We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
A Novel Class of Anti-HIV Agents with Multiple Copies of Enfuvirtide Enhances Inhibition of Viral Replication and Cellular Transmission In Vitro.
- Authors
Chien-Hsing Chang; Hinkula, Jorma; Meiyu Loo; Falkeborn, Tina; Rongxiu Li; Cardillo, Thomas M.; Rossi, Edmund A.; Goldenberg, David M.; Wahren, Britta
- Abstract
We constructed novel HIV-1 fusion inhibitors that may overcome the current limitations of enfuvirtide, the first such therapeutic in this class. The three prototypes generated by the Dock-and-Lock (DNL) technology to comprise four copies of enfuvirtide tethered site-specifically to the Fc end of different humanized monoclonal antibodies potently neutralize primary isolates (both R5-tropic and X4-tropic), as well as T-cell-adapted strains of HIV-1 in vitro. All three prototypes show EC50 values in the subnanomolar range, which are 10- to 100-fold lower than enfuvirtide and attainable whether or not the constitutive antibody targets HIV-1. The potential of such conjugates to purge latently infected cells was also demonstrated in a cell-to-cell viral inhibition assay by measuring their efficacy to inhibit the spread of HIV-1LAI from infected human peripheral blood mononuclear cells to Jurkat T cells over a period of 30 days following viral activation with 100 nM SAHA (suberoylanilide hydroxamic acid). The IgG-like half-life was not significantly different from that of the parental antibody, as shown by the mean serum concentration of one prototype in mice at 72 h. These encouraging results provide a rationale to develop further novel anti-HIV agents by coupling additional antibodies of interest with alternative HIV-inhibitors via recombinantly-produced, self-assembling, modules.
- Subjects
ENZYME inhibitors; ENFUVIRTIDE (Drug); THERAPEUTICS; PROTOTYPES; MICROBIOLOGICAL assay; T cells
- Publication
PLoS ONE, 2012, Vol 7, Issue 7, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0041235