Targeting the Interleukin-5 Pathway for Treatment of Eosinophilic Conditions Other than Asthma

Roufosse, Florence

doi:10.3389/fmed.2018.00049

Cited by 152 publications

(125 citation statements)

References 114 publications

(192 reference statements)

Supporting

Mentioning

118

Contrasting

Unclassified

Order By: Relevance

“…In fact, Siltuximab was associated with increased tumor cell proliferation in prostate cancer, despite STAT3 dysregulation being frequently observed [132,200]. A repurposing of agents, such as mepolizumab and benralizumab, being used to block IL-5 signaling in asthma, is also on the rise [2,201]. However, the downfall of targeting or administering cytokines directly is that treatment often comes with significant toxicity [202].…”

Section: Cytokine Receptor Targetingmentioning

confidence: 99%

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

Owen

Brockwell

Parker

2019

Cancers

432

326

View full text Add to dashboard Cite

Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates almost all immune regulatory processes, including those that are involved in tumor cell recognition and tumor-driven immune escape. Antitumor immune responses are largely driven by STAT1 and STAT2 induction of type I and II interferons (IFNs) and the downstream programs IFNs potentiate. Conversely, STAT3 has been widely linked to cancer cell survival, immunosuppression, and sustained inflammation in the tumor microenvironment. The discovery of JAK-STAT cross-regulatory mechanisms, post-translational control, and non-canonical signal transduction has added a new level of complexity to JAK-STAT governance over tumor initiation and progression. Endeavors to better understand the vast effects of JAK-STAT signaling on antitumor immunity have unearthed a wide range of targets, including oncogenes, miRNAs, and other co-regulatory factors, which direct specific phenotypical outcomes subsequent to JAK-STAT stimulation. Yet, the rapidly expanding field of therapeutic developments aimed to resolve JAK-STAT aberrations commonly reported in a multitude of cancers has been marred by off-target effects. Here, we discuss JAK-STAT biology in the context of immunity and cancer, the consequences of pathway perturbations and current therapeutic interventions, to provide insight and consideration for future targeting innovations.2 of 26 role in pathogenesis [3]. Yet, despite the seemingly linear order of events, the impact of mutations, selective dimerization, negative pathway regulation, and post-translational modifications of pathway members has branded the JAK-STAT axis a complex signaling cascade, of which many regulatory processes are still poorly understood.STATs have emerged as somewhat of a double-edged sword, being widely explored in the context of cancer. While several members of the STAT family, which encompasses STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6 as a whole, have been linked to tumor initiation and progression (STAT3 and STAT5), others are integral in antitumor defense and the maintenance of an effective and long-term immune response (STAT1 and STAT2) through evolutionarily conserved programs [1]. With increasing emphasis on immune-based agents as important therapeutics in the fight against solid tumor growth and spread, understanding the function of STAT specificity, redundancy, and connectedness in cancer is a critical component of achieving immunotherapeutic augmentation and success.Here, we investigate the good and the bad of STAT signaling in the context of immune regulation and cancer, and discuss how STATs can be targeted to bolster antitumor immune defense. JAK-STAT Signaling and InterferonsThe presence of stimulatory or inhibitory signals governs the innate and adaptive immune activity that controls both effective immune surveillance and facilitates escape. Such signals determine the fate of plastic immune cells, such as T lymphocytes, and regulate their recruitment, survival, status, and eventual death ...

show abstract

Section: Cytokine Receptor Targetingmentioning

confidence: 99%

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

Owen

Brockwell

Parker

2019

Cancers

432

326

View full text Add to dashboard Cite

show abstract

“…IL-5 exerts its effects on proliferation, differentiation, and maturation via receptors that comprise an IL-5-specific α-and common β-subunit [19]. The IL-5 receptor α (IL-5Rα) chain is highly expressed in human eosinophils and, to a lesser extent, by basophils and mast cells [20]. IL-5 contributes in supporting the growth and protection of parasites [37].…”

Section: Introductionmentioning

confidence: 99%

“…Benralizumab has been explored for the treatment of diseases other than asthma with prominent tissue eosinophilia, including hypereosinophilic syndromes (HES) and chronic obstructive pulmonary disease (COPD). HES are rare and often debilitating chronic inflammatory disorders characterized by blood and tissue eosinophilia, with associated eosinophil-mediated organ damage and/or dysfunction [20]. In a phase II trial, benralizumab reduced absolute eosinophil counts compared with placebo for patients with platelet-derived growth factor receptor A (PDGFRA)-negative HES [29].…”

mentioning

confidence: 99%

Safety of Eosinophil-Depleting Therapy for Severe, Eosinophilic Asthma: Focus on Benralizumab

Jackson

Korn²,

Mathur

et al. 2020

Drug Saf

View full text Add to dashboard Cite

Eosinophils play a pivotal role in the inflammatory pathology of asthma and have been the target of new biologic treatments for patients with eosinophilic asthma. Given the central role of interleukin (IL)-5 in the eosinophil lifecycle, several therapies directed against the IL-5 pathway have been developed, including the anti-IL-5 antibodies mepolizumab and reslizumab and the IL-5 receptor α (IL-5Rα)-directed cytolytic antibody benralizumab. Eosinophil-depleting therapies represent a relatively new class of asthma treatment, and it is important to understand their long-term efficacy and safety. Eosinophils have been associated with host protection and tumor growth, raising potential concerns about the consequences of long-term therapies that deplete eosinophils. However, evidence for these associations in humans is conflicting and largely indirect or based on mouse models. Substantial prospective clinical trial and postmarketing data have accrued, providing insight into the potential risks associated with eosinophil depletion. In this review, we explore the current safety profile of eosinophil-reducing therapies, with particular attention to the potential risks of malignancies and severe infections and a focus on benralizumab. Benralizumab is an IL-5Rα-directed cytolytic monoclonal antibody that targets and efficiently depletes blood and tissue eosinophils through antibody-dependent cell-mediated cytotoxicity. Benralizumab is intended to treat patients with severe, uncontrolled asthma with eosinophilic inflammation.

show abstract

“…Three monoclonal antibodies, two blocking IL‐5 directly (Reslizumab and Mepolizumab), and one blocking the IL‐5Rα (Benralizumab) received market authorization over the past two years. All IL‐5 pathway interfering antibodies and in particular both anti‐IL‐5 antibodies have a very good safety profile collected over the past 10 years of clinical testing and use …”

Section: Introductionmentioning

confidence: 99%

Active vaccination against interleukin‐5 as long‐term treatment for insect‐bite hypersensitivity in horses

Fettelschoss‐Gabriel

Fettelschoss

Olomski

et al. 2018

Allergy

View full text Add to dashboard Cite

Background Insect‐bite hypersensitivity ( IBH ) in horses is a chronic allergic dermatitis caused by insect bites. Horses suffer from pruritic skin lesions, caused by type‐I/type‐ IV allergic reactions accompanied by prominent eosinophil infiltration into the skin. Interleukin‐5 ( IL ‐5) is the key cytokine for eosinophils and we have previously shown that targeting IL ‐5 by vaccination reduces disease symptoms in horses. Objective Here, we analyzed the potential for long‐term therapy by assessing a second follow‐up year of the previously published study. Methods The vaccine consisted of equine IL ‐5 ( eIL ‐5) covalently linked to a cucumber mosaic virus‐like particle ( VLP ) containing a universal T cell epitope (Cu MV TT ) using a semi‐crossover design to follow vaccinated horses during a second treatment season. Thirty Icelandic horses were immunized with 300 μg of eIL ‐5‐Cu MV TT without adjuvant. Results The vaccine was well tolerated and did not reveal any safety concerns throughout the study. Upon vaccination, all horses developed reversible anti‐ eIL ‐5 auto‐antibody titers. The mean course of eosinophil levels was reduced compared to placebo treatment leading to significant reduction of clinical lesion scores. Horses in their second vaccination year showed a more pronounced improvement of disease symptoms when compared to first treatment year, most likely due to more stable antibody titers induced by a single booster injection. Hence, responses could be maintained over two seasons and the horses remained protected against disease symptoms. Conclusion Yearly vaccination against IL ‐5 may be a long‐term solution for the treatment of IBH and other eosinophil‐mediated diseases in horses and other species including humans.

show abstract

Targeting the Interleukin-5 Pathway for Treatment of Eosinophilic Conditions Other than Asthma

Cited by 152 publications

References 114 publications

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

Safety of Eosinophil-Depleting Therapy for Severe, Eosinophilic Asthma: Focus on Benralizumab

Active vaccination against interleukin‐5 as long‐term treatment for insect‐bite hypersensitivity in horses

Contact Info

Product

Resources

About