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Departments of
*
Immunology,
Drug Metabolism and Pharmacokinetics,
Oncology, and
§
Structural Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406; and
¶
IDEC Pharmaceuticals Corporation, San Diego, CA 92121
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 Fc
receptor binding. In initial clinical trials, these
properties have translated to a reduced incidence of CD4+ T
cell depletion.
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