Targeting the IL4 receptor with MDNA55 in patients with recurrent glioblastoma: Results of a phase IIb trial.

BACKGROUND: MDNA55 is an interleukin 4 receptor (IL4R)-targeting toxin in development for recurrent GBM, a universally fatal disease. IL4R is overexpressed in GBM as well as cells of the tumor microenvironment. High expression of IL4R is associated with poor clinical outcomes. METHODS: MDNA55-05 is an open-label, single-arm phase IIb study of MDNA55 in recurrent GBM (rGBM) patients with an aggressive form of GBM (de novo GBM, IDH wild-type, and nonresectable at recurrence) on their 1st or 2nd recurrence. MDNA55 was administered intratumorally as a single dose treatment (dose range of 18 to 240 ug) using convection-enhanced delivery (CED) with up to 4 stereo-tactically placed catheters. It was co-infused with a contrast agent (Gd-DTPA, Magnevist®) to assess distribution in and around the tumor margins. The flow rate of each catheter did not exceed 10µL/min to ensure that the infusion duration did not exceed 48 h. The primary endpoint was mOS, with secondary endpoints determining the effects of IL4R status on mOS and PFS. RESULTS: MDNA55 showed an acceptable safety profile at doses up to 240 µg. In all evaluable patients (n = 44) mOS was 11.64 months (80% one-sided CI 8.62, 15.02) and OS-12 was 46%. A subgroup (n = 32) consisting of IL4R High and IL4R Low patients treated with high-dose MDNA55 (>180 ug) showed the best benefit with mOS of 15 months, OS-12 of 55%. Based on mRANO criteria, tumor control was observed in 81% (26/32), including those patients who exhibited pseudo-progression (15/26). CONCLUSIONS: MDNA55 demonstrated tumor control and promising survival and may benefit rGBM patients when treated at high-dose irrespective of IL4R expression level.Trial Registration: Clinicaltrials.gov NCT02858895.

Evaluation of adult patients with atopic dermatitis treated with dupilumab: A single-center real-life experience.

BACKGROUND: Adult atopic dermatitis (AD), especially adult-onset type appears to have different clinical manifestations. Dupilumab is an IL-4 receptor antagonist used in patients with moderate and severe atopic dermatitis, aged 12 years and older and it works by inhibiting the IL-4 and IL-13 signaling pathway. The purpose of our study is to retrospectively investigate the side effect profile and drug efficacy of thirteen adult patients who received dupilumab treatment and to evaluate the drug use status and the results during the COVID-19 pandemicour stuAdult atopic dermatitis (AD), especially adult-onset type appears to have different clinical manifestations. Dupilumab is an IL-4 receptor antagonist used in patients with moderate and severe atopic dermatitis, aged 12 years and older and it works by inhibiting the IL-4 and IL-13 signaling pathway. The purpose of our study is to retrospectively investigate the side effect profile and drug efficacy of thirteen adult patients who received dupilumab treatment and to evaluate the drug use status and the results during the COVID-19 pandemicAdult atopic dermatitis (AD), especially adult-onset type appears to have different clinical manifestations. Dupilumab is an IL-4 receptor antagonist used in patients with moderate and severe atopic dermatitis, aged 12 years and older and it works by inhibiting the IL-4 and IL-13 signaling pathway. The purpose of dy is to retrospectively investigate the side effect profile and drug efficacy of thirteen adult patients who received dupilumab treatment and to evaluate the drug use status and the results during the COVID-19 pandemicAdult atopic dermatitis (AD), especially adult-onset type appears to have different clinical manifestations. Dupilumab is an IL-4 receptor antagonist used in patients with moderate and severe atopic dermatitis, aged 12 years and older and it works by inhibiting the IL-4 and IL-13 signaling pathway. The purpose of our study is to retrospectively investigate the side effect profile and drug efficacy of thirteen adult patients who received dupilumab treatment and to evaluate the drug use status and the results during the COVID-19 pandemic. MATERIALS AND METHODS: Thirteen patients with clinical and/or histopathological diagnoses of atopic dermatitis who received dupilumab treatment and were subsequently followed up in Bezmialem Vakif University dermatology outpatient clinic between April 2019 and October 2021 were included in our study.Patient files were reviewed, and patients were interviewed in-person or by phone to learn about the COVID-19 contagion.Descriptive statistical analysis was performed with Microsoft Excel, and the data obtained were calculated as mean and percentage. RESULTS: All of our patients responded to the treatment after one course of dupilumab injection and also CRP and LDH levels decreased. Conjunctivitis side effect was found at a slightly higher rate than in previous clinical studies. The treatment was continued during the COVID-19 pandemic in most patients. Meanwhile, four patients had COVID-19 infection, but one of them was not using dupixent at that time. CONCLUSION: We can conclude that dupilumab is an effective and safe therapy for patients with severe AD also in cases of severe infections.

A novel reduced immunogenicity bispecific targeted toxin simultaneously recognizing human epidermal growth factor and interleukin-4 receptors in a mouse model of metastatic breast carcinoma.

PURPOSE: To develop a targeted biological drug that when systemically injected can penetrate to metastatic breast cancer tumors, one needs a drug of high potency and reduced immunogenicity. Thus, we bioengineered a novel bispecific ligand-directed toxin (BLT) targeted by dual high-affinity cytokines with a PE(38)KDEL COOH terminus. Our purpose was to reduce toxin immunogenicity using mutagenesis, measure the ability of mutated drug to elicit B-cell antitoxin antibody responses, and show that mutated drug was effective against systemic breast cancer in vivo. EXPERIMENTAL DESIGN: A new BLT was created in which both human epidermal growth factor (EGF) and interleukin 4 cytokines were cloned onto the same single-chain molecule with truncated Pseudomonas exotoxin (PE(38)). Site-specific mutagenesis was used to mutate amino acids in seven key epitopic toxin regions that dictate B-cell generation of neutralizing antitoxin antibodies. Bioassays were used to determine whether mutation reduced potency, and ELISA studies were done to determine whether antitoxin antibodies were reduced. Finally, a genetically altered luciferase xenograft model was used; this model could be imaged in real time to determine the effect on the systemic malignant human breast cancer MDA-MB-231. RESULTS: EGF4KDEL 7mut was significantly effective against established systemic human breast cancer and prevented metastatic spread. Mutagenesis reduced immunogenicity by approximately 90% with no apparent loss in in vitro or in vivo activity. CONCLUSIONS: Because EGF4KDEL 7mut was highly effective even when we waited 26 days to begin therapy and because immunogenicity was significantly reduced, we can now give multiple drug treatments for chemotherapy-refractory breast cancer in clinical trials.

Novel molecular therapy.

Anti-inflammatory treatment, mainly with inhaled corticosteroids, is the cornerstone of asthma therapy. There are a number of new more specific therapies based on a molecular approach. Despite some promising results from some novel molecular therapies there are also some studies which have shown no effect of these treatments.

Anti-interleukin-4 therapy.

Interleukin 4 (IL-4) mediates important pro-inflammatory functions in asthma, including T helper cell type 2 lymphocyte differentiation, induction of IgE production, up-regulation of IgE receptors, expression of vascular cell-adhesion molecule 1, promotion of eosinophil transmigration into the lungs, inhibition of T-lymphocyte apoptosis, and mucus hypersecretion. The role of IL-4 in the pathogenesis of asthma is supported by identification of polymorphisms linked to asthma in the IL-4 gene promoter and proteins involved in IL-4 signaling. Several approaches to IL-4 antagonism are or have been in clinical development. This article examines IL-4 and the antagonists that have been developed. Early trial results and the future of anti-IL-4 therapy are discussed.

Effect of IL-12 and soluble IL-4 receptor on the herpesvirus infection in human SCID chimeras whose Th2 cells predominate.

Th2 cytokines, commonly detected in burn patients, have been shown as inhibitors for the generation of Th1 cells that are essential for the host's resistance against herpes simplex virus type 1 (HSV-1) infection. In this study, the possibility of immunological treatment through the regulation of Th1/Th2 responses was examined in two kinds of human severe combined immunodeficiency (SCID) chimera models reflecting human immune functions. SCID mice injected with a mixture of PBMC from a healthy donor and Th2 cells experimentally generated from the same healthy PBMC (Th2 SCID chimeras) were more susceptible to HSV-1 infection when compared with SCID mice injected with healthy donor PBMC (healthy SCID chimeras). When Th2 SCID chimeras were individually treated with human IL-12 (hIL-12) or human soluble IL-4 receptor (hsIL-4R), hIFN-gamma was not produced in their sera after antihuman CD3 mAb stimulation. However, hIFN-gamma production in sera of Th2 SCID chimeras treated with the combination therapy of hIL-12 and hsIL-4R was recovered at levels observed in healthy SCID chimeras. When Th2 SCID chimeras infected with HSV-1 were treated with saline, hIL-12, hsIL-4R or a combination of hIL-12 and hsIL-4R, 13%, 13%, 25% or 100% of them survived, respectively. Also, Th1 responses (hIFN-gamma production) were demonstrated in Th2 SCID chimeras that became resistant against HSV-1 infection after the combination treatment. These results suggest that individuals whose Th2 cells predominated may be immunologically controlled by the combination treatment between a Th1 response inducer and a Th2 response inhibitor.

Soluble IL-4 receptor improves the skin-graft-associated cytomegalovirus infection in thermally injured mice.

The susceptibility of thermally injured mice (TI-mice) to murine cytomegalovirus (MCMV) infection is markedly influenced by burn-associated type 2 T cell responses, which are common with severe thermal injuries. In the present study, the effect of soluble IL-4 receptor (sIL-4R) on the skin-graft-associated MCMV infection was investigated. The marked growth of MCMV was demonstrated in the salivary glands of TI-mice grafted with MCMV seropositive [MCMV sero(+)] skin. However, the growth of MCMV was not demonstrated in the salivary glands of TI-mice grafted with MCMV sero(+) skin and treated with 50ng per mouse of sIL-4R. Compared with grafted normal mice, production of type 1 cytokines was markedly decreased when splenic T cells from TI-mice grafted with MCMV sero(+) skin were stimulated with anti-CD3 monoclonal antibody (mAb). The impaired type 1 cytokine production was recovered in cultures of splenic T cells from grafted TI-mice previously treated with sIL-4R. After grafting with MCMV sero(+) skin, the growth of MCMV was markedly inhibited in the salivary glands of severe combined immunodeficient (SCID) mice inoculated with T cells from TI-mice treated with sIL-4R. These results suggest that sIL-4R regulates the skin-graft-associated MCMV infection in TI-mice.

A combination therapy using IL-12 and soluble IL-4 receptor on herpes simplex virus Type 1 infection in a human-SCID chimera model of thermal injury.

Herpes simplex virus type 1 (HSV-1) is a severe pathogen in thermally injured patients. Type 1 T cells are essential for the host's anti-HSV protective immunity. Type 2 cytokines, commonly detected in thermally injured patients, have been described as inhibitors for the type 1 T cell generation. Therefore, the antiviral effects of combination therapy with a type 1 T cell inducer [interleukin (IL)-12] and a type 2 T cell inhibitor [soluble IL-4 receptor (sIL-4R)] were investigated in severe combined immunodeficiency (SCID) mice inoculated with peripheral blood lymphocytes (PBL) of thermally injured patients. Patient PBL-SCID chimeras (SCID mice inoculated with patient PBL) were susceptible to infection with 1 x 10(3) PFU/kg of HSV-1 (0% survival), while healthy PBL-SCID chimeras (SCID mice inoculated with PBL from healthy donors) were resistant (92% survival). When patient PBL-SCID chimeras exposed to HSV-1 were treated with saline, human recombinant (r) IL-12 or human sIL-4R, 0, 0, or 12.5% of them survived, respectively. However, 75% of these chimeras survived when they were treated with rIL-12 and sIL-4R in combination. These results indicate that HSV-1 infection in patient PBL-SCID chimeras was therapeutically controlled by the inducer of type 1 T cell responses and the inhibitor of type 2 T cell responses in combination.

Effect of a combination therapy between IL-12 and soluble IL-4 receptor (sIL-4R) on Candida albicans and herpes simplex virus type I infections in thermally injured mice.

The effectiveness of a combination using IL-12 and soluble IL-4 receptor (sIL-4R) to treat severe infections of herpes simplex virus type 1 (HSV-1) and Candida albicans in thermally injured mice was investigated. Although sIL-4R decreased burn-associated type 2 T-cell responses, the effect of sIL-4R was minimal on the morbidity and mortality of thermally injured mice exposed to 250 times LD50 of HSV-1 or 10 times LD50 of C. albicans. Compared with 100% mortality in control mice, mortality for HSV-1 and C. albicans was 40 and 20%, respectively, in thermally injured mice that received IL-12 and sIL-4R in combination. After stimulation with anti-CD3 monoclonal antibody, splenic T cells from thermally injured mice exposed to large amounts of HSV-1 or C. albicans did not produce gamma interferon (IFN-gamma) into their culture fluids. However, IFN-gamma was produced by splenic T cells from thermally injured and infected mice treated with IL-12 and sIL-4R in combination. These results suggest that therapeutic treatment with a combination of IL-12 and sIL-4R may be effective by inducing type 1 T-cell responses in thermally injured mice exposed to large amounts of HSV-1 or C. albicans.

The role of soluble interleukin-4 receptor and interleukin-5 antibody in preventing late-phase allergy-induced eustachian tube dysfunction.

OBJECTIVES: We investigated the role of soluble interleukin (IL)-4 receptors (sIL-4R) and IL-5 antibodies (IL-5Ab) in preventing allergic eustachian tube dysfunction (ETD) and middle ear effusion (MEE). STUDY DESIGN: Brown-Norway rats were sensitized to ovalbumin (OVA) and challenged transtympanically. Two groups of rats received either IL-4R or IL-5Ab transtympanically 1 hour before challenge. Three additional groups were used as controls. Following the second transtympanic challenge, the ventilatory and clearance functions of the eustachian tube (ET) were assessed at 0, 2, and 8 hours. Histology was prepared using cut paraffin sections stained with hematoxylin and eosin. RESULTS: sIL-4R-pretreated rats showed no significant changes in ventilatory or clearance functions of the ET or inflammatory changes in ET mucosa, whereas IL-5Ab pretreatment showed significant late ventilatory and clearance dysfunction as well as inflammatory mucosal changes. CONCLUSION: These data demonstrate that the late-phase allergic inflammatory response that leads to subsequent formation of ETD and MEE is prevented by pretreatment with sIL-4R and, more modestly, with IL-5Ab.

Th2 cytokines and asthma. Interleukin-4: its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists.

Interleukin-4 (IL-4) mediates important pro-inflammatory functions in asthma including induction of the IgE isotype switch, expression of vascular cell adhesion molecule-1 (VCAM-1), promotion of eosinophil transmigration across endothelium, mucus secretion, and differentiation of T helper type 2 lymphocytes leading to cytokine release. Asthma is a complex genetic disorder that has been linked to polymorphisms in the IL-4 gene promoter and proteins involved in IL-4 signaling. Soluble recombinant IL-4 receptor lacks transmembrane and cytoplasmic activating domains and can therefore sequester IL-4 without mediating cellular activation. We report the results of initial clinical trials, which demonstrate clinical efficacy of this naturally occurring IL-4 antagonist as a therapeutic agent in asthma.

Efficacy of soluble IL-4 receptor for the treatment of adults with asthma.

BACKGROUND: IL-4 mediates important proinflammatory functions in asthma, including induction of the IgE isotype switch, increased expression of vascular cell adhesion molecule 1 and promotion of eosinophil transmigration across the endothelium, stimulation of mucus production, and T(H)2 lymphocyte differentiation, leading to release of IL-4, IL-5, IL-9, and IL-13. OBJECTIVE: The current study evaluated the therapeutic potential of inhaled recombinant human soluble interleukin-4 receptor (IL-4R) as an IL-4 antagonist. METHODS: This study was a randomized, double-blind, placebo-controlled study in 62 subjects involving 12 once weekly nebulizations of 0.75, 1.5, or 3.0 mg of IL-4R or placebo. During screening, subjects documented dependence on inhaled corticosteroids by an exacerbation in asthma induced by one or two 50% dose reductions at 2-week intervals. After restabilization for 2 weeks on the dose above which their asthma flared, inhaled steroids were discontinued, patients were randomized, and study medication was started on day 0. RESULTS: IL-4R was well tolerated. Efficacy was demonstrated by a decline in FEV(1) observed in the placebo group (-0.4 L and -13% predicted), which did not occur in the group receiving 3.0 mg of IL-4R (-0.1 L and -2% predicted; P =.05 over the 3-month treatment period). Daily patient-measured morning FEV(1) also demonstrated a significant decline in the placebo group (-0.5 L and -18% predicted), which did not occur in the group receiving 3.0 mg of IL-4R (-0.1 L and -4% predicted; P =.02 over the 3-month treatment period). The efficacy of IL-4R was further confirmed by the absence of increase in asthma symptom scores in the group receiving 3.0 mg of IL-4R (Delta 0.1) compared with that seen in the placebo group (Delta 1.4 over 1 month; P =.07). Study discontinuation for asthma exacerbation was not significantly different between groups (placebo, 56%; 3.0 mg of IL-4R, 47%; P = not significant). CONCLUSION: These promising data suggest that IL-4R is safe and effective in the treatment of moderate persistent asthma.

New treatments for asthma: current and future aspects.

Inhaled beta 2-agonists continue to be the mainstay of asthma therapy, along with inhaled corticosteroids (ICS). A recent advance has been the recognition that 'add-on' or adjunctive therapies to ICS, such as long-acting beta 2-agonists and leukotriene antagonists, are a superior option to increased doses of ICS. Traditionally, inhaled beta 2-agonists and ICS have been administered via separate devices, but combined administration of a long-acting inhaled beta 2-agonist and an ICS by a single inhaler has recently become available in clinical practice. For the future, biotechnology is providing a number of potential therapies for asthma that are directed against some of the inflammatory mediators, such as immunoglobulin E and interleukin-4 and -5, thought to be involved in the pathophysiology of the disease. These biotechnological therapies may eventually provide the opportunity to tailor treatment to the needs of individual patients, and to manipulate the immune system away from allergic responses.

Citoquinas: la internet biológica ¿futura terapia en el asma bronquial? / Cytokines: the biological internet, the future therapy of bronchial asthma?

Las citoquinas son polipéptidos producidos por variadas células nucleadas que actúan como intercomunicadores celulares. Participan en funciones de defensa y reparación del adño del organismo y restablecimiento de la homeostasis. En los últimos años y gracias al desarrollo de la biología molecular, ha sido posible identificar y producir en el laboratorio numerosas citoquinas disponibles en el tratamiento de diversas enfermedades. En el asma bronquial existe un desbalance de algunas citoquinas con predominio de la producción de las interleuquinas (ILs) dependientes de los linfocitos tipo Th-2, como IL-4 e IL-5, las cuales inducen la producción de IgE y la eosinofilia, respectivamente. Actualmente están en marcha estudios clínicos tendientes a bloquear o impedir la acción de la IL-4 e IL-5 mediante anticuerpos monoclonales anti-IL o mediante la acción inhibidora sobre estas citoquinas que ejerce la IL-12. En esta revisión bibliográfica se analiza el estado actual de esta nueva futura terapia del asma

Allergy and asthma: classic TH2 diseases (?).

More than a decade of cytokine immunology has revealed a central role for pro-allergic TH2-like cytokines in the immune pathogenesis of allergic diseases and asthma. Of these, IL-4, IL-5, and IL-13 are produced mostly by T lymphocytes; more recently, numerous other immune cell types have been found capable of producing these cytokines as well, although their role in mediating atopic disease pathogenesis is less well understood. In contrast, the counterregulatory cytokine IFN-gamma can inhibit both the production and activities of the pro-allergic cytokines; therefore, central to the atopic diseases is a paradigm of cytokine imbalance, with overproduction of the TH2-like cytokines, and a relative deficiency of IFN-gamma production. Intriguing recent evidence is that all humans are TH2-like cytokine "skewed" at birth, due to maternal-fetal immune biology imperatives. However, further investigations suggest that IFN-gamma is likely to be pro-inflammatory in many if not most aspects of chronic allergic inflammation. Therefore, our understanding of these "classic TH2" diseases evolves, with important insights that will serve to optimize therapeutic strategies and investigations in the new millennium.

Host immune reactivity determines the efficacy of combination immunotherapy and antifungal chemotherapy in candidiasis.

In immunocompetent mice with candidiasis, successful therapy with amphotericin B and fluconazole relies on the induction of protective, T helper (Th) type 1 responses, an effect potentiated by concomitant interleukin (IL)-4 neutralization. To assess the therapeutic efficacy of combined treatments with antifungals and immunomodulators in conditions of immunosuppression, leukopenic or neutropenic mice with disseminated candidiasis were treated with amphotericin B or fluconazole alone or in combination with soluble IL-4 receptor (sIL-4R) or recombinant (r) IL-12 or IL-10 neutralizing monoclonal antibodies. We found that (1) the synergistic effect of sIL-4R and antifungals is retained in immunocompromised mice; (2) synergism with amphotericin B was superior to that with fluconazole, particularly in leukopenic mice; (3) rIL-12 synergized with fluconazole in neutropenic mice; and (4) IL-10 neutralization was always of limited efficacy. This study indicates that the therapeutic efficacy of antifungals is differentially potentiated by cytokines or cytokine antagonists and is influenced by host immune reactivity.

Soluble interleukin-4 receptor (sIL-4R) in allergic diseases.

The mediator interleukin-4 (IL-4) plays an important role in the development of allergic inflammatory responses. IL-4 controls the production of IgE, expands IL-4 producing T cell subsets and stabilises effector cells functions. Based on this concept, it was aimed to neutralize secreted IL-4 molecules using recombinant soluble IL-4 receptors. The molecular characterization of soluble IL-4 receptors allowed the design of a recombinant drug initially evaluated in cell culture, then in animal models, followed by investigations of T cell functions from allergic patients in vitro. Based on these data, phase I/II studies have been initiated to take this approach from bench to bedside. Initial data reveal that this approach is safe and without drug-related toxicity. Stabilization of lung functions in moderate asthma patients has been reported. These results have proven the concept for a central role of IL-4 in the immunopathogenesis of allergic diseases. The immediate future will reveal whether neutralization of IL-4 with suitable drugs will provide an additional tool in the management of allergic patients.