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

Autor: Newman, Roland, Hariharan, Kandasamy, Reff, Mitchell, Anderson, Darrel R., Braslawsky, Gary, Santoro, Denise, Hanna, Nabil, Bugelski, Peter J., Brigham-Burke, Michael, Crysler, Carl, Gagnon, Robert C., Dal Monte, Paul, Doyle, Michael L., Hensley, Preston C., Reddy, Manjula P., Sweet, Raymond W., Truneh, Alemseged
Zdroj: Clinical Immunology; February 2001, Vol. 98 Issue: 2 p164-174, 11p
Abstrakt: Keliximab, a Primatized IgG1 CD4 mAb, was reconfigured to an IgG4 antibody. The γ4 constant region was further modified by substituting glutamic acid for serine at position 235 in the CH2 domain (IgG4-E), to remove residual binding to Fcγ receptors, and substitution of serine with proline at position 228 in the hinge region (IgG4-PE) for greater stability. Pharmacokinetic analysis in rats gave a t1/2of approximately 4 days for IgG4-E and 9 days for IgG4-PE, consistent with a greater stability of the IgG4-PE molecule. The effects on T cell subsets were assessed in chimpanzees given escalating doses of IgG4-PE: 0.05 mg/kg on Day 16, 1.5 mg/kg dose on Day 43, and 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 vitroand in vivoresults demonstrate the potential of this IgG4-PE mAb for use in human trials.
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