| Effective Phagocytosis of Low Her2 Tumor Cell Lines with Engineered, Aglycosylated IgG Displaying High FcγRIIa Affinity and Selectivity. | |
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MedLine Citation:
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PMID: 23030766 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Glycans anchored to residue N297 of the antibody IgG Fc domain are critical in mediating binding towards FcγRs to direct both adaptive and innate immune responses. However, using a full length bacterial IgG display system, we have isolated aglycosylated Fc domains with mutations that confer up to a 160-fold increase in the affinity towards the low affinity FcγRIIa-R131 allele as well as high selectivity against binding to the remarkably homologous human inhibitory receptor, FcγRIIb. The mutant Fc domain (AglycoT-Fc1004) contained a total of 5 amino acid substitutions that conferred an activating to inhibitory ratio of 25 (A/I ratio; FcyRIIa-R131 : FcγRIIb). Incorporation of this engineered Fc into trastuzumab, an anti-Her2 antibody, resulted in a 75% increase in tumor cell phagocytosis by macrophages compared to the parental glycosylated trastuzumab with both medium and low Her2-expressing cancer cells. A mathematical model has been developed to help explain how receptor affinity and the A/I ratio relate to improved antibody dependent cell-mediated phagocytosis. Our model provides guidelines for the future engineering of Fc domains with enhanced effector function. |
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Authors:
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Sang Taek Jung; William Kelton; Tae Hyun Kang; Daphne Tw Ng; Jan Terje Andersen; Inger Sandlie; Casim A Sarkar; George Georgiou |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-10-3 |
Journal Detail:
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Title: ACS chemical biology Volume: - ISSN: 1554-8937 ISO Abbreviation: ACS Chem. Biol. Publication Date: 2012 Oct |
Date Detail:
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Created Date: 2012-10-3 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101282906 Medline TA: ACS Chem Biol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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