologic treatment of moderate to severe atopic dermatitis in adults. The antibody blocks a subunit of the interleukin (IL)-4 and IL-13 receptor, thus inhibiting effects of two key cytokines in type 2 polarized inflammation. In addition to the studies on dupilumab recent clinical investigations on the effects on anti-IL-13 (lebrikizumab, tralokinumab), anti-IL-31 receptor (nemolizumab), anti-IL-22 (fezakinumab), and on small molecules targeting the histamine-4-receptor (ZPL389) and the Janus kinase inhibitor baricitinib have been published as full papers in the last 2 years. SUMMARY: A couple of promising novel therapeutical targets have recently been investigated and published in clinical trials on atopic dermatitis.

Therapeutic Targeting of the Interleukin-4/Interleukin-13 Signaling Pathway: In Allergy and Beyond.

Inflammation triggered by interleukin-4 (IL-4)/IL-13 is mediated by IL-4 and IL-13 receptors that are present on multiple cell types, including epithelial cells, smooth muscle, fibroblasts endothelial cells and immune cells. IL-4 exerts its activities by interacting with two specific cell surface receptors: one designated the type 1 IL-4 receptor (IL-4R); the other designated the type 2 IL-4R, a receptor complex that is also the functional receptor for IL-13. "Traditionally," IL-4 and IL-13 have been studied in the context of T helper 2-associated immune responses (i.e., type 2 immunity). In these settings, IL-4, IL-13 and their cognate receptor chains display pivotal roles where IL-4 is considered an instigator of type 2 immune responses and IL-13 an effector molecule. Thus, therapeutic targeting of the IL-4/IL-13 pathway is under extensive research, mainly for the treatment of allergic diseases. Nonetheless, in addition to IL-4's and IL-13's roles in type 2 immune responses, recent data highlight key activities for IL-4 and IL-13 in additional settings including metabolism, bone resorption, and even cognitive learning. This review summarizes the established knowledge that has accumulated regarding the roles of IL-4, IL-13, and their receptors in allergic diseases, with an emphasis on asthma, atopic dermatitis and eosinophilic esophagitis. Further, we provide an overview of the pharmacological entities targeting these cytokines and/or their receptors, which have been developed and clinically examined over the years. Finally, we will briefly highlight emerging evidence of potential new roles for IL-4 and IL-13 in other pathologies.

Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma.

BACKGROUND: Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. We assessed its efficacy and safety in patients with uncontrolled asthma. METHODS: We randomly assigned 1902 patients 12 years of age or older with uncontrolled asthma in a 2:2:1:1 ratio to receive add-on subcutaneous dupilumab at a dose of 200 or 300 mg every 2 weeks or matched-volume placebos for 52 weeks. The primary end points were the annualized rate of severe asthma exacerbations and the absolute change from baseline to week 12 in the forced expiratory volume in 1 second (FEV1) before bronchodilator use in the overall trial population. Secondary end points included the exacerbation rate and FEV1 in patients with a blood eosinophil count of 300 or more per cubic millimeter. Asthma control and dupilumab safety were also assessed. RESULTS: The annualized rate of severe asthma exacerbations was 0.46 (95% confidence interval [CI], 0.39 to 0.53) among patients assigned to 200 mg of dupilumab every 2 weeks and 0.87 (95% CI, 0.72 to 1.05) among those assigned to a matched placebo, for a 47.7% lower rate with dupilumab than with placebo (P<0.001); similar results were seen with the dupilumab dose of 300 mg every 2 weeks. At week 12, the FEV1 had increased by 0.32 liters in patients assigned to the lower dose of dupilumab (difference vs. matched placebo, 0.14 liters; P<0.001); similar results were seen with the higher dose. Among patients with a blood eosinophil count of 300 or more per cubic millimeter, the annualized rate of severe asthma exacerbations was 0.37 (95% CI, 0.29 to 0.48) among those receiving lower-dose dupilumab and 1.08 (95% CI, 0.85 to 1.38) among those receiving a matched placebo (65.8% lower rate with dupilumab than with placebo; 95% CI, 52.0 to 75.6); similar results were observed with the higher dose. Blood eosinophilia occurred after the start of the intervention in 52 patients (4.1%) who received dupilumab as compared with 4 patients (0.6%) who received placebo. CONCLUSIONS: In this trial, patients who received dupilumab had significantly lower rates of severe asthma exacerbation than those who received placebo, as well as better lung function and asthma control. Greater benefits were seen in patients with higher baseline levels of eosinophils. Hypereosinophilia was observed in some patients. (Funded by Sanofi and Regeneron Pharmaceuticals; LIBERTY ASTHMA QUEST ClinicalTrials.gov number, NCT02414854 .).

Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma.

BACKGROUND: Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. Its effectiveness in reducing oral glucocorticoid use in patients with severe asthma while maintaining asthma control is unknown. METHODS: We randomly assigned 210 patients with oral glucocorticoid-treated asthma to receive add-on dupilumab (at a dose of 300 mg) or placebo every 2 weeks for 24 weeks. After a glucocorticoid dose-adjustment period before randomization, glucocorticoid doses were adjusted in a downward trend from week 4 to week 20 and then maintained at a stable dose for 4 weeks. The primary end point was the percentage reduction in the glucocorticoid dose at week 24. Key secondary end points were the proportion of patients at week 24 with a reduction of at least 50% in the glucocorticoid dose and the proportion of patients with a reduction to a glucocorticoid dose of less than 5 mg per day. Severe exacerbation rates and the forced expiratory volume in 1 second (FEV1) before bronchodilator use were also assessed. RESULTS: The percentage change in the glucocorticoid dose was -70.1% in the dupilumab group, as compared with -41.9% in the placebo group (P<0.001); 80% versus 50% of the patients had a dose reduction of at least 50%, 69% versus 33% had a dose reduction to less than 5 mg per day, and 48% versus 25% completely discontinued oral glucocorticoid use. Despite reductions in the glucocorticoid dose, in the overall population, dupilumab treatment resulted in a severe exacerbation rate that was 59% (95% confidence interval [CI], 37 to 74) lower than that in the placebo group and resulted in an FEV1 that was 0.22 liters (95% CI, 0.09 to 0.34) higher. Injection-site reactions were more common with dupilumab than with placebo (9% vs. 4%). Transient blood eosinophilia was observed in more patients in the dupilumab group than in the placebo group (14% vs. 1%). CONCLUSIONS: In patients with glucocorticoid-dependent severe asthma, dupilumab treatment reduced oral glucocorticoid use while decreasing the rate of severe exacerbations and increasing the FEV1. Transient eosinophilia was observed in approximately 1 in 7 dupilumab-treated patients. (Funded by Sanofi and Regeneron Pharmaceuticals; LIBERTY ASTHMA VENTURE ClinicalTrials.gov number, NCT02528214 .).

Targeting the interleukin-4 and interleukin-13 pathways in severe asthma: current knowledge and future needs.

PURPOSE OF REVIEW: Severe asthma is a heterogeneous disease that can be classified into phenotypes and endotypes based upon clinical or biological characteristics. Interleukin (IL)-4 and IL-13 play a key role in type 2 (T2) asthma. This article reviews the signaling pathway of IL-4 and IL-13 and highlights its targeted therapy in severe asthma. RECENT FINDINGS: Several clinical trials of biologics targeting the IL-4/IL-13 pathway have recently been completed. In patients with severe, uncontrolled asthma, targeting IL-13 alone with biologics including lebrikizumab and tralokinumab has not shown consistent reduction in asthma exacerbations. Simultaneous targeting of both IL-4 and IL-13 by blocking IL-4 receptor α using dupilumab has yielded more consistent results in reducing asthma exacerbations and improving lung function, especially in patients with increased blood eosinophils. Other biomarkers of T2 inflammation such as exhaled nitric oxide and serum periostin may also predict response to biologics targeting the IL-4/IL-13 pathway. SUMMARY: No biologic targeting the IL-4/IL-13 pathway is currently available for treatment of asthma, but emerging data suggest that biologics targeting IL-4 and IL-13 together may benefit patients with T2 high asthma. Additional data are needed about long-term efficacy and safety prior to incorporating these drugs into routine clinical practice.

Interleukin-4 receptor signaling and its binding mechanism: A therapeutic insight from inhibitors tool box.

Studies on Interlukin-4 (IL-4) disclosed great deal of information about its various physiological and pathological roles. All these roles depend upon its interaction and signaling through either type-I (IL-4Rα/common γ-chain) or type-II (IL-4Rα/IL-13Rα) receptors. Another cytokine, IL-13, shares some of the functions of IL-4, because both cytokines use a common receptor subunit, IL-4Rα. Here in this review, we discuss the structural details of IL-4 and IL-4Rα subunit and the structural similarities between IL-4 and IL-13. We also describe detailed chemistry of type-I and type-II receptor complexes and their signaling pathways. Furthermore, we elaborate the strength of type-II hetero dimer signals in response to IL-4 and IL-13. These cytokines are prime players in pathogenesis of allergic asthma, allergic hypersensitivity, different cancers, and HIV infection. Recent advances in the structural and binding chemistry of these cytokines various types of inhibitors were designed to block the interaction of IL-4 and IL-13 with their receptor, including several IL-4 mutant analogs and IL-4 antagonistic antibodies. Moreover, different targeted immunotoxins, which is a fusion of cytokine protein with a toxin or suicidal gene, are the new class of inhibitors to prevent cancer progression. In addition few small molecular inhibitors such as flavonoids have also been developed which are capable of binding with high affinity to IL-4Rα and, therefore, can be very effective in blocking IL-4-mediated responses.