CD4 immunoadhesins in anti-HIV therapy: new developments.

Abstract

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.

• Authors: S M Chamow, A M Duliege, A Ammann, J O Kahn, J D Allen, J W Eichberg, R A Byrn, D J Capon, R H Ward, A Ashkenazi
• Journal: International journal of cancer. Supplement = Journal international du cancer. Supplement (Int J Cancer Suppl) Vol. 7 Pg. 69-72 ( 1992) ISSN: 0898-6924 [Print] United States
• PMID: 1428410 (Publication Type: Journal Article, Review)

Chemical References

• CD4 Antigens
• Immunoglobulin G
• Immunoglobulin Heavy Chains
• Recombinant Fusion Proteins

Topics

• Acquired Immunodeficiency Syndrome (immunology, therapy)
• CD4 Antigens (immunology, therapeutic use)
• HIV
• HIV Infections (immunology, therapy)
• Humans
• Immunoglobulin G (therapeutic use)
• Immunoglobulin Heavy Chains (therapeutic use)
• Immunotherapy (methods)
• Recombinant Fusion Proteins (therapeutic use)