Development of anti-CD4 MAb hu5A8 for treatment of HIV-1 infection: preclinical assessment in non-human primates.
The anti-CD4 MAb 5A8 is a potent inhibitor of CD4-mediated infection of HIV-1. CD4 is obligatory for infection with primary HIV-1 isolates. Humanized 5A8 (hu5A8) was constructed to reduce the potential immunogenicity and enhance the in vivo half-life when used in humans. hu5A8 is a molecularly engineered human IgG4 antibody retaining the binding and functional properties of the murine version of 5A8 (mu5A8). This humanized MAb has been shown to be very effective in inhibiting HIV-1 infection of human CD4+ T cells and macrophages in vitro and to reduce viral load in rhesus monkeys chronically infected with simian immunodeficiency virus (SIV). 5A8 was evaluated in a good laboratory practice (GLP)-compliant tissue cross-reactivity study on human (three donors/37 tissues) and rhesus monkey (two donors/37 tissues) tissues. hu5A8 bound to the surface of human T cells and macrophages, but only to T cells from rhesus monkeys. The antibody did not cross react with other tissues. The highly identical staining patterns of hu5A8 in human and rhesus monkey tissues support the use of rhesus monkeys as a preclinical model for humans. In a GLP-compliant safety study in rhesus monkeys, weekly administration of hu5A8 at 5 mg/kg or 25 mg/kg for 8 weeks was shown to be safe and well tolerated in all monkeys. Although hu5A8 induced anti-hu5A8 antibody response in healthy rhesus monkeys, it was not immunogenic in chimpanzees. Together, the results from these preclinical studies support the studies of the anti-HIV-1 effect of hu5A8 in HIV-1 infected individuals.
Boon
Louis
L
Tanox Pharma B.V., Amsterdam, The Netherlands.
Holland
Betty
B
Gordon
Wayne
W
Liu
Patrick
P
Shiau
Fred
F
Shanahan
William
W
Reimann
Keith A
KA
Fung
Michael
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D000918:Antibody Specificity; D015704:CD4 Antigens / Q000276:immunology*; D003429:Cross Reactions; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D015497:HIV-1; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007150:Immunohistochemistry; D008253:Macaca mulatta; D008297:Male; D002679:Pan troglodytes
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D007074:Immunoglobulin G