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Engineering Antibodies to Enhance Activity and Increase Half-life

Sievers, Stuart A. and Patel, Sonal N. and Bennett, Kathleen and Klein, Florian and Nussenzweig, Michel C. and Bjorkman, Pamela J. (2014) Engineering Antibodies to Enhance Activity and Increase Half-life. AIDS Research and Human Retroviruses, 30 (S1). A210. ISSN 0889-2229. doi:10.1089/aid.2014.5456.abstract.

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Background: HIV/AIDS remains one of the most serious current threats to global public health. Although anti-HIV drugs have been effective among the wealthiest populations, a vaccine and/or new methods to prevent infections are needed lo control HIV globally. Strategies to combat HIV-1 require structural knowledge of how antibodies recognize HIV envelope proteins and how the immune system eliminates viruses. Until recently, only a small number of broadly neutralizing antibodies against HIV-1 had been characterized, and the immunological basis for their breadth and potency remains poorly understood. However. it was recently demonstrated that antibodies could be engineered to greatly enhance their breadth and potency (Diskin et al., Science 2011). Unfortunately, this and other engineering efforts have resulted in a decrease in antibody half-life in mouse and non-human primate models. This decrease in half-life correlates with an increase in reactivity to a variety of antigens, termed polyreactivity. Methods: In order to make better targets for passive delivery therapies, we are working to increase the half-life of antibodies while maintaining their breadth and potency using a variety of computational and structured-based techniques. One technique involves reducing the spatial aggregation propensity, in which an algorithm finds dynamically exposed hydrophobic patches on the surlace of proteins (Chemansetty et al., PNAS 2009). To this end, we have constructed several mutations in regions that have been predicted to have high aggregation propensities, and have tested them for polyreactivity and potency in neutralization assays. Results: Initial results show that these novel reagents have reduced polyreactivily, yet they still maintain their potency in in vitro neutralization assays. Conclusions: We are currently pursuing in vivo experiments in mice to further understand the relationship between antibody potency, polyreactivity, and half-life.

Item Type:Article
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URLURL TypeDescription
Nussenzweig, Michel C.0000-0003-0592-8564
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2014 Mary Ann Liebert, Inc. publishers.
Issue or Number:S1
Record Number:CaltechAUTHORS:20150211-082514507
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Official Citation:Engineering Antibodies to Enhance Activity and Increase Half-life Sievers Stuart A., Patel Sonal N., Bennett Kathleen, Klein Florian, Nussenzweig Michel C., and Bjorkman Pamela J.. AIDS Research and Human Retroviruses. October 2014, 30(S1): A210-A210. doi:10.1089/aid.2014.5456.abstract.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:54691
Deposited By: Ruth Sustaita
Deposited On:12 Feb 2015 00:44
Last Modified:10 Nov 2021 20:36

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