CD4 immunoadhesins in anti-HIV therapy: new developments.
CD4, the cell-surface receptor for the human immunodeficiency virus (HIV), is a member of the immunoglobulin (Ig) gene superfamily. It contains 4 extracellular sequences homologous to Ig variable domains, the first of which (V1) is sufficient for binding to HIV. To develop CD4 as an anti-HIV therapeutic, we engineered a CD4 immunoadhesin (CD4-IgG)--a fusion protein containing the V1 and V2 domains of CD4 with the hinge and Fc regions of human Ig heavy chain. A chimeric protein of this type has several advantages compared to the soluble receptor, including a greatly extended in vivo half-life and greater avidity for HIV; moreover, like an antibody, it performs effector functions via its Fc domains, such as complement activation and antibody-dependent cell-mediated cytotoxicity. In vivo experiments show that CD4-IgG protects against HIV-I IIIB infection of chimpanzees when administered prior to viral challenge. In addition, CD4-IgG is transferred efficiently across the placenta from mother to fetus in rhesus monkeys. To evaluate its safety in humans, we conducted a phase-I clinical trial in adult patients with AIDS and AIDS-related complex. We found that, in a total of 16 patients, administration of CD4-IgG was well tolerated at doses up to 1000 micrograms/kg of body weight, with no important clinical or immunological toxicities noted. Given its unique properties, particularly the ability of CD4-IgG to cross the placenta, we plan to focus future clinical efforts on preventing infection of newborns via maternal-fetal transfer of HIV.
Chamow
S M
SM
Genentech, Inc., South San Francisco, CA 94080.
Duliege
A M
AM
Ammann
A
A
Kahn
J O
JO
Allen
J D
JD
Eichberg
J W
JW
Byrn
R A
RA
Capon
D J
DJ
Ward
R H
RH
Ashkenazi
A
A
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000628:therapy*; D015704:CD4 Antigens / Q000276:immunology* / Q000627:therapeutic use*; D006678:HIV; D015658:HIV Infections / Q000276:immunology / Q000628:therapy*; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007143:Immunoglobulin Heavy Chains / Q000627:therapeutic use; D007167:Immunotherapy / Q000379:methods; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use
D015704:CD4 Antigens; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D011993:Recombinant Fusion Proteins