| Development of a human whole blood assay for prediction of cytokine release similar to anti-CD28 superagonists using multiplex cytokine and hierarchical cluster analysis. | |
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MedLine Citation:
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PMID: 21689786 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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Mindi R Walker; Dorie A Makropoulos; Ram Achuthanandam; Scott Van Arsdell; Peter J Bugelski |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-6-17 |
Journal Detail:
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Title: International immunopharmacology Volume: - ISSN: 1878-1705 ISO Abbreviation: - Publication Date: 2011 Jun |
Date Detail:
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Created Date: 2011-6-21 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100965259 Medline TA: Int Immunopharmacol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011. Published by Elsevier B.V. |
Affiliation:
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Biologics Toxicology, Center of Excellence in Biotechnology, Centocor R&D Inc., Radnor, PA, United States. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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