A humanized form of a CD4-specific monoclonal antibody exhibits decreased antigenicity and prolonged plasma half-life in rhesus monkeys while retaining its unique biological and antiviral properties.
Certain monoclonal antibodies (MAbs) directed against CD4 can efficiently block HIV-1 replication in vitro. To explore CD4-directed passive immunotherapy for prevention or treatment of AIDS virus infection, we previously examined the biological activity of a nondepleting CD4-specific murine MAb, mu5A8. This MAb, specific for domain 2 of CD4, blocks HIV-1 replication at a post-gp120-CD4 binding step. When administered to normal rhesus monkeys, all CD4+ target cells were coated with antibody, yet no cell clearance or measurable immunosuppression occurred. However, strong anti-mouse Ig responses rapidly developed in all monkeys. In the present study, we report a successfully humanized form of mu5A8 (hu5A8) that retains binding to both human and monkey CD4 and anti-AIDS virus activity. When administered intravenously to normal rhesus monkeys, hu5A8 bound to all target CD4+ cells without depletion and showed a significantly longer plasma half-life than mu5A8. Nevertheless, an anti-hu5A8 response directed predominantly against V region determinants did eventually appear within 2 to 4 weeks in most animals. However, when hu5A8 was administered to rhesus monkeys chronically infected with the simian immunodeficiency virus of macaques, anti-hu5A8 antibodies were not detected. Repeated administration of hu5A8 in these animals resulted in sustained plasma levels and CD4+ cell coating with humanized antibody for 6 weeks. These studies demonstrate the feasibility of chronic administration of CD4-specific MAb as a potential means of treating or preventing HIV-1 infection.
Reimann
K A
KA
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Lin
W
W
Bixler
S
S
Browning
B
B
Ehrenfels
B N
BN
Lucci
J
J
Miatkowski
K
K
Olson
D
D
Parish
T H
TH
Rosa
M D
MD
Oleson
F B
FB
Hsu
Y M
YM
Padlan
E A
EA
Letvin
N L
NL
Burkly
L C
LC
D000595:Amino Acid Sequence; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000097:blood; D000911:Antibodies, Monoclonal / Q000097:blood / Q000235:genetics / Q000276:immunology; D001483:Base Sequence; D015704:CD4 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007116:Immunization, Passive / Q000379:methods*; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D008212:Lymphocyte Depletion; D008253:Macaca mulatta; D051379:Mice; D008969:Molecular Sequence Data; D011993:Recombinant Fusion Proteins; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology; D014779:Virus Replication
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D007135:Immunoglobulin Variable Region; D011993:Recombinant Fusion Proteins