title: A novel class of anti-HIV agents with multiple copies of enfuvirtide enhances inhibition of viral replication and cellular transmission in vitro.
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 EC(50) 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-1(LAI) 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.
authors: Immunomedics, Inc., Morris Plains, New Jersey, United States of America. kchang@immunomedics.com
authors: Chien-Hsing
authors: CH
authors: Chang
authors: Jorma
authors: J
authors: Hinkula
authors: Meiyu
authors: M
authors: Loo
authors: Tina
authors: T
authors: Falkeborn
authors: Rongxiu
authors: R
authors: Li
authors: Thomas M
authors: TM
authors: Cardillo
authors: Edmund A
authors: EA
authors: Rossi
authors: David M
authors: DM
authors: Goldenberg
authors: Britta
authors: B
authors: Wahren
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D004355:Drug Stability; D000077560:Enfuvirtide; D005260:Female; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007074:Immunoglobulin G / Q000378:metabolism; D019169:Jurkat Cells; D051379:Mice; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014775:Virus Activation / Q000187:drug effects; D053586:Virus Internalization / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*; D000077337:Vorinostat
chemical_list: D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D006877:Hydroxamic Acids; D007074:Immunoglobulin G; D010446:Peptide Fragments; D000077560:Enfuvirtide; D000077337:Vorinostat