Evaluation of CD4-CD4i antibody architectures yields potent, broadly cross-reactive anti-human immunodeficiency virus reagents.
The envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) has several adaptations that allow the virus to evade antibody neutralization. Nevertheless, a few broadly cross-reactive neutralizing antibodies as well as reagents containing portions of CD4, the HIV receptor, have demonstrated partial efficacy in suppressing viral replication. One type of reagent designed for improved HIV neutralization fuses the CD4 D1-D2 domains to the variable regions of an antibody recognizing the CD4-induced (CD4i) coreceptor binding site on the gp120 portion of the HIV envelope spike. We designed, expressed, purified, and tested the neutralization potencies of CD4-CD4i antibody reagents with different architectures, antibody combining sites, and linkers. We found that fusing CD4 to the heavy chain of the CD4i antibody E51 yields a bivalent reagent including an antibody Fc region that expresses well, is expected to have a long serum half-life, and has comparable or greater neutralization activity than well-known broadly neutralizing anti-HIV antibodies. A CD4 fusion with the anti-HIV carbohydrate antibody 2G12 also results in a potent neutralizing reagent with more broadly neutralizing activity than 2G12 alone.
Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
Anthony P
AP
West
Rachel P
RP
Galimidi
Christopher P
CP
Foglesong
Priyanthi N P
PN
Gnanapragasam
Joshua S
JS
Klein
Pamela J
PJ
Bjorkman
D019380:Anti-HIV Agents / Q000276:immunology*; D018033:Antibodies, Bispecific / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use; D000914:Antibodies, Viral; D001665:Binding Sites; D015704:CD4 Antigens / Q000276:immunology*; D003429:Cross Reactions / Q000276:immunology; D003432:Cross-Linking Reagents; D004355:Drug Stability; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007141:Immunoglobulin Fc Fragments
D019380:Anti-HIV Agents; D018033:Antibodies, Bispecific; D000914:Antibodies, Viral; D015704:CD4 Antigens; D003432:Cross-Linking Reagents; D015699:HIV Envelope Protein gp120; D007141:Immunoglobulin Fc Fragments