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Evaluation of CD4-CD4i Antibody Architectures Yields Potent, Broadly Cross-Reactive Anti-Human Immunodeficiency Virus Reagents

West, Anthony P., Jr. and Galimidi, Rachel P. and Foglesong, Christopher P. and Gnanapragasam, Priyanthi N. P. and Klein, Joshua S. and Bjorkman, Pamela J. (2010) Evaluation of CD4-CD4i Antibody Architectures Yields Potent, Broadly Cross-Reactive Anti-Human Immunodeficiency Virus Reagents. Journal of Virology, 84 (1). pp. 261-269. ISSN 0022-538X. PMCID PMC2798438. http://resolver.caltech.edu/CaltechAUTHORS:20100114-152105619

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Abstract

The envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) has several adaptations that allow the virus to evade antibody neutralization. Nevertheless, a few broadly cross-reactive neutralizing antibodies as well as reagents containing portions of CD4, the HIV receptor, have demonstrated partial efficacy in suppressing viral replication. One type of reagent designed for improved HIV neutralization fuses the CD4 D1-D2 domains to the variable regions of an antibody recognizing the CD4-induced (CD4i) coreceptor binding site on the gp120 portion of the HIV envelope spike. We designed, expressed, purified, and tested the neutralization potencies of CD4-CD4i antibody reagents with different architectures, antibody combining sites, and linkers. We found that fusing CD4 to the heavy chain of the CD4i antibody E51 yields a bivalent reagent including an antibody Fc region that expresses well, is expected to have a long serum half-life, and has comparable or greater neutralization activity than well-known broadly neutralizing anti-HIV antibodies. A CD4 fusion with the anti-HIV carbohydrate antibody 2G12 also results in a potent neutralizing reagent with more broadly neutralizing activity than 2G12 alone.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1128/JVI.01528-09DOIArticle
http://jvi.asm.org/content/84/1/261PublisherArticle
http://jvi.asm.org/content/84/1/261/suppl/DC1PublisherSupplemental Material
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2798438/PubMed CentralArticle
ORCID:
AuthorORCID
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2010 American Society for Microbiology. Received 22 July 2009; Accepted 19 October 2009; Published ahead of print on 28 October 2009. We thank the CAVD Neutralizing Antibody Core Laboratories for performing in vitro neutralization assays, the Caltech Protein and Peptide Microanalysis Facility for performing N-terminal sequencing, Noreen Tiangco for cloning the 21c genes, Maria Politzer for subcloning and DNA preparation, Marta Murphy for figure preparation, Edward Berger (National Institutes of Health) for the CD4-scFv17b gene, William Olson at Progenics Pharmaceuticals for providing CD4-IgG2, Dennis Burton (Scripps Research Institute) for the anti-gD and 2G12 genes, and James Robinson (Tulane University) for the 21c cell line. This work was supported by a grant from the Bill and Melinda Gates Foundation through the Grand Challenges in Global Health Initiative.
Funders:
Funding AgencyGrant Number
Bill and Melinda Gates FoundationUNSPECIFIED
PubMed Central ID:PMC2798438
Record Number:CaltechAUTHORS:20100114-152105619
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20100114-152105619
Official Citation:West, Anthony P., Jr., Galimidi, Rachel P., Foglesong, Christopher P., Gnanapragasam, Priyanthi N. P., Klein, Joshua S., Bjorkman, Pamela J. Evaluation of CD4-CD4i Antibody Architectures Yields Potent, Broadly Cross-Reactive Anti-Human Immunodeficiency Virus Reagents J. Virol. 2010 84: 261-269
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:17192
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:28 Jan 2010 23:44
Last Modified:09 Nov 2017 00:11

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