Elimination of Fc receptor-dependent effector functions of a modified IgG4monoclonal antibody to human CD4

Several CD4 mAbs have entered the clinic for the treatment of autoimmune di seases or transplant rejection. Most of these mAbs caused CD4 cell depletio n, and some were murine mAbs which were further hampered by human anti-mous e Ab responses. To obviate these concerns, a primatized CD4 mAb, clenolixim ab, was generated by fusing the V domains of a cynomolgus macaque mAb to hu man constant regions. The heavy chain constant region is a modified IgG4 co ntaining two single residue substitutions designed to ablate residual Fc re ceptor binding activity and to stabilize heavy chain dimer formation. This study compares and contrasts the in vitro properties of clenoliximab with i ts matched IgG1 derivative, keliximab, which shares the same variable regio ns. Both mAbs show potent inhibition of in vitro T cell responses, lack of binding to complement component C1q, and inability to mediate complement-de pendent cytotoxicity. However, ctenoliximab shows markedly reduced binding to Pc receptors and therefore does not mediate Ab-dependent cell-mediated c ytotoxicity or modulation/loss of CD4 from the surface of T cells, except i n the presence of rheumatoid factor or activated monocytes. Thus, clenolixi mab retains the key immunomodulatory attributes of keliximab without the li ability of strong Fc gamma receptor binding. In initial clinical trials, th ese properties have translated to a reduced incidence of CD4(+) T cell depl etion.