{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T10:16:48Z","timestamp":1770718608923,"version":"3.49.0"},"reference-count":56,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2005,12,7]],"date-time":"2005-12-07T00:00:00Z","timestamp":1133913600000},"content-version":"vor","delay-in-days":4692,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Eur J Immunol"],"published-print":{"date-parts":[[1993,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>CD3 antibodies are proven immunosuppressants capable of reversing transplant rejection episodes. Their general application has been limited both by their immunogenicity and, in particular, by the \u201cfirst\u2010dose\u201d cytokine\u2010release syndrome experienced by patients after the initial administration of antibody. We have produced a set of variants of the humanized YTH 12.5 CD3 monoclonal antibody (mAb) (Routledge et al., <jats:italic>Eur. J. Immunol<\/jats:italic>. 1991. <jats:italic>21<\/jats:italic>: 2717) bearing different human heavy (H) chain constant regions, with the intention of finding a form of the antibody that is not able to activate T cells. Comparison of the variants having \u03b3l, \u03b32, \u03b33 and \u03b34 H chains in a competitive binding assay showed that antibody avidity was not affected by IgG subclass. Using a sensitive indicator of FcR binding activity (the capacity of the CD3 mAb to redirect cytotoxic T cells to kill the monocytic cell line U\u2010937) we demonstrated a functional hierarchy of \u03b3l = \u03b34 \u03b12 = \u03b33 mb &gt; \u03b32. An aglycosyl version of the \u03b3l CD3 mAb, produced by site\u2010directed mutagenesis (Asn<jats:sup>297<\/jats:sup> to Ala), still had considerable activity in this assay (intermediate to the \u03b3l and \u03b12 CD3 mAb), albeit at a level approximately 10\u2010fold lower than that of the parental \u03b3l form. When we tested their ablity to stimulate T cell proliferation <jats:italic>in vitro<\/jats:italic> in the presence of 5% human serum, all of the wild\u2010type immunoglobulin isotypes were found to be active, although there were T cell donor\u2010dependent variations in the extent of the responses. The aglycosyl \u03b3l mAb was, however, completely non\u2010mitogenic in all of ten donors tested, unless the assay was performed in IgG\u2010free medium. Despite being non\u2010stimulatory, this mAb was also able to inhibit the mixed lymphocyte reaction responses of both naive and primed T cells. Comparison of the yl and aglycosyl \u03b31 mAb in an experimental mouse model for CD3 mAb\u2010induced cytokine release indicated that removal of the carbohydrate moiety from the \u03b3l constant region reduced the in vivo tumor necrosis factor\u2010a response by a factor of at least 16\u2010fold. These data suggest that the aglycosyl \u03b3l CD3 mAb is a promising candidate for immunosuppressive therapy without \u201cfirst dose\u201d side effects.<\/jats:p>","DOI":"10.1002\/eji.1830230216","type":"journal-article","created":{"date-parts":[[2007,3,1]],"date-time":"2007-03-01T18:53:06Z","timestamp":1172775186000},"page":"403-411","source":"Crossref","is-referenced-by-count":180,"title":["The generation of a humanized, non\u2010mitogenic CD3 monoclonal antibody which retains in vitro immunosuppressive properties"],"prefix":"10.1002","volume":"23","author":[{"given":"Sarah","family":"Bolt","sequence":"first","affiliation":[]},{"given":"Edward","family":"Routledge","sequence":"additional","affiliation":[]},{"given":"Irene","family":"Lloyd","sequence":"additional","affiliation":[]},{"given":"Lucienne","family":"Chatenoud","sequence":"additional","affiliation":[]},{"given":"Heather","family":"Pope","sequence":"additional","affiliation":[]},{"given":"Scott D.","family":"Gorman","sequence":"additional","affiliation":[]},{"given":"Mike","family":"Clark","sequence":"additional","affiliation":[]},{"given":"Herman","family":"Waldmann","sequence":"additional","affiliation":[]}],"member":"311","published-online":{"date-parts":[[2005,12,7]]},"reference":[{"key":"e_1_2_1_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1986.tb04429.x"},{"key":"e_1_2_1_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/312413a0"},{"key":"e_1_2_1_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/321431a0"},{"key":"e_1_2_1_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/324480a0"},{"key":"e_1_2_1_6_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.173.1.7"},{"key":"e_1_2_1_7_2","doi-asserted-by":"crossref","first-page":"165","DOI":"10.4049\/jimmunol.135.1.165","volume":"135","author":"Clement L. 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