Development of a human whole blood assay for prediction of cytokine release similar to anti-CD28 superagonists using multiplex cytokine and hierarchical cluster analysis.
Int Immunopharmacol
; 11(11): 1697-705, 2011 Nov.
Article
em En
| MEDLINE
| ID: mdl-21689786
ABSTRACT
Anti-CD28 superagonist (SA) mediated cytokine release syndrome (CRS), an adverse event resulting in systemic release of cytokines, is an emergent issue in drug development. CRS is of potential concern for all monoclonal antibodies (mAbs) particularly those directed against cell surface targets on lymphocytes. Concern regarding patient safety requires development of novel methods to predict these adverse reactions. Due to the inability of animal studies to predict CRS, we have developed a whole blood in vitro screen to support First in Human studies and assess the potential for mAbs to cause anti-CD28 SA-like CRS. For this purpose we have immobilized marketed mAbs, whose potential for causing CRS and milder infusion reactions is known, on Protein A beads and used these beads to stimulate cytokine release. After culture, supernatants are harvested and frozen for later multiplex analysis of cytokines using Searchlight™ technology. We have employed hierarchicalluster analysis (HCA) to allow comparison of 12 different cytokine levels across numerous donors, treatments, and experiments. Results conclusively distinguish test mAb responses from an anti-CD28 superagonist mAb response. As part of a global analysis of preclinical data, the results of this assay can facilitate entry into First in Human clinical trials, help with selection of starting doses and may allow more rapid dose escalation using smaller cohorts.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ensaio de Imunoadsorção Enzimática
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Citocinas
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Antígenos CD28
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos
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Doenças do Sistema Imunitário
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Anticorpos Monoclonais
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Int Immunopharmacol
Ano de publicação:
2011
Tipo de documento:
Article