title: CD4-anchoring HIV-1 fusion inhibitor with enhanced potency and in vivo stability.
abstract: In this study, we describe a novel CD4-targeting bifunctional human immunodeficiency virus (HIV-1) fusion inhibitor (CD4-BFFI) that blocks HIV-1 entry by inhibiting both HIV-1 attachment and fusion and is highly potent against both R5 and X4 HIV-1 viruses in various antiviral assays, including peripheral blood mononuclear cell (PBMC) infection assays. Previously, we have reported a CCR5 antibody-based bifunctional HIV-1 fusion inhibitor (BFFI) that was highly active in blocking R5 HIV-1 infection but was ineffective against X4 viruses infecting human PBMCs (Kopetzki, E., Jekle, A., Ji, C., Rao, E., Zhang, J., Fischer, S., Cammack, N., Sankuratri, S., and Heilek, G. (2008) Virology J. 5, 56-65). CD4-BFFI, which consists of two HIV-1 fusion inhibitor (FI) T-651 variant peptides recombinantly fused to the Fc end of a humanized anti-CD4 monoclonal antibody, has demonstrated more than 100-fold greater antiviral activity than T-651 variant or the parental CD4 monoclonal antibody. Mechanistic studies revealed that CD4-BFFI primarily blocks the HIV-1-cell fusion step through its FI peptide moieties. The enhanced antiviral activity of CD4-BFFI is most likely due to avid binding of the bivalent FI peptides as well as the increased local concentration of CD4-BFFI via attachment to the target cell surface receptor CD4. In vivo pharmacokinetic studies demonstrated that CD4-BFFI was stable in monkey blood, and a dose of 10 mg/kg maintained serum concentrations greater than 2,000-fold over the IC(90) value for 7 days postdosing. This novel bifunctional inhibitor with improved potency and favorable pharmacokinetic properties may offer a novel approach for HIV-1 therapy.
authors.affiliation: Virology Diseases Area, Roche Palo Alto, Palo Alto, California 94304, USA. changhua.ji@roche.com
authors.forename: Changhua
authors.initials: C
authors.lastname: Ji
authors.forename: Erhard
authors.initials: E
authors.lastname: Kopetzki
authors.forename: Andreas
authors.initials: A
authors.lastname: Jekle
authors.forename: Kay-Gunnar
authors.initials: KG
authors.lastname: Stubenrauch
authors.forename: Xingrong
authors.initials: X
authors.lastname: Liu
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Eileen
authors.initials: E
authors.lastname: Rao
authors.forename: Tilman
authors.initials: T
authors.lastname: Schlothauer
authors.forename: Stephan
authors.initials: S
authors.lastname: Fischer
authors.forename: Nick
authors.initials: N
authors.lastname: Cammack
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Heilek
authors.forename: Stefan
authors.initials: S
authors.lastname: Ries
authors.forename: Surya
authors.initials: S
authors.lastname: Sankuratri
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D023581:HIV Fusion Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism* / Q000821:virology; D008252:Macaca fascicularis; D010455:Peptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000911:Antibodies, Monoclonal; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens; D023581:HIV Fusion Inhibitors; D007141:Immunoglobulin Fc Fragments; D010455:Peptides; D019713:Receptors, CCR5; D011993:Recombinant Fusion Proteins