Abstract:
:One of the major obstacles in the successful clinical application of monoclonal antibodies has been the development of host immune responses to murine Ig constant and variable regions. While the CDR grafting of MAbs may alleviate many of these problems, the potential remains that one or more murine CDRs on the human Ig backbone of a "humanized" MAb may still be immunogenic. Studies were undertaken employing a MAb of potential clinical utility, CC49, to define those CDRs that are essential for antigen binding and those that may be immunogenic in humans. We previously developed a humanized CC49 (HuCC49) by grafting the MAb CC49 hypervariable regions onto frameworks of human MAbs. To identify those CDRs essential for binding, a panel of variant HuCC49 MAbs was generated here by systematically replacing each of the murine CDRs with their human counterparts. The relative affinity constant of each variant was determined. Serum from a patient who received murine CC49 was used to determine the potential immunogenicity of each CDR in humans. The serum was shown to react with the anti-CC49 variable region. Results showed that patients' anti-idiotypic responses are directed mainly against LCDR3 and moderately against LCDR1 and HCDR2. These studies demonstrate for the first time that variants containing individual CDR substitutions of a humanized MAb can be constructed, and each CDR can be defined for the two most important properties for potential clinical utility: antigen binding and immunogenicity.
journal_name
Mol Immunoljournal_title
Molecular immunologyauthors
Iwahashi M,Milenic DE,Padlan EA,Bei R,Schlom J,Kashmiri SVdoi
10.1016/s0161-5890(99)00094-2subject
Has Abstractpub_date
1999-10-01 00:00:00pages
1079-91issue
15-16eissn
0161-5890issn
1872-9142journal_volume
36pub_type
杂志文章abstract::Major histocompatibility complex (MHC) molecules present peptide antigens to T lymphocytes and initiate immune responses. The peptides loaded onto MHC class I or MHC class II molecules can be derived from cytosolic proteins, both self and foreign. A variety of cellular processes, including endocytosis, vesicle traffic...
journal_title:Molecular immunology
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pub_type: 杂志文章
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journal_title:Molecular immunology
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doi:10.1016/j.molimm.2018.07.013
更新日期:2018-09-01 00:00:00
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journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/j.molimm.2007.06.153
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pub_type: 杂志文章
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journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/s0161-5890(97)00065-5
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journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/j.molimm.2020.05.007
更新日期:2020-08-01 00:00:00
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journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/j.molimm.2016.10.004
更新日期:2016-11-01 00:00:00
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journal_title:Molecular immunology
pub_type: 杂志文章,评审
doi:10.1016/j.molimm.2009.10.008
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journal_title:Molecular immunology
pub_type: 杂志文章
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更新日期:2016-10-01 00:00:00
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pub_type: 杂志文章
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更新日期:2016-10-01 00:00:00
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pub_type: 杂志文章
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journal_title:Molecular immunology
pub_type: 杂志文章
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pub_type: 杂志文章
doi:10.1016/0161-5890(93)90002-s
更新日期:1993-06-01 00:00:00
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pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 杂志文章
doi:10.1016/0161-5890(92)90047-2
更新日期:1992-09-01 00:00:00
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doi:10.1016/j.molimm.2012.05.017
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