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| Open AccessA potent Henipavirus cross-neutralizing antibody reveals a dynamic fusion-triggering pattern of the G-tetramer
There are no approved interventions for Hendra or Nipah viruses. Here, the authors isolate a G glycoprotein-specific antibody with cross-neutralizing and in vivo protective activities, and structurally resolve its binding pattern to the G protein.
- Pengfei Fan
- , Mengmeng Sun
- & Sandra Chiu
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Article
| Open AccessCEA-CD3 bispecific antibody cibisatamab with or without atezolizumab in patients with CEA-positive solid tumours: results of two multi-institutional Phase 1 trials
Cibisatamab is a T-cell bispecific antibody targeting the carcinoembryonic antigen (CEA) on tumor cells and CD3 epsilon chain on T cells. Here the authors report the results of two clinical trials of cibisatamab as monotherapy (NCT02324257) and in combination with atezolizumab (anti-PD-L1; NCT02650713) in patients with CEA-positive solid tumors.
- Neil H. Segal
- , Ignacio Melero
- & Guillem Argilés
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| Open AccessThe hinge-engineered IgG1-IgG3 hybrid subclass IgGh47 potently enhances Fc-mediated function of anti-streptococcal and SARS-CoV-2 antibodies
Here, the authors elongated the hinge structure of IgG1 monoclonal antibodies. The modified IgG1-IgG3 hybrid subclass showed enhanced Fc-mediated function compared to IgG1 in two distinct biological systems, Streptococcus pyogenes and SARS-CoV-2.
- Arman Izadi
- , Yasaman Karami
- & Pontus Nordenfelt
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Article
| Open AccessVISTA checkpoint inhibition by pH-selective antibody SNS-101 with optimized safety and pharmacokinetic profiles enhances PD-1 response
VISTA is a pH-dependent inhibitory checkpoint for T-cells that is abundant on myeloid lineage cells and antagonists of VISTA may successfully reinvigorate anti-tumour immunity. Here, the authors show that the antibody SNS-101, which is currently being investigated in humans in a clinical trial, is characterized by pH-sensitivity that endows it with favorable pharmacokinetic and safety profiles, and enhanced therapeutic effect when combined with PD-1 checkpoint inhibitors.
- Thomas Thisted
- , F. Donelson Smith
- & Edward H. van der Horst
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Article
| Open AccessFilamentous fungus-produced human monoclonal antibody provides protection against SARS-CoV-2 in hamster and non-human primate models
The filamentous fungus expression system Thermothelomyces heterothallica (C1) is a protein expression system that may be useful for large scale antibody production. Here the authors characterise the production of a human monoclonal antibody that neutralises SARS-CoV-2 and compare functional properties in vitro and in animal models to antibodies produced using other methods.
- Franziska K. Kaiser
- , Mariana Gonzalez Hernandez
- & Albert D.M.E. Osterhaus
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| Open AccessStructure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies
The T cell receptor β-chain is expressed in two isoforms, TRBC1 and TRBC2, with clonally expanded mature T cell lymphomas expressing one of them exclusively, while healthy T cells randomly express either TRBC1 or TRBC2. Here authors show structure-based design of a TRBC2-specific antibody, and depletion of malignant T cells carrying TRBC1 or TRBC2 with CAR-T cells against the cognate receptor chain in murine models.
- Mathieu Ferrari
- , Matteo Righi
- & Martin Pule
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Article
| Open Accessi-shaped antibody engineering enables conformational tuning of biotherapeutic receptor agonists
In contrast to their clinical success as inhibitors and targeting agents, antibodies have generally been ineffective as receptor agonists. Here, Romei et al. leverage a natural homotypic interface to tune antibody geometry, enabling optimization of agonist activity for multiple therapeutic targets.
- Matthew G. Romei
- , Brandon Leonard
- & Greg A. Lazar
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Article
| Open AccessAntibody-dependent enhancement of toxicity of myotoxin II from Bothrops asper
The recent emergence of monoclonal antibodies able to neutralize snake toxins have revolutionized the approach of developing novel therapies to treat snakebite envenoming, at least in animal models. Here, the authors show antibody-dependent enhancement of toxicity (ADET) for a toxin derived from snake venom and highlight the importance of this phenomenon when testing therapeutic antibodies against snake venoms in animal models.
- Christoffer V. Sørensen
- , Julián Fernández
- & Andreas H. Laustsen
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| Open AccessCharacterizations of a neutralizing antibody broadly reactive to multiple gluten peptide:HLA-DQ2.5 complexes in the context of celiac disease
Targeting gluten antigens presents a plausible therapy option for celiac disease. Here the authors generate and characterize a broadly neutralizing antibody recognizing more than 25 gluten peptide:HLA-DQ2.5 complexes, with structural analyses implicating its mode of interaction, and with mouse in vivo studies supporting its therapeutic feasibility.
- Yuu Okura
- , Yuri Ikawa-Teranishi
- & Tomoyuki Igawa
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| Open AccessA single nanobody neutralizes multiple epochally evolving human noroviruses by modulating capsid plasticity
GII.4 human noroviruses cause pandemic gastroenteritis and undergo epochal evolution. This study shows that a single Llama-derived nanobody neutralizes multiple GII.4 variants using a mechanism by targeting capsid plasticity.
- Wilhelm Salmen
- , Liya Hu
- & B. V. Venkataram Prasad
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| Open AccessA human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models
β-cell dysfunction in type 2 diabetes is associated with pathological aggregates of IAPP that accumulate in pancreatic islets. Here, the authors describe a novel antibody cloned from healthy elderly donors that selectively targets IAPP oligomers and protects from IAPP toxicity.
- Fabian Wirth
- , Fabrice D. Heitz
- & Jan Grimm
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Article
| Open AccessA subset of type-II collagen-binding antibodies prevents experimental arthritis by inhibiting FCGR3 signaling in neutrophils
Rheumatoid arthritis (RA) involves several types of autoantibodies, which are usually considered pathogenic. In this study, the authors use phage display to develop antibodies targeting type-II collagen that are protective in multiple experimental models of RA.
- Zhongwei Xu
- , Bingze Xu
- & Rikard Holmdahl
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Article
| Open AccessA rapid cell-free expression and screening platform for antibody discovery
Antibody discovery is bottlenecked by the individual expression and evaluation of antigen specific hits. Here, the authors build an antibody screening workflow leveraging cell-free protein synthesis that enables expression and evaluation of hundreds of antibody fragments in less than 24 h.
- Andrew C. Hunt
- , Bastian Vögeli
- & Michael C. Jewett
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Article
| Open AccessAntibody blockade of Jagged1 attenuates choroidal neovascularization
Current treatment for neovascular age-related macular degeneration (nAMD) does not help all patients. Here, the authors show that using antibodies to block Jagged1 reduces disease burden in a model of nAMD, which could enable new treatment options.
- Torleif Tollefsrud Gjølberg
- , Jonas Aakre Wik
- & Eirik Sundlisæter
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Article
| Open AccessAn anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity
The success of HER2-targeted cancer therapy is limited by treatment resistance. Here, the authors engineer an anti-HER2 biparatopic antibody with multiple mechanisms of action including induction of HER2 clustering to trigger complement dependent cytotoxicity, signal inhibition, antibody dependent cellular cytotoxicity and phagocytosis.
- Nina E. Weisser
- , Mario Sanches
- & Surjit Dixit
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Article
| Open AccessCross-protective antibodies against common endemic respiratory viruses
Immunocompromised patients are vulnerable to respiratory viral infections. Here, the authors characterize cross-neutralizing antibodies to respiratory syncytial virus, human metapneumovirus, and human parainfluenza viruses and show effective protection in male hamsters.
- Madelyn Cabán
- , Justas V. Rodarte
- & Jim Boonyaratanakornkit
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Article
| Open AccessDiscovery and optimization of a broadly-neutralizing human monoclonal antibody against long-chain α-neurotoxins from snakes
The treatment of snakebite envenoming is currently suboptimal. Existing antivenoms often lack efficacy and may cause adverse reactions. Here, the authors derive, develop, and demonstrate the utility of toxin-specific broadly-neutralizing human monoclonal antibodies with established reactivity across related venom toxins from different snake species and show efficacy in rodent models.
- Line Ledsgaard
- , Jack Wade
- & Aneesh Karatt-Vellatt
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| Open AccessShark nanobodies with potent SARS-CoV-2 neutralizing activity and broad sarbecovirus reactivity
SARS-CoV-2 variants of concern continue to emerge, reducing vaccine efficacy and limiting therapeutic options. Here, Chen and colleagues describe the identification and design of shark nanobodies with pansarbecovirus activity.
- Wei-Hung Chen
- , Agnes Hajduczki
- & M. Gordon Joyce
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| Open AccessThe rapid and highly parallel identification of antibodies with defined biological activities by SLISY
The covid pandemic has highlighted the need for rapid antibody development. Here, authors develop an approach called SLISY, which uses NGS with phage display to simultaneously assess millions of clones to rapidly isolate specific antibodies against SARS-CoV-2 and its evolving variants.
- Steve Lu
- , Austin K. Mattox
- & Kenneth W. Kinzler
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Article
| Open AccessThe Fab region of IgG impairs the internalization pathway of FcRn upon Fc engagement
Disrupting the association between the Immunoglobulin G constant fragment (Fc) and the neonatal Fc receptor (FcRn) by engineered antibodies is a promising strategy to reduce autoantibody levels in autoimmune diseases. Here authors show that the variable fragment (Fab) of immunoglobulins could disturb the Fc-FcRn interaction, therefore the therapeutic effect of Fc-only fragments might surpass that of Fc-engineered antibodies with enhanced binding to FcRn.
- Maximilian Brinkhaus
- , Erwin Pannecoucke
- & Gestur Vidarsson
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| Open AccessIgG-like bispecific antibodies with potent and synergistic neutralization against circulating SARS-CoV-2 variants of concern
COVID-19 can be treated with monoclonal antibodies against SARS-CoV-2, but emerging new variants might show resistance towards existing therapy. Here authors show that anti-SARS-CoV-2 spike human single-chain antibody fragments could gain neutralizing activity against variants of concern upon engineering into a human bispecific antibody.
- Matthew R. Chang
- , Luke Tomasovic
- & Wayne A. Marasco
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| Open AccessEngineering SARS-CoV-2 specific cocktail antibodies into a bispecific format improves neutralizing potency and breadth
Bispecific antibodies can have advantages compared to antibody cocktails. Here, the authors engineer and characterize two different approaches for generating bispecific SARS-CoV-2 specific antibodies and find that only one design increases antigen-binding and virus neutralizing activities.
- Zhiqiang Ku
- , Xuping Xie
- & Zhiqiang An
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Article
| Open AccessStructure-guided and phage-assisted evolution of a therapeutic anti-EGFR antibody to reverse acquired resistance
Acquired resistance to cetuximab can be mediated by generation of mutations in the EGFR ectodomain. Here the authors report a structure-guided and phage-assisted evolution approach for cetuximab evolution to reverse resistance without altering the binding epitope or undermining antibody efficacy.
- Xinlei Zhuang
- , Zhe Wang
- & Liqiang Pan
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Article
| Open AccessCo-optimization of therapeutic antibody affinity and specificity using machine learning models that generalize to novel mutational space
Optimising antibody properties such as affinity can be detrimental to other key properties. Here the authors use machine learning to simplify the identification of antibodies with co-optimal levels of affinity and specificity for a clinical-stage antibody that displays high levels of on- and off-target binding.
- Emily K. Makowski
- , Patrick C. Kinnunen
- & Peter M. Tessier
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| Open AccessMonospecific and bispecific monoclonal SARS-CoV-2 neutralizing antibodies that maintain potency against B.1.617
Despite effective vaccines against SARS-CoV-2, therapeutic options such as anti-virals and neutralizing antibodies are critical in treating disease, especially given the breakthrough infections of emerging VOCs. Here, Peng et al. generate two potent monoclonal antibodies and a bispecific antibody with two antigenrecognition variable regions targeting SARS-CoV-2 spike, provide CryoEM structures and show in vitro and in vivo efficacy of a humanized antibody against wildtype virus and delta variant.
- Lei Peng
- , Yingxia Hu
- & Sidi Chen
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Article
| Open AccessCancer immune therapy with PD-1-dependent CD137 co-stimulation provides localized tumour killing without systemic toxicity
The toxicity arising from generalised stimulation of T cells restricts applicability of CD137 agonists in cancer immune therapy. Here authors show that a bispecific antibody blocking PD-1 while activating CD137 efficiently restricts T cell activation to the tumour microenvironment, resulting in efficient tumour control and reduced liver toxicity.
- Yunqian Qiao
- , Yangmin Qiu
- & Xuan Wang
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Article
| Open AccessA broadly neutralizing humanized ACE2-targeting antibody against SARS-CoV-2 variants
Here the authors report the isolation and structural and biological characterization of a humanized angiotensin-converting enzyme 2 (ACE2)-blocking antibody, which exterts potent inhibitory activity against SARS-CoV and circulating global SARS-CoV-2 lineages both in vitro and in hACE2 mouse model.
- Yanyun Du
- , Rui Shi
- & Jinghua Yan
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| Open AccessA human CD137×PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade
The anti-tumour effect of immune checkpoint inhibitors is potentiated by CD137 agonists in preclinical models, but translation of these results to the clinical practice is hampered by toxicity. Authors describe here a human CD137xPD-L1 bispecific antibody with improved anti-cancer activity whilst maintaining low toxicity in non-human primates.
- Cecile Geuijen
- , Paul Tacken
- & Mark Throsby
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| Open AccessEngineered ACE2 receptor therapy overcomes mutational escape of SARS-CoV-2
Hoshino et al., engineer a human virus receptor, hACE2, and demonstrate its potential for overcoming SARS-CoV-2 mutations that otherwise hinder therapeutic interventions. Overall, the data provide insights in to the therapeutic potential of engineered receptors.
- Yusuke Higuchi
- , Tatsuya Suzuki
- & Atsushi Hoshino
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| Open AccessAntibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance
Intratumor heterogeneity in breast cancer can limit the clinical success of antibody-drug conjugates (ADCs). In this study, the authors develop dual payload Her2-ADCs that show potent anti-tumor activity against heterogeneous breast tumors in vivo.
- Chisato M. Yamazaki
- , Aiko Yamaguchi
- & Kyoji Tsuchikama
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| Open AccessAntibody-based CCR5 blockade protects Macaques from mucosal SHIV transmission
CCR5 is a co-receptor for many transmitted HIV strains. Here, the authors show that biweekly injection of the CCR5-specific antibody Leronlimab protects rhesus macaques against infection following repeated intrarectal challenges of a CCR5-tropic SHIV.
- Xiao L. Chang
- , Gabriela M. Webb
- & Jonah B. Sacha
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| Open AccessDevelopment of selective bispecific Wnt mimetics for bone loss and repair
Antibody-based Wnt agonists are able to phenocopy Wnt signaling in vivo resulting in increased bone density, repair, and strength. Here, the authors show that Wnt agonists can reverse bone loss associated with ovariectomy and build stronger bone when administered after fracture.
- Tristan W. Fowler
- , Troy L. Mitchell
- & Yang Li
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Article
| Open AccessA human antibody selective for transthyretin amyloid removes cardiac amyloid through phagocytic immune cells
Analyzing memory B cell repertoires of the healthy elderly enabled Michalon et al. to develop a recombinant human antibody selective for transthyretin amyloid. This antibody removes cardiac amyloid through recruitment of phagocytic immune cells.
- Aubin Michalon
- , Andreas Hagenbuch
- & Jan Grimm
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| Open AccessA SARS-CoV-2 neutralizing antibody with extensive Spike binding coverage and modified for optimal therapeutic outcomes
Antibodies against SARS-CoV-2 S protein can provide a treatment strategy for COVID-19. Here, Guo et al. provide the crystal structure of a SARS-CoV2 neutralizing antibody isolated from a convalescent patient and highlight the therapeutic efficacy in a rhesus monkey model of an engineered version with optimized pharmacokinetic and safety profile.
- Yu Guo
- , Lisu Huang
- & Zihe Rao
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Article
| Open AccessSARS-CoV-2 neutralizing human recombinant antibodies selected from pre-pandemic healthy donors binding at RBD-ACE2 interface
Antibodies targeting the spike protein of coronaviruses are potential candidates for therapeutic development. Here, Bertoglio et al. use phage display to select anti-SARS-CoV-2 spike antibodies from the human naïve universal antibody gene libraries HAL9/10 that block interaction with ACE2 receptor to inhibit infection.
- Federico Bertoglio
- , Doris Meier
- & Michael Hust
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| Open AccessA therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein
Therapies and vaccines for COVID-19, caused by the SARS-CoV-2 viral pandemic, are urgently needed. Here the authors establish and screen an antibody library from a convalescent COVID-19 patient to isolate a neutralizing antibody with the ability to reduce viral titer and alleviate symptoms in ferret, hamster, and rhesus monkey infection models.
- Cheolmin Kim
- , Dong-Kyun Ryu
- & Soo-Young Lee
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Article
| Open AccessFormat chain exchange (FORCE) for high-throughput generation of bispecific antibodies in combinatorial binder-format matrices
Bispecific antibodies have been generated in many different formats and it is becoming clear that rational design alone cannot create optimal functionalities. Here the authors introduce the high throughput methodology, Format Chain Exchange (FORCE), to enable combinatorial generation of bispecific antibodies.
- Stefan Dengl
- , Klaus Mayer
- & Ulrich Brinkmann
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Article
| Open AccessA cross-reactive human IgA monoclonal antibody blocks SARS-CoV-2 spike-ACE2 interaction
Here, Ejemel et al. report the identification and characterization of a cross-neutralizing human IgA monoclonal antibody, named MAb362, that binds the receptor-binding domain of SARS-CoV-2 Spike, blocking its interaction with the ACE2 host receptor.
- Monir Ejemel
- , Qi Li
- & Yang Wang
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Article
| Open AccessTargeted inhibition of activated protein C by a non-active-site inhibitory antibody to treat hemophilia
Activated protein C (APC) is a plasma serine protease with antithrombotic and cytoprotective functions. Here, the authors develop a monoclonal antibody that specifically inhibits APC’s anticoagulant function without compromising its cytoprotective function, and shows efficacy in animal models.
- Xiao-Yan Zhao
- , Andreas Wilmen
- & Volker Laux
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Article
| Open AccessSalmonella Typhimurium biofilm disruption by a human antibody that binds a pan-amyloid epitope on curli
Curli amyloid fibers are important components of bacterial biofilms formed by E. coli and Salmonella. Here, Tursi et al. show that a human monoclonal antibody with pan-amyloid binding activity can disrupt biofilms formed by Salmonella Typhimurium in vitro and in vivo.
- Sarah A. Tursi
- , Rama Devudu Puligedda
- & Çagla Tükel
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Article
| Open AccessTargeting mutant p53-expressing tumours with a T cell receptor-like antibody specific for a wild-type antigen
Several cancers harbour mutant p53 and express higher levels of p53-derived peptide-MHCs. Here, the authors report affinity matured human antibody, P1C1TM, specific for the p53125-134 peptide in complex with the HLA-A24 class I MHC molecule and show its efficacy and specificity for mutant p53 expressing tumours.
- Lionel Low
- , Angeline Goh
- & Cheng-I Wang
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Article
| Open AccessHuman immunoglobulin G hinge regulates agonistic anti-CD40 immunostimulatory and antitumour activities through biophysical flexibility
Conserved regions of the antibody molecule impact its downstream biological effects. Here the authors show that a rigid hinge conformation increases the agonistic activity of CD40 and DR5 antibodies, distinctly from FcγR-binding, suggesting that the hinge and FcR binding regions can be separately modified to optimize therapies.
- Xiaobo Liu
- , Yingjie Zhao
- & Fubin Li
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Article
| Open AccessOptimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcγR affinity
Agonistic 4-1BB antibodies developed for cancer immunotherapy have suffered from either hepatotoxicity or insufficient anti-cancer activity. Here the authors determine the contribution of FcγR binding and agonistic strength to these outcomes, and engineer a 4-1BB antibody with potent anti-tumor effect and no liver toxicity in mice.
- Xinyue Qi
- , Fanlin Li
- & Xuanming Yang
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Article
| Open AccessImprovement of antibody functionality by structure-guided paratope engraftment
Quaternary contacts mediated by an extended heavy-chain framework region 3 (FR3) have been shown to improve binding to HIV envelope and virus neutralization for a few antibodies. Here, Liu et al. engraft such an FR3 loop onto several potent broadly neutralizing antibodies, resulting in improved neutralization activity and pharmacokinetics.
- Qingbo Liu
- , Yen-Ting Lai
- & Paolo Lusso
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Article
| Open AccessSingle human B cell-derived monoclonal anti-Candida antibodies enhance phagocytosis and protect against disseminated candidiasis
Late diagnosis and ineffective treatment of fungal infections lead to high mortality. Here, Rudkin et al. generate anti-Candida human monoclonal antibodies with diagnostic and therapeutic potential, by expressing recombinant antibodies from genes cloned from B cells of patients suffering candidiasis.
- Fiona M. Rudkin
- , Ingrida Raziunaite
- & Neil A. R. Gow
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Article
| Open AccessIn vivo neutralization of dendrotoxin-mediated neurotoxicity of black mamba venom by oligoclonal human IgG antibodies
Current anti-venoms against black mamba (Dendroaspis polylepis) bites are animal-derived and associated with several limitations. Here, Laustsen and colleagues develop an experimental recombinant anti-venom based on oligoclonal human IgG antibodies and establish its potential protective value in neutralizing dendrotoxin-mediated neurotoxicity using venom challenge in vivo models.
- Andreas H. Laustsen
- , Aneesh Karatt-Vellatt
- & John McCafferty
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| Open AccessAn in vitro paradigm to assess potential anti-Aβ antibodies for Alzheimer’s disease
The optimal Aβ species to target for the potential treatment of Alzheimer’s disease has not yet been established. Here, the authors describe an in vitro assay that uses extracts from brain tissue from patients with Alzheimer’s disease, and application to human iPSC-derived neurons, to compare the neuroprotective potential of several anti-Aβ antibodies.
- Ming Jin
- , Brian O’Nuallain
- & Dominic M. Walsh
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Article
| Open AccessStructural basis for the recognition of complex-type N-glycans by Endoglycosidase S
Endoglycosidase S only recognizes one particular type of glycan within IgG antibodies but the molecular basis for this high specificity is not fully understood. Here, the authors present the crystal structure of product-bound Endoglycosidase S, revealing the determinants for its glycan specificity.
- Beatriz Trastoy
- , Erik Klontz
- & Marcelo E. Guerin
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| Open AccessFetal demise and failed antibody therapy during Zika virus infection of pregnant macaques
Zika virus (ZIKV) infection in pregnant women has been associated with fetal developmental defects. Here, the authors show that a Brazilian ZIKV isolate causes fetal demise in non-human primates and that antibody treatment at time of peak viremia is insufficient to clear ZIKV replication from amniotic fluid.
- Diogo M. Magnani
- , Thomas F. Rogers
- & David I. Watkins