Preclinical efficacy and safety of mepolizumab (SB-240563), a humanized monoclonal antibody to IL-5, in cynomolgus monkeys

Hart, Timothy K.; Cook, Richard T.; Zia‐Amirhosseini, Parnian; Minthorn, Elisabeth A.; Sellers, Teresa S.; Maleeff, Beverly E.; Eustis, Scot L.; Schwartz, Lester W.; Tsui, Ping; Appelbaum, Edward R.; Martin, Elise C.; Bugelski, Peter J.; Herzyk, Danuta J.

doi:10.1067/mai.2001.116576

Cited by 218 publications

(137 citation statements)

References 42 publications

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“…Many of the therapeutic antibodies raised against soluble antigens such as circulating TNF, vascular endothelial growth factor (VEGF), IgE, and various cytokines (e.g., interleukin (IL)-8, IL-5, IL-12/IL-23) have undergone extensive research in both various animal models and clinical studies in patients (13,(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64). For this class of compounds, application of PK-PD modeling approaches can prove highly effective for the design of successful translational strategies (4,5,9,10).…”

Section: Introductionmentioning

confidence: 99%

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

Tabrizi

Funelas

Suria

2010

AAPS J

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Abstract. The advancement of therapeutic monoclonal antibodies during various stages of the drug development process can be effectively streamlined when appropriate translational strategies are applied. Design of successful translational strategies for development of monoclonal antibodies should allow for understanding of the dose-and concentration-response relationships with respect to both beneficial and toxic effects from early phases of drug development. Evaluation of relevant biomarkers during early stages of drug development should facilitate the successful design of safe and effective dosing strategies. Moreover, application of quantitative pharmacology is critical for translation of exposure-response relationships early on.

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Section: Introductionmentioning

confidence: 99%

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

Tabrizi

Funelas

Suria

2010

AAPS J

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“…Importantly, noneosinophilic asthma has a poor response to inhaled corticosteroids (19,20) and is pathologically distinct with fewer mast cells, and less subepithelial fibrosis (21). Sputum eosinophilia has also guided the use of mepolizumab, a monoclonal antibody that blocks IL-5, a key mediator in the differentiation, recruitment, and activation of eosinophils (22). Although early clinical trials of mepolizumab in relatively unselected patients with asthma were unsuccessful, the results of clinical trials of mepolizumab improved with patient selection based on the presence of sputum eosinophilia (23,24).…”

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confidence: 99%

Subtypes of Asthma Defined by Epithelial Cell Expression of Messenger RNA and MicroRNA

Woodruff

2013

Annals ATS

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Human asthma can be subcategorized in several ways, but one powerful approach is to subtype asthma on the basis of underlying cellular and molecular mechanisms. Groups of patients with a disease that share a common underlying biology are termed an "endotype." Endotypes of asthma have been studied at both the cellular level (by cytological examination of induced sputum) and, increasingly, at the molecular level. Genome-wide analyses of mRNA expression within the lung have been useful in the identification of molecular endotypes of asthma and point to protein biomarkers of those endotypes that can be measured in the blood. More recently, studies of microRNA expression in airway epithelial cells in asthma have identified additional candidate biomarkers of asthma endotypes. One potentially valuable property of microRNAs is that they can also be measured in extracellular fluids and therefore have the potential to serve directly as noninvasively measured biomarkers.

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“…Conversely, pharmacokinetic studies that uses BAL measurements to quantify partitioning into the lung lumen under-estimate the partitioning due to dilution with the lavage fluid. 34,35 In contrast synovial concentration of a therapeutic antibody in RA patients has been estimated to be within 3-6-fold of the plasma concentration. 36 This further indicates a large therapeutic window.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary pharmacodynamics of an anti-GM-CSFRα antibody enables therapeutic dosing that limits exposure in the lung

Campbell

Nys

Eghobamien

et al. 2016

mAbs

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Preclinical efficacy and safety of mepolizumab (SB-240563), a humanized monoclonal antibody to IL-5, in cynomolgus monkeys

Cited by 218 publications

References 42 publications

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

Subtypes of Asthma Defined by Epithelial Cell Expression of Messenger RNA and MicroRNA

Pulmonary pharmacodynamics of an anti-GM-CSFRα antibody enables therapeutic dosing that limits exposure in the lung

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