Expression and characterization of CD4-IgG2, a novel heterotetramer that neutralizes primary HIV type 1 isolates.
CD4-IgG2 is a novel fusion protein comprising human IgG2 in which the Fv portions of both heavy and light chains have been replaced by the V1 and V2 domains of human CD4. This tetrameric protein is being developed as an immunoprophylactic agent to reduce the probability of infection following HIV-1 exposure, in settings such as occupational or perinatal exposure to the virus. CD4-IgG2 has been expressed in Chinese hamster ovary cells and is secreted as a fully assembled heterotetramer. The protein binds with nanomolar affinity to purified gp120 from both a laboratory-adapted strain and a primary isolate of HIV-1. Pharmacokinetic studies in rabbits demonstrated that CD4-IgG2 has a plasma terminal half-life greater than 1 day, compared with 15 min for soluble CD4 (sCD4). CD4-IgG2 does not bind to Fc receptors on the surface of U937 monocyte/macrophage cells. Compared to molecules that incorporate the Fc portion of IgG1, CD4-IgG2 has less potential to mediate functions such as antibody-dependent enhancement of infection or transplacental transmission of HIV-1. When tested in a virus-free HIV-1 envelope glycoprotein-mediated cell fusion assay, the tetrameric CD4-IgG2 molecule inhibited syncytium formation more effectively than monomeric sCD4 or a dimeric CD4-gamma 2 fusion protein. This suggests the protein will block cell-to-cell transmission of HIV-1. Moreover, CD4-IgG2 effectively neutralized a panel of laboratory-adapted strains and primary isolates of HIV-1, including strains with different tropisms and isolated from different stages of the disease, at concentrations that should be readily achieved in vivo.
Allaway
G P
GP
Progenics Pharmaceuticals, Inc., Tarrytown, New York 10591, USA.
Davis-Bruno
K L
KL
Beaudry
G A
GA
Garcia
E B
EB
Wong
E L
EL
Ryder
A M
AM
Hasel
K W
KW
Gauduin
M C
MC
Koup
R A
RA
McDougal
J S
JS
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D016860:CD4 Immunoadhesins / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D015726:Giant Cells / Q000821:virology; D015658:HIV Infections / Q000517:prevention & control*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D009500:Neutralization Tests; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology
D000998:Antiviral Agents; D016860:CD4 Immunoadhesins; C096753:CD4-IgG(2); D011993:Recombinant Fusion Proteins