Rational design of a trispecific antibody targeting the HIV-1 Env with elevated anti-viral activity

Nature Communications
James J SteinhardtYuxing Li

Abstract

HIV-1 broadly neutralizing antibodies (bNAbs) are being explored as passively administered therapeutic and preventative agents. However, the extensively diversified HIV-1 envelope glycoproteins (Env) rapidly acquire mutations to evade individual bNAbs in monotherapy regimens. The use of a "single" agent to simultaneously target distinct Env epitopes is desirable to overcome viral diversity. Here, we report the use of tandem single-chain variable fragment (ScFv) domains of two bNAbs, specific for the CD4-binding site and V3 glycan patch, to form anti-HIV-1 bispecific ScFvs (Bi-ScFvs). The optimal Bi-ScFv crosslinks adjacent protomers within one HIV-1 Env spike and has greater neutralization breadth than its parental bNAbs. Furthermore, the combination of this Bi-ScFv with a third bNAb recognizing the Env membrane proximal external region (MPER) results in a trispecific bNAb, which has nearly pan-isolate neutralization breadth and high potency. Thus, multispecific antibodies combining functional moieties of bNAbs could achieve outstanding neutralization capacity with augmented avidity.

References

Nov 15, 1991·Proceedings of the National Academy of Sciences of the United States of America·D R BurtonR A Lerner
Jun 10, 2000·Science·B KorberT Bhattacharya
Sep 6, 2001·Biomolecular Engineering·J KriangkumM R Suresh
Nov 21, 2001·British Medical Bulletin·B KorberV Detours
Sep 5, 2002·Nature Reviews. Immunology·Dennis R Burton
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Sep 10, 2005·Nature Biotechnology·Philipp Holliger, Peter J Hudson
Oct 10, 2006·Biophysical Journal·Sri Rama Koti AinavarapuJulio M Fernandez
Mar 3, 2007·Virus Research·Juan Cristina, Mauro Costa-Mattioli
Mar 6, 2009·Journal of Structural Biology·Gabriel C LanderBridget Carragher
Aug 4, 2010·The Journal of Experimental Medicine·John PietzschMichel C Nussenzweig
Aug 19, 2011·Nature·Laura M WalkerPascal Poignard
Apr 5, 2012·Clinical & Developmental Immunology·Zuhaida Asra AhmadMuhajir Hamid
Oct 3, 2012·Advanced Drug Delivery Reviews·Xiaoying ChenWei-Chiang Shen
Jul 23, 2013·Methods : a Companion to Methods in Enzymology·Gabriele Proetzel, Derry C Roopenian
Jul 24, 2013·Proceedings of the National Academy of Sciences of the United States of America·Craig S PaceDavid D Ho
Sep 18, 2013·Proceedings of the National Academy of Sciences of the United States of America·Joshua A HorwitzMichel C Nussenzweig
May 24, 2014·Journal of Acquired Immune Deficiency Syndromes : JAIDS·Ming SunDavid D Ho
Jul 12, 2014·Science·Dan H Barouch, Steven G Deeks
Nov 5, 2014·Frontiers in Immunology·Gestur VidarssonTheo Rispens
Nov 26, 2014·Proceedings of the National Academy of Sciences of the United States of America·Devin SokDennis R Burton
Jan 31, 2015·Cell·Rachel P GalimidiPamela J Bjorkman
Feb 24, 2015·Current Opinion in HIV and AIDS·Jintanat AnanworanichMerlin L Robb
Feb 25, 2015·Nature·Matthew R GardnerMichael Farzan
Mar 12, 2015·Current Opinion in HIV and AIDS·Stuart A SieversPamela J Bjorkman
Mar 12, 2015·Current Opinion in HIV and AIDS·Barney S Graham, Donna M Ambrosino
May 3, 2015·Cold Spring Harbor Perspectives in Medicine·Chih-Lin Lin, Jia-Horng Kao
May 20, 2015·Nature Immunology·Dennis R Burton, John R Mascola
Sep 4, 2015·Clinical and Experimental Immunology·Julie E LedgerwoodUNKNOWN VRC 602 Study Team
Nov 8, 2015·Advanced Drug Delivery Reviews·Quanyin HuZhen Gu

❮ Previous
Next ❯

Citations

May 10, 2019·Journal of Virology·Christoph H FellingerMichael Farzan
Jun 9, 2019·Nature Reviews. Drug Discovery·Aran F LabrijnPaul W H I Parren
Aug 4, 2019·Journal of Virology·David WenselMark Krystal
Jan 28, 2020·Emerging Microbes & Infections·Yubin LiuTaisheng Li
Jan 28, 2020·Annual Review of Medicine·Shelly T Karuna, Lawrence Corey
Mar 11, 2020·Antimicrobial Agents and Chemotherapy·Peng-Nien HuangJohn Tsu-An Hsu
Jun 12, 2020·Emerging Microbes & Infections·Yuezhi LinXiaojun Wang
Aug 1, 2020·Current Opinion in HIV and AIDS·Marina Tuyishime, Guido Ferrari
Aug 31, 2018·Retrovirology·Neal N PadteDavid D Ho
May 15, 2019·PLoS Pathogens·Giulia CalendaElena Martinelli
Jul 17, 2020·Current HIV/AIDS Reports·Andrew Kapoor, C Sabrina Tan
May 12, 2020·Frontiers in Cellular and Infection Microbiology·Matthew R Gardner
Jul 30, 2020·International Journal of Molecular Sciences·Lucille LamendourFlorence Velge-Roussel
Apr 24, 2018·The Journal of Clinical Investigation·Guido Ferrari
Jul 6, 2018·Journal of Pathogens·Noel Jacques Awi, Sin-Yeang Teow
May 21, 2019·Current Opinion in HIV and AIDS·Irene A AbelaAlexandra Trkola
Jun 14, 2019·PLoS Pathogens·Panpan ZhouLinqi Zhang
Mar 11, 2020·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Wanwisa PromsoteAmarendra Pegu
Jan 30, 2020·Molecular Therapy : the Journal of the American Society of Gene Therapy·Kevin E LindsayPhilip J Santangelo
Jun 15, 2021·Frontiers in Public Health·David A SpencerAnn J Hessell
Jul 10, 2020·International Immunopharmacology·Shahrzad AhangarzadehAbbas Alibakhshi
Dec 12, 2018·ACS Infectious Diseases·Nizar Mohammad AbuharfeilFawzi M Alsheyab
Jul 16, 2020·ACS Chemical Biology·Rebecca M LimJianming Xie
Nov 23, 2021·Journal of the International AIDS Society·Maurine D MinerDavid Montefiori

❮ Previous
Next ❯

Methods Mentioned

BETA
biolayer interferometry
biosensors
electron microscopy
dynamic
size exclusion chromatography
biosensor
transfection
affinity purification
Biolayer
light interferometry

Software Mentioned

GraphPad Prism
Structure Analysis - Distance
UCSF Chimera
Chimera
ForteBio Data Analysis
Malvern Zetasizer

Related Concepts

Related Feeds

Antivirals

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Antivirals (ASM)

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Antibody Specificity

Antibodies produced by B cells are highly specific for antigen as a result of random gene recombination and somatic hypermutation and affinity maturation. As the main effector of the humoral immune system, antibodies can neutralize foreign cells. Find the latest research on antibody specificity here.