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

Einav, Tal and Yazdi, Shahrzad and Coey, Aaron and Bjorkman, Pamela J. and Phillips, Rob (2018) Harnessing Avidity: Quantifying Entropic and Energetic Effects of Linker Length and Rigidity Required for Multivalent Binding of Antibodies to HIV-1 Spikes. . (Unpublished)

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Due to the low density of envelope (Env) spikes on the surface of HIV-1, neutralizing IgG antibodies rarely bind bivalently using both antigen-binding arms (Fabs) to crosslink between spikes (inter-spike crosslinking), instead resorting to weaker monovalent binding that is more sensitive to Env mutations. Synthetic antibodies designed to bivalently bind a single Env trimer (intra-spike crosslinking) were previously shown to exhibit increased neutralization potencies. In initial work, diFabs joined by varying lengths of rigid double-stranded DNA (dsDNA) were considered. Anticipating future experiments to improve synthetic antibodies, we investigate whether linkers with different rigidities could enhance diFab potency by modeling DNA-Fabs containing different combinations of rigid dsDNA and flexible single-stranded DNA (ssDNA) and characterizing their neutralization potential. Model predictions suggest that while a long flexible polymer may be capable of bivalent binding, it exhibits weak neutralization due to the large loss in entropic degrees of freedom when both Fabs are bound. In contrast, 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 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:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper
Einav, Tal0000-0003-0777-1193
Bjorkman, Pamela J.0000-0002-2277-3990
Phillips, Rob0000-0003-3082-2809
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. bioRxiv preprint first posted online Sep. 3, 2018. 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.), R01 GM085286, and 1R35 GM118043-01 (MIRA) (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.
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
NIHR01 GM085286
NIH1R35 GM118043-01
Caltech-City of Hope Biomedical InitiativeUNSPECIFIED
Burroughs-Wellcome FundUNSPECIFIED
Marine Biological LaboratoryUNSPECIFIED
Subject Keywords:HIV-1; Avidity, Neutralizing antibodies; Statistical mechanics
Record Number:CaltechAUTHORS:20200117-131810813
Persistent URL:
Official Citation:Harnessing Avidity: Quantifying Entropic and Energetic Effects of Linker Length and Rigidity Required for Multivalent Binding of Antibodies to HIV-1 Spikes. Tal Einav, Shahrzad Yazdi, Aaron Coey, Pamela J. Bjorkman, Rob Phillips. bioRxiv 406454; doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:100797
Deposited By: Tony Diaz
Deposited On:17 Jan 2020 21:28
Last Modified:16 Nov 2021 17:56

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