Differential effects of administration of a human anti-CD4 monoclonal antibody, HM6G, in nonhuman primates.
A human sequence IgGkappa anti-CD4 monoclonal antibody (mAb), HM6G, originally isolated from a human immunoglobulin transgenic mouse was specific for and bound with high binding avidity to the CD4 antigen expressed on human, chimpanzee, and cynomolgus monkey T cells. Prior to testing this mAb in human clinical trials, a number of preclinical primate studies were performed. In chimpanzees, HM6G did not deplete circulating CD4(+) T cells and was cleared in a dose-dependent manner. In contrast, this mAb administered to cynomolgus monkeys depleted CD4(+) T cells (albeit only at high doses) and its clearance, which had reached saturation even at very low doses, was much slower. These differences were most likely due to the additional and rather substantial expression of the CD4 antigen on chimpanzee monocytes. In monkeys, the T cell depletion was mitigated by infusing the mAb over 30 min or longer (as opposed to 30 s) while only slightly altering the clearance. As expected, the human mAb did not induce an immune response in chimpanzees, although it did induce a low titer response in monkeys. These disparate pharmacokinetic and pharmacodynamic results suggest prudence when extrapolating results obtained in nonhuman models to humans.
Fishwild
D M
DM
GenPharm International, San Jose, California, 95131, USA. dfishwild@genpharm.com
Hudson
D V
DV
Deshpande
U
U
Kung
A H
AH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016466:CHO Cells; D002452:Cell Count; D006224:Cricetinae; D006801:Humans; D007700:Kinetics; D008252:Macaca fascicularis / Q000276:immunology*; D051379:Mice; D002679:Pan troglodytes / Q000276:immunology*; D011323:Primates
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens