A primatized MAb to human CD4 causes receptor modulation, without marked reduction in CD4+ T cells in chimpanzees: in vitro and in vivo characterization of a MAb (IDEC-CE9.1) to human CD4.
A Primatized anti-CD4 monoclonal antibody (MAb), CE9.1, with V-domain from cynomolgus macaque (showing 92% homology with human consensus sequence V-domains), and a human IgG1 constant region, was characterized in vitro and in vivo in chimpanzees. This MAb binds human CD4 with Kd of 1.0 nM and was also able to bind to human IgG Fc receptors (Fc gamma R). However, despite being of the IgG1 subclass, CE9.1 did not bind to complement component C1q, nor did it mediate complement-dependent cytotoxicity. Examination of T cells from a number of species showed restricted reactivity for CE9.1, recognizing only human and chimpanzee CD4. In both human and chimpanzee MLRs, it had an IC50 of about 10.0 ng/mL. Therefore, a chimpanzee in vivo model was used to characterize CE9.1, CE9.1 caused transient decrease in the number of lymphocytes bearing the CD4 receptor starting at doses of 0.3 mg/kg in an in vivo dose ranging study in one chimpanzee. This effect was reversed within approximately 7 days. In a multiple high-dose study in which 10.0 mg/kg of CE9.1 was administered at intervals of 1-3 months, there was a dramatic loss of CD4 marker with a reciprocal increase in the number of CD3+ CD8- CD4- cells. The CD4 receptor was totally undetectable on these lymphocytes for 1-2 weeks, with a gradual, but complete, reversal within 4 weeks. We interpret these observations as receptor modulation because, although there was apparent loss of CD4+ lymphocytes, an equivalent number of CD3+CD8- T lymphocytes were present in circulation in all four chimpanzees treated with 10.0 mg/kg CE9.1. Even at this high dose, only limited reduction of CD4+ T lymphocytes was observed in these animals. These observations are in sharp contrast to what has been reported in rodents or in human clinical studies using other IgG1 mAbs to human CD4. CD8 counts, although variable, remained unaffected by CE9.1 treatment. No adverse events were observed following administration of CE9.1 to chimpanzees, and there was no detectable host immune responses to the Primatized MAb.
Anderson
D
D
IDEC Pharmaceuticals Corporation, San Diego, California 92121, USA.
Chambers
K
K
Hanna
N
N
Leonard
J
J
Reff
M
M
Newman
R
R
Baldoni
J
J
Dunleavy
D
D
Reddy
M
M
Sweet
R
R
Truneh
A
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D001666:Binding Sites, Antibody; D015704:CD4 Antigens / Q000276:immunology* / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D017637:Clonal Deletion; D003168:Complement Fixation Tests; D003429:Cross Reactions; D006801:Humans; D007275:Injections, Intravenous; D007959:Lymphocyte Culture Test, Mixed; D002679:Pan troglodytes; D011961:Receptors, Fc / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D013045:Species Specificity
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins