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Elimination of Fc receptor-dependent effector functions of a modified IgG4 monoclonal antibody to human CD4.

Authors :
Reddy MP
Kinney CA
Chaikin MA
Payne A
Fishman-Lobell J
Tsui P
Dal Monte PR
Doyle ML
Brigham-Burke MR
Anderson D
Reff M
Newman R
Hanna N
Sweet RW
Truneh A
Source :
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2000 Feb 15; Vol. 164 (4), pp. 1925-33.
Publication Year :
2000

Abstract

Several CD4 mAbs have entered the clinic for the treatment of autoimmune diseases or transplant rejection. Most of these mAbs caused CD4 cell depletion, and some were murine mAbs which were further hampered by human anti-mouse Ab responses. To obviate these concerns, a primatized CD4 mAb, clenoliximab, was generated by fusing the V domains of a cynomolgus macaque mAb to human constant regions. The heavy chain constant region is a modified IgG4 containing two single residue substitutions designed to ablate residual Fc receptor binding activity and to stabilize heavy chain dimer formation. This study compares and contrasts the in vitro properties of clenoliximab with its matched IgG1 derivative, keliximab, which shares the same variable regions. Both mAbs show potent inhibition of in vitro T cell responses, lack of binding to complement component C1q, and inability to mediate complement-dependent cytotoxicity. However, clenoliximab shows markedly reduced binding to Fc receptors and therefore does not mediate Ab-dependent cell-mediated cytotoxicity or modulation/loss of CD4 from the surface of T cells, except in the presence of rheumatoid factor or activated monocytes. Thus, clenoliximab retains the key immunomodulatory attributes of keliximab without the liability of strong Fcgamma receptor binding. In initial clinical trials, these properties have translated to a reduced incidence of CD4+ T cell depletion.

Details

Language :
English
ISSN :
0022-1767
Volume :
164
Issue :
4
Database :
MEDLINE
Journal :
Journal of immunology (Baltimore, Md. : 1950)
Publication Type :
Academic Journal
Accession number :
10657642
Full Text :
https://doi.org/10.4049/jimmunol.164.4.1925