کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10825830 | 1064678 | 2014 | 9 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Antibody humanization by redesign of complementarity-determining region residues proximate to the acceptor framework
ترجمه فارسی عنوان
انسانی شدن آنتی بادی با طراحی مجدد جایگزین منطقه تعریف مکمل در نزدیکی چارچوب پذیرنده
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کلمات کلیدی
FACSCDREC50DEEFDPBGMECAntibody humanization - انسداد آنتی بادیELISA - تست الیزاEnzyme-linked immunosorbent assay - تست الیزاdead-end elimination - حذف مردهfluorescence-activated cell sorting - دسته بندی سلول های فعال فلورسنسcomputational protein design - طراحی پروتئین محاسباتیComplementarity-determining region - منطقه تعریف کننده تکمیلیhalf maximal effective concentration - نیمه حداکثر غلظت موثر
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
چکیده انگلیسی
Antibodies are key components of the adaptive immune system and are well-established protein therapeutic agents. Typically high-affinity antibodies are obtained by immunization of rodent species that need to be humanized to reduce their immunogenicity. The complementarity-determining regions (CDRs) contain the residues in a defined loop structure that confer antigen binding, which must be retained in the humanized antibody. To design a humanized antibody, we graft the mature murine CDRs onto a germline human acceptor framework. Structural defects due to mismatches at the graft interface can be fixed by mutating some framework residues to murine, or by mutating some residues on the CDRs' backside to human or to a de novo designed sequence. The first approach, framework redesign, can yield an antibody with binding better than the CDR graft and one equivalent to the mature murine, and reduced immunogenicity. The second approach, CDR redesign, is presented here as a new approach, yielding an antibody with binding better than the CDR graft, and immunogenicity potentially less than that from framework redesign. Application of both approaches to the humanization of anti-α4 integrin antibody HP1/2 is presented and the concept of the hybrid humanization approach that retains “difficult to match” murine framework amino acids and uses de novo CDR design to minimize murine amino acid content and reduce cell-mediated cytotoxicity liabilities is discussed.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Methods - Volume 65, Issue 1, 1 January 2014, Pages 68-76
Journal: Methods - Volume 65, Issue 1, 1 January 2014, Pages 68-76
نویسندگان
Karl J.M. Hanf, Joseph W. Arndt, Ling Ling Chen, Matthew Jarpe, P. Ann Boriack-Sjodin, You Li, Herman W.T. van Vlijmen, R. Blake Pepinsky, Kenneth J. Simon, Alexey Lugovskoy,