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Super Potent Bispecific Llama VHH Antibodies Neutralize HIV via a Combination of gp41 and gp120 Epitopes

1
Department of Biology, Faculty of Sciences, Utrecht University, 3584 CH Utrecht, The Netherlands
2
QVQ Holding bv, Yalelaan 1, 3584 CL Utrecht, The Netherlands
3
Institute de Biologie Structurale (IBS), CNRS, CEA, Université Grenoble Alpes, F-38000 Grenoble, France
4
Immunocore Ltd., 101 Park Drive, Milto, Abingdon OX14 4RY, UK
5
Division of Infection and Immunity, University College London, London WC1E 6BT, UK
6
Pepscan B.V., Zuidersluisweg 2, 8243 RC Lelystad, The Netherlands
7
European Molecular Biology Laboratory, Grenoble Outstation, 6 rue Jules Horowitz, 38042 Grenoble, France
8
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, 4002 Basel, Switzerland
*
Author to whom correspondence should be addressed.
These authors contributed equally.
Antibodies 2019, 8(2), 38; https://doi.org/10.3390/antib8020038
Received: 17 March 2019 / Revised: 19 May 2019 / Accepted: 30 May 2019 / Published: 18 June 2019
(This article belongs to the Special Issue Nanobody)
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Abstract

Broad and potent neutralizing llama single domain antibodies (VHH) against HIV-1 targeting the CD4 binding site (CD4bs) have previously been isolated upon llama immunization. Here we describe the epitopes of three additional VHH groups selected from phage libraries. The 2E7 group binds to a new linear epitope in the first heptad repeat of gp41 that is only exposed in the fusion-intermediate conformation. The 1B5 group competes with co-receptor binding and the 1F10 group interacts with the crown of the gp120 V3 loop, occluded in native Env. We present biophysical and structural details on the 2E7 interaction with gp41. In order to further increase breadth and potency, we constructed bi-specific VHH. The combination of CD4bs VHH (J3/3E3) with 2E7 group VHH enhanced strain-specific neutralization with potencies up to 1400-fold higher than the mixture of the individual VHHs. Thus, these new bivalent VHH are potent new tools to develop therapeutic approaches or microbicide intervention. View Full-Text
Keywords: Aids; HIV; Llama Antibodies; bi-specific VHH; pepscan; competition studies; epitope mapping; co-crystallisation Aids; HIV; Llama Antibodies; bi-specific VHH; pepscan; competition studies; epitope mapping; co-crystallisation
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Strokappe, N.M.; Hock, M.; Rutten, L.; Mccoy, L.E.; Back, J.W.; Caillat, C.; Haffke, M.; Weiss, R.A.; Weissenhorn, W.; Verrips, T. Super Potent Bispecific Llama VHH Antibodies Neutralize HIV via a Combination of gp41 and gp120 Epitopes. Antibodies 2019, 8, 38.

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