NDLI: Affinity maturation and characterization of a human monoclonal antibody against HIV-1 gp41

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Affinity maturation and characterization of a human monoclonal antibody against HIV-1 gp41

Content Provider	PubMed Central
Author	Montgomery, Donna L. Wang, Ying-jie Renee, Hrin Luftig, Micah Su, Bin Miller, Michael D. Wang, Fubao Peter, Haytko Huang, Lingyi Vitelli, Salvatore Condra, Jon Liu, Xiaomei Hampton, Richard Andrea, Carfi Pessi, Antonello Bianchi, Elisabetta Joyce, Joseph Lloyd, Chris Romas, Geleziunas Bramhill, David King, Vicki M. Finnefrock, Adam C. Strohl, William An, Zhiqiang
Copyright Year	2009
Abstract	The human D5 monoclonal antibody binds to the highly conserved hydrophobic pocket on the N-terminal heptad repeat (NHR) trimer of HIV-1 gp41 and exhibits modest yet relatively broad neutralization activity. Both binding and neutralization depend on residues in the complementarity determining regions (CDRs) of the D5 IgG variable domains on heavy chain (VH) and light chain (VL). In an effort to increase neutralization activity to a wider range of HIV-1 strains, we have affinity matured the parental D5 scFv by randomizing selected residues in 5 of its 6 CDRs. The resulting scFv variants derived from four different CDR changes showed enhanced binding affinities to gp41 NHR mimetic (5-helix) which correlated to improved neutralization potencies by up to 8-fold. However, when converted to IgG1s, these D5 variants had up to a 12-fold reduction in neutralization potency over their corresponding scFvs despite their slightly enhanced in vitro binding affinities. Remarkably, D5 variant IgG1s bearing residue changes in CDRs that interact with epitope residues N-terminal to the hydrophobic pocket (such as VH CDR3 and VL CDR3) retained more neutralization potency than those containing residue changes in pocket-interacting CDRs (such as VH CDR2). These results provide compelling evidence for the existence of a steric block to an IgG that extends to the gp41 NHR hydrophobic pocket region, and can be a useful guide for developing therapeutic antibodies and vaccines circumventing this block.
Starting Page	462
File Format	PDF
ISSN	19420870
e-ISSN	19420870
Journal	mAbs
Issue Number	5
Volume Number	1
Language	English
Publisher	Landes Bioscience
Publisher Date	2009-01-01
Access Restriction	Open
Rights Holder	Landes Bioscience
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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Identification of a HIV Gp41-Specific Human Monoclonal Antibody With Potent Antibody-Dependent Cellular Cytotoxicity

Affinity maturation by targeted diversification of the CDR-H2 loop of a monoclonal Fab derived from a synthetic naïve human antibody library and directed against the internal trimeric coiled-coil of gp41 yields a set of Fabs with improved HIV-1 neutralization potency and breadth

Insights into the Structural Basis of Antibody Affinity Maturation from Next-Generation Sequencing

Characterization of a monoclonal antibody directed against the biologically active site of human interleukin 1

Selection of a Novel gp41-specific HIV-1 Neutralizing Human Antibody by Competitive Antigen Panning

In vitro affinity maturation of a natural human antibody overcomes a barrier to in vivo affinity maturation

Neutralization of divergent human immunodeficiency virus type 1 variants and primary isolates by IAM-41-2F5, an anti-gp41 human monoclonal antibody.

Characterization and large production of human monoclonal antibodies against the HIV-1 envelope.

The function and affinity maturation of HIV-1 gp120-specific monoclonal antibodies derived from colostral B cells

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