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Harnessing Avidity: Quantifying the Entropic and Energetic Effects of Linker Length and Rigidity for Multivalent Binding of Antibodies to HIV-1

Einav, Tal and Yazdi, Shahrzad and Coey, Aaron and Bjorkman, Pamela J. and Phillips, Rob (2019) Harnessing Avidity: Quantifying the Entropic and Energetic Effects of Linker Length and Rigidity for Multivalent Binding of Antibodies to HIV-1. Cell Systems, 9 (5). pp. 466-474. ISSN 2405-4712. PMCID PMC6892280.

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IgG antibodies increase their apparent affinities by using both of their Fabs to simultaneously attach to antigens. HIV-1 foils this strategy by having few, and highly separated, Envelope (Env) spike targets for antibodies, forcing most IgGs to bind monovalently. Here, we develop a statistical mechanics model of synthetic diFabs joined by DNA linkers of different lengths and flexibilities. This framework enables us to translate the energetic and entropic effects of the linker into the neutralization potency of a diFab. We demonstrate that the strongest neutralization potencies are predicted to require a rigid linker that optimally spans the distance between two Fab binding sites on an Env trimer and that avidity can be further boosted by incorporating more Fabs into these constructs. These results inform the design of multivalent anti-HIV-1 therapeutics that utilize avidity effects to remain potent against HIV-1 in the face of the rapid mutation of Env spikes.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Einav, Tal0000-0003-0777-1193
Bjorkman, Pamela J.0000-0002-2277-3990
Phillips, Rob0000-0003-3082-2809
Additional Information:© 2019 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license ( Received 22 May 2019, Revised 10 September 2019, Accepted 17 September 2019, Available online 23 October 2019. We thank Anthony Bartolotta, Justin Bois, Jim Eisenstein, Vahe Galstyan, Peng He, Willem Kegel, David Hsieh, Giacomo Koszegi, Pankaj Mehta, Jiseon Min, Olexei Motrunich, Noah Olsman, Vahe Singh, and Richard Zhu for useful discussions; Christopher Barnes for measuring modeled 3BNC60-Env complexes; and Marta Murphy for help preparing figures. This research was supported by NIH NIAID grants 1R01AI129784 and HIVRAD P01 AI100148 (P.J.B.), the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery grant 1040753 (P.J.B.), La Fondation Pierre-Gilles de Gennes (R.P.), the Rosen Center at Caltech (R.P.), 1R35 GM118043-01 Maximizing Investigators’ Research Award (MIRA), United States, and R01 GM085286 (R.P.), and a Caltech-COH Biomedical Research Initiative (P.J.B.). We thank the Burroughs Wellcome Fund for their support through the Career Award at the Scientific Interface (S.Y.) as well as for the Physiology Course at the Marine Biological Laboratory where part of this work was done. Author Contributions: T.E., A.P.W., R.P., and P.J.B. conceived the project. T.E., S.Y., and R.P. developed the model and performed analyses. T.E., R.P., and P.J.B. wrote the paper with input from other authors. The authors declare no competing interests.
Group:Rosen Bioengineering Center
Funding AgencyGrant Number
NIHP01 AI100148
Bill and Melinda Gates Foundation1040753
La Fondation Pierre-Gilles de GennesUNSPECIFIED
Donna and Benjamin M. Rosen Bioengineering CenterUNSPECIFIED
NIH1R35 GM118043-01
NIHR01 GM085286
Caltech-City of Hope Biomedical InitiativeUNSPECIFIED
Burroughs Wellcome FundUNSPECIFIED
Marine Biological LaboratoryUNSPECIFIED
Subject Keywords:HIV-1; avidity; neutralizing antibodies; statistical mechanics
Issue or Number:5
PubMed Central ID:PMC6892280
Record Number:CaltechAUTHORS:20191023-142258650
Persistent URL:
Official Citation:Tal Einav, Shahrzad Yazdi, Aaron Coey, Pamela J. Bjorkman, Rob Phillips, Harnessing Avidity: Quantifying the Entropic and Energetic Effects of Linker Length and Rigidity for Multivalent Binding of Antibodies to HIV-1, Cell Systems, Volume 9, Issue 5, 2019, Pages 466-474.e7, ISSN 2405-4712, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:99410
Deposited By: Tony Diaz
Deposited On:23 Oct 2019 21:48
Last Modified:18 Dec 2019 17:50

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