Safety profile, pharmacokinetics, and biologic activity of MEDI-563, an anti–IL-5 receptor α antibody, in a phase I study of subjects with mild asthma

Busse, William W.; Katial, Rohit; Gossage, David L.; Sari, Suha; Wang, Bing; Kolbeck, Roland; Coyle, Anthony J.; Koike, Masamichi; Spitalny, George L.; Kiener, Peter A.; Geba, Gregory P.; Molfino, Néstor A.

doi:10.1016/j.jaci.2010.04.005

Cited by 264 publications

(178 citation statements)

References 42 publications

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“…The basal expansion of monocytes and neutrophils in these mice, and the recruitment of both of these cellular subsets with exogenous IL-5 administration, implicates these leukocytes as potential targets of IL-5 in vivo. This observation is consistent with one prior report suggesting IL-5 is necessary for eosinophil and neutrophil recruitment in a mouse model of filariasis and may explain the phenomenon of anti-IL-5Ra-mediated neutropenia in a recent clinical study (47,48).…”

Section: Discussionsupporting

confidence: 93%

“…Although our findings are the first to demonstrate IL-5Ra expression on neutrophils and macrophages in vitro and in vivo, these findings are consistent with other reports that document IL-5Ra mRNA up-regulation in neutrophils and a known chemotactic effect of IL-5 on monocytes and neutrophils (although receptor expression was never established in these studies) (36,47,49). Furthermore, these data also provide an explanation for the reduction in circulating neutrophils and monocytes in patients with asthma treated with anti-IL5Ra (48).…”

Section: Discussionsupporting

confidence: 91%

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Interleukin 5 Is Protective during Sepsis in an Eosinophil-Independent Manner

Linch

Danielson

Kelly

et al. 2012

Am J Respir Crit Care Med

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Rationale: The immune response in sepsis is characterized by overt immune dysfunction. Studies indicate immunostimulation represents a viable therapy for patients. One study suggests a potentially protective role for interleukin 5 (IL-5) in sepsis; however, the loss of eosinophils in this disease presents a paradox. Objectives: To assess the protective and eosinophil-independent effects of IL-5 in sepsis. Methods: We assessed the effects of IL-5 administration on survival, bacterial burden, and cytokine production after polymicrobial sepsis. In addition, we examined the effects on macrophage phagocytosis and survival using fluorescence microscopy and flow cytometry. Measurements and Main Results: Loss of IL-5 increased mortality and tissue damage in the lung, IL-6 and IL-10 production, and bacterial burden during sepsis. Therapeutic administration of IL-5 improved mortality in sepsis. Interestingly, IL-5 administration resulted in neutrophil recruitment in vivo. IL-5 overexpression in the absence of eosinophils resulted in decreased mortality from sepsis and increased circulating neutrophils and monocytes, suggesting their importance in the protective effects of IL-5. Furthermore, novel data demonstrate IL-5 receptor expression on neutrophils and monocytes in sepsis. IL-5 augmented cytokine secretion, activation, phagocytosis, and survival of macrophages. Importantly, macrophage depletion before the onset of sepsis eliminated IL-5-mediated protection. The protective effects of IL-5 were confirmed in humans, where IL-5 levels were elevated in patients with sepsis. Moreover, neutrophils and monocytes from patients expressed the IL-5 receptor. Conclusions: Taken together, these data support a novel role for IL-5 on noneosinophilic myeloid populations, and suggest treatment with IL-5 may be a viable therapy for sepsis.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 91%

Interleukin 5 Is Protective during Sepsis in an Eosinophil-Independent Manner

Linch

Danielson

Kelly

et al. 2012

Am J Respir Crit Care Med

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“…Table 1 summarises these studies and the various IL-5/IL-5R approaches [13,[34][35][36][37][38][39][40][41][42]. Although patients receiving these monoclonal antibodies have demonstrated consistent reductions in eosinophil numbers in blood and sputum, clinical responses have been quite variable [43,44].…”

Section: Anti-il-5 Therapeutic Approachesmentioning

confidence: 99%

Anti-interleukin-5 therapy in severe asthma

et al. 2013

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Asthma is a chronic inflammatory disorder of the airways that leads to acute symptoms, exacerbations and sometimes, for a small part of the asthmatic population, fatal or near-fatal exacerbations.This as yet significant minority of individuals present with severe asthma and have persisting daily symptoms, and exacerbations despite compliance with high doses of inhaled steroids and additional treatment. For more than a decade, the pharmacological management of patients with severe asthma has focused on evaluating specific cytokines. The rationale of this approach is based on the distinguished key role played by eosinophils in the asthma inflammatory processes. Eosinophils are recruited from the circulation to airways where they cause airway damage via different mechanisms. Eosinophils are regulated in terms of their recruitment, activation, growth, differentiation and survival by interleukin (IL)-5. Abundant data from in vitro experiments, animal models and clinical trials has confirmed that IL-5 inhibition may be an effective approach for the treatment of asthma, especially severe asthma. Interfering with eosinophil function or reducing their numbers has been one of the most important goals of therapeutic monoclonal antibodies, which target cytokine receptor interactions in asthma, particularly IL-5. This review will consider new treatments options for severe asthma, particularly those targeting IL-5, that have already been evaluated in clinical trials in asthmatic patients. @ERSpublications Rationale, recent advances and future developments of anti-IL-5 therapy in patients with severe asthma http://ow.ly/n3viv

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“…Agents such as anti-IL-4 mAb, anti-IL-5 mAb, and anti-CCR3 mAb blocked the formation of airway inflammation in animal models of asthma, but failed in clinical trials (Antoniu, 2009;Busse et al, 2010;Corren et al, 2010;Castro et al, 2011;Pavord et al, 2012). It is likely that in preclinical studies, these agents were effective as preventative therapy, but not necessarily able to reverse established disease.…”

Section: Fig 6 Effect Of Anti-cd69 Mab On Ova-induced Ahrmentioning

confidence: 99%

Anti-CD69 monoclonal antibody treatment inhibits airway inflammation in a mouse model of asthma

Wang

Dai

Wang

et al. 2015

J. Zhejiang Univ. Sci. B

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Abstract:Objective: Airway inflammation and airway hyper-responsiveness (AHR) are principle pathological manifestations of asthma. Cluster of differentiation 69 (CD69) is a well-known co-stimulatory factor associated with the activation, proliferation as well as apoptosis of immune cells. This study aims to examine the effect of anti-CD69 monoclonal antibody (mAb) on the pathophysiology of a mouse model of asthma. Methods: A murine model of ovalbumin (OVA)-induced allergic airway inflammation was used in this study. Briefly, mice were injected with 20 μg chicken OVA intraperitoneally on Days 0 and 14, followed by aerosol provocation with 1% (0.01 g/ml) OVA on Days 24, 25, and 26. Anti-CD69 mAb or isotype IgG was injected intraperitoneally after OVA challenge; dexamethasone (DXM) was administrated either before or after OVA challenge. AHR, mucus production, and eosinophil infiltration in the peribronchial area were examined. The levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-5 (IL-5) in bronchoalveolar lavage fluid (BALF) were also assayed as indices of airway inflammation on Day 28 following OVA injection. Results: Pretreatment with DXM together with anti-CD69 mAb treatment after OVA provocation completely inhibited AHR, eosinophil infiltration and mucus overproduction, and significantly reduced BALF IL-5. However, treatment with DXM alone after OVA challenge only partially inhibited AHR, eosinophil infiltration and mucus overproduction, and did not diminish BALF IL-5. Treatment with either DXM or anti-CD69 mAb did not alter the concentration of BALF GM-CSF. Conclusions: Anti-CD69 mAb treatment inhibits established airway inflammation as effectively as DXM pretreatment. This study provides a potential alternative therapeutic opportunity for the clinical management of asthma and its exacerbation.

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Safety profile, pharmacokinetics, and biologic activity of MEDI-563, an anti–IL-5 receptor α antibody, in a phase I study of subjects with mild asthma

Cited by 264 publications

References 42 publications

Interleukin 5 Is Protective during Sepsis in an Eosinophil-Independent Manner

Interleukin 5 Is Protective during Sepsis in an Eosinophil-Independent Manner

Anti-interleukin-5 therapy in severe asthma

Anti-CD69 monoclonal antibody treatment inhibits airway inflammation in a mouse model of asthma

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