Modification of the Fc region of a primatized IgG antibody to human CD4 retains its ability to modulate CD4 receptors but does not deplete CD4(+) T cells in chimpanzees

Keliximab, a Primatized IgG1 CD4 mAb, was reconfigured to an IgG4 antibody. The gamma4 constant region was further modified by substituting glutamic a cid for serine at position 235 in the CH2 domain (IgG4-E), to remove residu al binding to Fc gamma receptors, and substitution of serine with proline a t position 228 in the hinge region (IgG4-PE) for greater stability. Pharmac okinetic analysis in rats gave a t(1/2) approximately 4 days for IgG4-E and 9 days for IgG4-PE, consistent with a greater stability of the IgG4-PE mol ecule. The effects on T cell subsets were assessed in chimpanzees given esc alating doses of IgG4-PE: 0.05 mg/kg on Day 16, 1.5 mg/kg dose on Day 43, a nd 15 mg/kg on Day 85. Receptor modulation was observed at the two highest doses, but no depletion of T cells at any dose. The in vitro and in vivo re sults demonstrate the potential of this IgG4-PE mAb for use in human trials . (C) 2000 Academic Press.