A Bispecific Antibody That Simultaneously Recognizes the V2- and V3-Glycan Epitopes of the HIV-1 Envelope Glycoprotein Is Broader and More Potent than Its Parental Antibodies

ABSTRACT Broadly neutralizing antibodies (bNAbs) can prevent and control an HIV-1 infection, but their breadth is invariably too limited for use as monotherapy. To address this problem, bi- and trispecific antibody-like constructs have been developed. These engineered antibodies typically have great...

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Autores principales:	Meredith E. Davis-Gardner, Barnett Alfant, Jesse A. Weber, Matthew R. Gardner, Michael Farzan
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	broadly neutralizing antibodies bispecific antibodies human immunodeficiency virus 1 antibody neutralization human immunodeficiency virus Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/b24d26652273424fb366dd8cdb7de9b5
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spelling	oai:doaj.org-article:b24d26652273424fb366dd8cdb7de9b52021-11-15T15:56:58ZA Bispecific Antibody That Simultaneously Recognizes the V2- and V3-Glycan Epitopes of the HIV-1 Envelope Glycoprotein Is Broader and More Potent than Its Parental Antibodies10.1128/mBio.03080-192150-7511https://doaj.org/article/b24d26652273424fb366dd8cdb7de9b52020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03080-19https://doaj.org/toc/2150-7511ABSTRACT Broadly neutralizing antibodies (bNAbs) can prevent and control an HIV-1 infection, but their breadth is invariably too limited for use as monotherapy. To address this problem, bi- and trispecific antibody-like constructs have been developed. These engineered antibodies typically have greater breadth than the native bNAbs from which they were derived, but they are not more potent because they do not, in most cases, simultaneously engage more than a single epitope of the HIV-1 envelope glycoprotein (Env). Here, we describe a new class of bispecific antibodies targeting the V2-glycan (apex) and V3-glycan regions of the HIV-1 envelope glycoprotein (Env). Specifically, bispecific antibodies with a single-chain (scFv) form of the CAP256.VRC26.25 V2-glycan (apex) antibody on one antibody arm and a full V3-glycan Fab on the other arm neutralizes more HIV-1 isolates than the bNAbs from which they were derived. Moreover, these bispecific antibodies are markedly more potent than their parental bNAbs, likely because they simultaneously engage both the apex and V3-glycan epitopes of Env. Our data show that simultaneous engagement of two critical epitopes of a single Env trimer can markedly increase the potency of a bispecific antibody. IMPORTANCE Broadly neutralizing antibodies (bNAbs) can prevent a new HIV-1 infection and can at least temporarily suppress an established infection. However, antibody-resistant viruses rapidly emerge in infected persons treated with any single bNAb. Several bispecific antibodies have been developed to increase the breadth of these antibodies, but typically only one arm of these bispecific constructs binds the HIV-1 envelope glycoprotein trimer (Env). Here, we develop and characterize bispecific constructs based on well-characterized V2-glycan and V3-glycan bNAbs and show that at least one member of this class is more potent than its parental antibodies, indicating that they can simultaneously bind both of these epitopes of a single Env trimer. These data show that bispecific antibody-like proteins can achieve greater neutralization potency than the bNAbs from which they were derived.Meredith E. Davis-GardnerBarnett AlfantJesse A. WeberMatthew R. GardnerMichael FarzanAmerican Society for Microbiologyarticlebroadly neutralizing antibodiesbispecific antibodieshuman immunodeficiency virus 1antibody neutralizationbroadly neutralizing antibodieshuman immunodeficiency virusMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	broadly neutralizing antibodies bispecific antibodies human immunodeficiency virus 1 antibody neutralization broadly neutralizing antibodies human immunodeficiency virus Microbiology QR1-502
spellingShingle	broadly neutralizing antibodies bispecific antibodies human immunodeficiency virus 1 antibody neutralization broadly neutralizing antibodies human immunodeficiency virus Microbiology QR1-502 Meredith E. Davis-Gardner Barnett Alfant Jesse A. Weber Matthew R. Gardner Michael Farzan A Bispecific Antibody That Simultaneously Recognizes the V2- and V3-Glycan Epitopes of the HIV-1 Envelope Glycoprotein Is Broader and More Potent than Its Parental Antibodies
description	ABSTRACT Broadly neutralizing antibodies (bNAbs) can prevent and control an HIV-1 infection, but their breadth is invariably too limited for use as monotherapy. To address this problem, bi- and trispecific antibody-like constructs have been developed. These engineered antibodies typically have greater breadth than the native bNAbs from which they were derived, but they are not more potent because they do not, in most cases, simultaneously engage more than a single epitope of the HIV-1 envelope glycoprotein (Env). Here, we describe a new class of bispecific antibodies targeting the V2-glycan (apex) and V3-glycan regions of the HIV-1 envelope glycoprotein (Env). Specifically, bispecific antibodies with a single-chain (scFv) form of the CAP256.VRC26.25 V2-glycan (apex) antibody on one antibody arm and a full V3-glycan Fab on the other arm neutralizes more HIV-1 isolates than the bNAbs from which they were derived. Moreover, these bispecific antibodies are markedly more potent than their parental bNAbs, likely because they simultaneously engage both the apex and V3-glycan epitopes of Env. Our data show that simultaneous engagement of two critical epitopes of a single Env trimer can markedly increase the potency of a bispecific antibody. IMPORTANCE Broadly neutralizing antibodies (bNAbs) can prevent a new HIV-1 infection and can at least temporarily suppress an established infection. However, antibody-resistant viruses rapidly emerge in infected persons treated with any single bNAb. Several bispecific antibodies have been developed to increase the breadth of these antibodies, but typically only one arm of these bispecific constructs binds the HIV-1 envelope glycoprotein trimer (Env). Here, we develop and characterize bispecific constructs based on well-characterized V2-glycan and V3-glycan bNAbs and show that at least one member of this class is more potent than its parental antibodies, indicating that they can simultaneously bind both of these epitopes of a single Env trimer. These data show that bispecific antibody-like proteins can achieve greater neutralization potency than the bNAbs from which they were derived.
format	article
author	Meredith E. Davis-Gardner Barnett Alfant Jesse A. Weber Matthew R. Gardner Michael Farzan
author_facet	Meredith E. Davis-Gardner Barnett Alfant Jesse A. Weber Matthew R. Gardner Michael Farzan
author_sort	Meredith E. Davis-Gardner
title	A Bispecific Antibody That Simultaneously Recognizes the V2- and V3-Glycan Epitopes of the HIV-1 Envelope Glycoprotein Is Broader and More Potent than Its Parental Antibodies
title_short	A Bispecific Antibody That Simultaneously Recognizes the V2- and V3-Glycan Epitopes of the HIV-1 Envelope Glycoprotein Is Broader and More Potent than Its Parental Antibodies
title_full	A Bispecific Antibody That Simultaneously Recognizes the V2- and V3-Glycan Epitopes of the HIV-1 Envelope Glycoprotein Is Broader and More Potent than Its Parental Antibodies
title_fullStr	A Bispecific Antibody That Simultaneously Recognizes the V2- and V3-Glycan Epitopes of the HIV-1 Envelope Glycoprotein Is Broader and More Potent than Its Parental Antibodies
title_full_unstemmed	A Bispecific Antibody That Simultaneously Recognizes the V2- and V3-Glycan Epitopes of the HIV-1 Envelope Glycoprotein Is Broader and More Potent than Its Parental Antibodies
title_sort	bispecific antibody that simultaneously recognizes the v2- and v3-glycan epitopes of the hiv-1 envelope glycoprotein is broader and more potent than its parental antibodies
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/b24d26652273424fb366dd8cdb7de9b5
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A Bispecific Antibody That Simultaneously Recognizes the V2- and V3-Glycan Epitopes of the HIV-1 Envelope Glycoprotein Is Broader and More Potent than Its Parental Antibodies

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