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

MP Reddy, CAS Kinney, MA Chaikin… - The Journal of …, 2000 - journals.aai.org
MP Reddy, CAS Kinney, MA Chaikin, A Payne, J Fishman-Lobell, P Tsui, PR Dal Monte…
The Journal of Immunology, 2000journals.aai.org
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 …
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 Fcγ receptor binding. In initial clinical trials, these properties have translated to a reduced incidence of CD4+ T cell depletion.
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