کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2831257 | 1163790 | 2011 | 9 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
A standardized conversion of IgG antibody to bispecific form with inversely altered affinities for Fcγ-receptors II and III
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کلمات کلیدی
FcRncomplement-mediated cytotoxicityPDMFcγREMEMADCCFTCDTTCMCmAbAntibody therapy - آنتی بادی درمانMonoclonal antibody - آنتی بادی مونوکلونالantibody-dependent cellular cytotoxicity - آنتی بادی-وابسته به سمیت سلولی سلولیbispecific antibody - آنتیبادی بخصوصیEagle's minimal essential medium - حداقل مواد ضروری عقابdithiothreitol - دیتیوتریتولfluorescein isothiocyanate - فلوئورسین ایسوتیوسیاناتDisulfide bonds - پیوند های دی سولفید
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شناسی مولکولی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
This work aims to enhance killing of antibody-coated human tumor cells by altering the antibody's affinity for two effector-cell Fcγ-receptors (FcγR). Affinity for the activating FcγRIII is raised, affinity for the inhibitory FcγRIIB is reduced, with the ratio between the two association constants increasing >1000-fold. We use as a standard tool the Fabâ²Î³ from a monoclonal antibody specific for human FcγRIII. This Fabâ²Î³ module is bonded to an IgG antibody by a tandem thioether link running between cysteine residues in the hinge vicinity of each protein, thus forming a bispecific FabIgG construct. Simultaneously, effector function of the IgG module is adjusted by leaving its hinge open and adding negative charges. FabIgG constructs derived from the chimeric IgG1 antibody rituximab show the following properties. (1) The titer for antibody-dependent cellular cytotoxicity is enhanced by 12-100-fold, reflecting the affinity of the Fabâ²Î³ module for effector-cell FcγRIII. (2) Two functions of the construct's Fcγ, activation of complement and prolonged metabolic survival, are moderately reduced. (3) In contrast, affinities of the Fcγ for all FcγR are severely reduced, with two anticipated consequences. First, attacks by macrophages on antibody-coated cells are favored by reduced engagement of the inhibitory FcγRIIB. Second, reduced engagement of activating FcγR by the Fcγ lowers the probability of untoward crosslinkings of FcγR, which have been shown to provoke toxicity. If the Fabâ²Î³ module possesses human constant regions, the linkage strategy requires prior genetic deletion of at least one cysteine residue. With both Fabâ²Î³ and IgG modules available, FabIgG can be prepared in 35 h.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Molecular Immunology - Volume 48, Issue 5, February 2011, Pages 760-768
Journal: Molecular Immunology - Volume 48, Issue 5, February 2011, Pages 760-768
نویسندگان
Weng S. Leong, Karen-Anne Thomas, Claude H. Chan, George T. Stevenson,