Affinity for the Interface Underpins Potency of Antibodies Operating In Membrane Environments

Edurne Rujas; Sara Insausti; Daniel P Leaman; Pablo Carravilla; Saul González-Resines; Valérie Monceaux; Rubén Sánchez-Eugenia; Miguel García-Porras; Ibon Iloro; Lei Zhang; Félix Elortza; Jean-Philippe Julien; Asier Saéz-Cirión; Michael B Zwick; Christian Eggeling; Akio Ojida; Carmen Domene; Jose M M Caaveiro; José L Nieva

doi:10.1016/j.celrep.2020.108037

Affinity for the Interface Underpins Potency of Antibodies Operating In Membrane Environments

Cell Rep. 2020 Aug 18;32(7):108037. doi: 10.1016/j.celrep.2020.108037.

Authors

Edurne Rujas¹, Sara Insausti², Daniel P Leaman³, Pablo Carravilla⁴, Saul González-Resines⁵, Valérie Monceaux⁶, Rubén Sánchez-Eugenia², Miguel García-Porras², Ibon Iloro⁷, Lei Zhang³, Félix Elortza⁷, Jean-Philippe Julien⁸, Asier Saéz-Cirión⁶, Michael B Zwick³, Christian Eggeling⁹, Akio Ojida¹⁰, Carmen Domene¹¹, Jose M M Caaveiro¹², José L Nieva¹³

Affiliations

¹ Instituto Biofisika (CSIC, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), PO Box 644, 48080 Bilbao, Spain; Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada.
² Instituto Biofisika (CSIC, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), PO Box 644, 48080 Bilbao, Spain.
³ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁴ Instituto Biofisika (CSIC, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), PO Box 644, 48080 Bilbao, Spain; Institute of Applied Optics and Biophysics Friedrich-Schiller-University Jena, Max-Wien Platz 4, 07743 Jena, Germany; Leibniz Institute of Photonic Technology e.V., Albert-Einstein-Straße 9, 07745 Jena, Germany.
⁵ Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AX, UK.
⁶ Institut Pasteur, Unité HIV Inflammation et Persistance, 28 rue du Docteur Roux, 75724 Paris Cedex 15, France.
⁷ Proteomics Platform, CIC bioGUNE, Parque Tecnológico de Vizcaya, 48160 Derio, Spain.
⁸ Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁹ Institute of Applied Optics and Biophysics Friedrich-Schiller-University Jena, Max-Wien Platz 4, 07743 Jena, Germany; Leibniz Institute of Photonic Technology e.V., Albert-Einstein-Straße 9, 07745 Jena, Germany.
¹⁰ Department of Chemical Biology, School of Pharmaceutical Sciences, Kyushu University, Fukuoka 819-0395, Japan.
¹¹ Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AX, UK; Department of Chemistry, University of Oxford, Oxford OX1 3TF, UK.
¹² Laboratory of Global Health Care, School of Pharmaceutical Sciences, Kyushu University, Fukuoka 819-0395, Japan. Electronic address: jose@phar.kyushu-u.ac.jp.
¹³ Instituto Biofisika (CSIC, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), PO Box 644, 48080 Bilbao, Spain. Electronic address: joseluis.nieva@ehu.es.

Abstract

The contribution of membrane interfacial interactions to recognition of membrane-embedded antigens by antibodies is currently unclear. This report demonstrates the optimization of this type of antibodies via chemical modification of regions near the membrane but not directly involved in the recognition of the epitope. Using the HIV-1 antibody 10E8 as a model, linear and polycyclic synthetic aromatic compounds are introduced at selected sites. Molecular dynamics simulations predict the favorable interactions of these synthetic compounds with the viral lipid membrane, where the epitope of the HIV-1 glycoprotein Env is located. Chemical modification of 10E8 with aromatic acetamides facilitates the productive and specific recognition of the native antigen, partially buried in the crowded environment of the viral membrane, resulting in a dramatic increase of its capacity to block viral infection. These observations support the harnessing of interfacial affinity through site-selective chemical modification to optimize the function of antibodies that target membrane-proximal epitopes.

Keywords: HIV-1 antibody; antibody engineering; antibody-membrane interaction; aromatic grafting; membrane biophysics; protein-membrane interaction; site-selective chemical modification.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Neutralizing / immunology*
Humans
Membrane Lipids / immunology*

Substances

Antibodies, Neutralizing
Membrane Lipids

Abstract

Publication types

MeSH terms

Substances

Grants and funding