Human monoclonal antibodies and engineered antibody domains as HIV-1 entry inhibitors
- 1 March 2009
- journal article
- review article
- Published by Ovid Technologies (Wolters Kluwer Health) in Current Opinion in HIV and AIDS
- Vol. 4 (2), 112-117
- https://doi.org/10.1097/coh.0b013e328322f95e
Abstract
To summarize the in-vivo efficacy of neutralizing human monoclonal antibodies against HIV-1, to discuss the recent finding that an engineered human antibody VH domain, domain antibody (dAb), exhibits exceptionally potent and broadly cross-reactive neutralizing activity against HIV-1 primary isolates by targeting a hidden conserved epitope that is not accessible by larger antibodies and to suggest the possibility of developing a novel class of potent HIV-1 inhibitors based on human dAbs. HIV-1 has evolved a number of strategies to evade humoral immunity, including protecting highly conserved and important structures from the access of antibodies generated by the immune system. We have recently demonstrated that a human dAb (size ∼15 kDa), m36, targets a highly protected structure on the HIV-1 envelope glycoprotein (Env), gp120, and exhibits exceptionally potent neutralizing activity against HIV-1 primary isolates, with potency on average higher than those of the broadly cross-reactive neutralizing human monoclonal antibody, scFv m9, and the inhibitory peptide, C34. The efficacy of the anti-HIV-1 therapy is significantly compromised by resistance to the currently used US Food and Drug Administration-approved antiretroviral drugs, which suggests an urgent need to develop novel classes of potent inhibitors. Several broadly cross-reactive neutralizing human monoclonal antibodies are highly effective against HIV-1 infection in vitro, but their administration to HIV-1-infected humans has only resulted in modest antiviral effects. Engineered human antibody fragments, dAbs, could be more potent because of their small size (about 10-fold smaller than that of an IgG), which allows targeting of highly conserved structures on the HIV-1 envelope glycoprotein that are not accessible by full-size antibodies and relatively efficient penetration into the densely packed lymphoid environment in which HIV-1 mostly replicates and spreads.Keywords
This publication has 41 references indexed in Scilit:
- Human domain antibodies to conserved sterically restricted regions on gp120 as exceptionally potent cross-reactive HIV-1 neutralizersProceedings of the National Academy of Sciences, 2008
- Construction of a Large Phage-Displayed Human Antibody Domain Library with a Scaffold Based On a Newly Identified Highly Soluble, Stable Heavy Chain Variable DomainJournal of Molecular Biology, 2008
- Potent Human Immunodeficiency Virus-Neutralizing and Complement Lysis Activities of Antibodies Are Not Obligatorily LinkedJournal of Virology, 2008
- In Vivo and In Vitro Escape from Neutralizing Antibodies 2G12, 2F5, and 4E10Journal of Virology, 2007
- Improved Pharmacokinetics of Recombinant Bispecific Antibody Molecules by Fusion to Human Serum AlbuminPublished by Elsevier BV ,2007
- Anti-V3 Humanized Antibody KD-247 Effectively Suppresses Ex Vivo Generation of Human Immunodeficiency Virus Type 1 and Affords Sterile Protection of Monkeys against a Heterologous Simian/Human Immunodeficiency Virus InfectionJournal of Virology, 2006
- Monoclonal antibody hNM01 in HIV-infected patients: a phase I studyJournal of Clinical Virology, 2004
- Comprehensive Cross-Clade Neutralization Analysis of a Panel of Anti-Human Immunodeficiency Virus Type 1 Monoclonal AntibodiesJournal of Virology, 2004
- Antibody neutralization and escape by HIV-1Nature, 2003
- A Potent Cross-Clade Neutralizing Human Monoclonal Antibody against a Novel Epitope on gp41 of Human Immunodeficiency Virus Type 1AIDS Research and Human Retroviruses, 2001