Featured
-
-
Article
| Open AccessHighly potent and broadly neutralizing anti-CD4 trimeric nanobodies inhibit HIV-1 infection by inducing CD4 conformational alteration
In this study, Zhu et al. report Nb457, an alpaca-derived nanobody with broad-spectrum anti-HIV1 activity and show that Nb457 induces conformational changes in CD4, blocking viral entry and completely inhibiting HIV-1 in its trimeric form.
- Linjing Zhu
- , Bilian Huang
- & Xilin Wu
-
Article
| Open AccessAllosteric nanobodies to study the interactions between SOS1 and RAS
Protein-protein interactions are central in cell metabolism but research tools for their characterization are missing. Here, the authors introduce strategies for the discovery of nanobodies that modulate the SOS1•RAS complex formation.
- Baptiste Fischer
- , Tomasz Uchański
- & Jan Steyaert
-
Article
| Open AccessRational correction of pathogenic conformational defects in HTRA1
Rare mutations in the high requirement temperature protein A1 (HTRA1) cause cerebral vasculopathy. Here, authors establish mechanistically distinct protein repair approaches to reverse the deleterious effects of pathogenic mutations interfering with the assembly and protease function of HTRA1.
- Nathalie Beaufort
- , Linda Ingendahl
- & Martin Dichgans
-
Article
| Open AccessThe binding mechanism of an anti-multiple myeloma antibody to the human GPRC5D homodimer
GPRC5D is an atypical Class C orphan GPCR and an attractive target for therapeutic interventions. Here, the authors present the cryo-EM structure of the human GPRC5D and scFv complex, and elucidate the precise antibody binding mode and recpetor dimerization interface.
- Pengfei Yan
- , Xi Lin
- & Fei Xu
-
Article
| Open AccessStructural basis for selectivity and antagonism in extracellular GPCR-nanobodies
Nanobodies are promising GPCR-targeting therapeutics. Here, the authors investigate a nanobody targeting atypical chemokine receptor 3 (ACKR3), and map trends in GPCR nanobody structure, mechanism, and selectivity.
- Roman R. Schlimgen
- , Francis C. Peterson
- & Brian F. Volkman
-
Article
| Open AccessLiver and pancreatic-targeted interleukin-22 as a therapeutic for metabolic dysfunction-associated steatohepatitis
Novel short-acting IL-22 bispecific biologics offer new hope for treating metabolic dysfunction-associated steatohepatitis (MASH), a global health concern with few treatment options. Here, the authors show these drugs significantly improve blood sugar control, liver fat, inflammation, and scarring.
- Haressh Sajiir
- , Sahar Keshvari
- & Sumaira Z. Hasnain
-
Article
| 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
-
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
-
Article
| Open AccessEngineering and evaluation of FXa bypassing agents that restore hemostasis following Apixaban associated bleeding
Direct oral anticoagulants (DOACs) targeting factor Xa that are used to prevent or treat thromboembolic disorders carry the risk of uncontrolled bleeding. Here, the authors present the computational design and evaluation of factor Xa-variants which can be used to reduce DOAC-associated bleeding.
- Wojciech Jankowski
- , Stepan S. Surov
- & Zuben E. Sauna
-
Article
| Open AccessPharmacological inhibition of α-synuclein aggregation within liquid condensates
Aggregated forms of α-synuclein are characteristic of Parkinson’s disease. Here the authors show that the condensation-driven aggregation pathway of α-synuclein can be inhibited using small molecules: the aminosterol claramine stabilizes α-synuclein condensates and inhibits α-synuclein primary nucleation in the aggregation process.
- Samuel T. Dada
- , Zenon Toprakcioglu
- & Michele Vendruscolo
-
Article
| 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
-
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
-
Article
| Open AccessAutologous cell transplantation for treatment of colorectal aganglionosis in mice
Neurointestinal diseases cause significant morbidity and effective treatments are lacking. Here, authors perform autologous cell transplantation of enteric neural stem cells in a mouse model of colonic aganglionosis and report restoration of colonic contractile activity.
- Weikang Pan
- , Ahmed A. Rahman
- & Ryo Hotta
-
Article
| Open AccessSpyMask enables combinatorial assembly of bispecific binders
Bispecific antibody architecture is often important for function but rarely optimized. Here, authors present a modular approach to assemble bispecifics in varied formats using a SpyTag/SpyCatcher approach called SpyMask, and build anti-HER2 bispecifics whose activities depend on binder orientation and bispecific geometry.
- Claudia L. Driscoll
- , Anthony H. Keeble
- & Mark R. Howarth
-
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
-
Article
| Open AccessA humanized mouse model for adeno-associated viral gene therapy
All natural AAV serotypes transduce murine hepatocytes more efficiently than their human counterparts in human liver chimeric mouse models. Here the authors developed a novel humanized mouse were human transduction of AAV can be studied.
- Mercedes Barzi
- , Tong Chen
- & Karl-Dimiter Bissig
-
Article
| 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
-
Article
| Open AccessStructural optimization of siRNA conjugates for albumin binding achieves effective MCL1-directed cancer therapy
Limited tumor cell delivery is a major challenge for the efficacious delivery of siRNAs to silence traditionally undruggable oncogenes. Here the authors optimize siRNAs for in situ binding to albumin through C18 lipid modifications and show the application of the lead conjugate structure for targeting MCL1 in orthotopic breast tumors in mice.
- Ella N. Hoogenboezem
- , Shrusti S. Patel
- & Craig L. Duvall
-
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
-
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
-
Article
| 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
-
Article
| Open AccessSystemically administered wound-homing peptide accelerates wound healing by modulating syndecan-4 function
A systemically administered peptide (CARSKNKDC) that homes to injured tissues, has inherent ability to promote wound healing. Here, the authors show that this peptide binds to syndecan-4 and activates ARF6 to trigger re-epithelialisation and the naturally occurring wound repair pathway.
- Horacio Maldonado
- , Bryan D. Savage
- & Tero A. H. Järvinen
-
Article
| Open AccessSimultaneous selection of nanobodies for accessible epitopes on immune cells in the tumor microenvironment
INSPIREseq discovers accessible epitopes in complex environments and leads to nanobodies targeting thousands of epitopes. This in vivo diversity selection identifies selective nanobodies, potentially expediting target discovery and drug development.
- Thillai V. Sekar
- , Eslam A. Elghonaimy
- & Todd A. Aguilera
-
Article
| 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
-
Article
| 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
-
Article
| Open AccessPAM-flexible genome editing with an engineered chimeric Cas9
CRISPR enzymes require a defined protospacer adjacent motif (PAM) which can be limiting for editing applications. Here the authors recombine the PAM-interacting domain of SpRY with the N-terminus of Sc + + to generate a chimeric enzyme with highly flexible PAM preference: SpRYc.
- Lin Zhao
- , Sabrina R. T. Koseki
- & Pranam Chatterjee
-
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
-
Article
| Open AccessmRNA vaccine quality analysis using RNA sequencing
mRNA vaccines must be rigorously analysed to measure their integrity and detect contaminants, which can be time-consuming and costly. Here, authors describe a method to analyse mRNA vaccine quality using long-read sequencing and a custom bioinformatic pipeline.
- Helen M. Gunter
- , Senel Idrisoglu
- & Tim R. Mercer
-
Article
| Open AccessComplementarity-determining region clustering may cause CAR-T cell dysfunction
The challenge of designing chimeric antigen receptor (CAR)-T cells for cancer therapy is not limited to finding targetable cellular proteins, but also in optimising the effector properties. Here authors show that single-chain variable fragment targeting moieties could unpredictably prompt spontaneous CAR-T cell activation via CAR clustering, which argues for empirical screening for tonic signalling.
- Tina Sarén
- , Giulia Saronio
- & Magnus Essand
-
Article
| Open AccessEnhancing bacteriophage therapeutics through in situ production and release of heterologous antimicrobial effectors
Du et al. genetically engineer bacteriophages into heterologous effector phage therapeutics, enabling dual phage- and effector-mediated targeting for a two-pronged attack against bacterial pathogens.
- Jiemin Du
- , Susanne Meile
- & Matthew Dunne
-
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
-
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
-
Article
| Open AccessDisrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson’s disease
ESCRT-III is involved in the endolysosomal system and disturbed in neurodegenerative diseases. Here the authors show that disruption of an interaction between ESCRT-III member CHMP2B and α-synuclein by a peptide inhibitor mitigates neurodegeneration in Parkinson’s disease models.
- Satra Nim
- , Darren M. O’Hara
- & Philip M. Kim
-
Article
| Open AccessEfficient in planta production of amidated antimicrobial peptides that are active against drug-resistant ESKAPE pathogens
Antimicrobial peptides (AMPs) are next-generation antibiotics that can be used to combat drugresistant pathogens. Here, the authors report efficient production of bioactive amidated AMPs by transient expression in Nicotiana benthamiana line expressing the mammalian enzyme peptidylglycine α-amidating mono-oxygenase.
- Shahid Chaudhary
- , Zahir Ali
- & Magdy Mahfouz
-
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
-
Article
| Open AccessNoncanonical amino acids as doubly bio-orthogonal handles for one-pot preparation of protein multiconjugates
Site-specific protein multi-conjugates are important for both scientific and translational research. Here, the authors genetically encode unnatural amino acids which contain both tetrazine and azide, and use the doubly bio-orthogonal handles to generate bi- and tri-conjugate proteins in high yields.
- Yong Wang
- , Jingming Zhang
- & Tao Liu
-
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
-
Article
| Open AccessEvolution of protease activation and specificity via alpha-2-macroglobulin-mediated covalent capture
Custom proteases find applications as therapeutics, in research and in biotechnological applications. Here, the authors establish a protease selection system based on bacterial alpha-2-macroglobulin protease inhibitors and evolve staphylococcal proteases for increased activity and altered specificity.
- Philipp Knyphausen
- , Mariana Rangel Pereira
- & Florian Hollfelder
-
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
-
Article
| 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
-
Review Article
| Open AccessAssessing and advancing the safety of CRISPR-Cas tools: from DNA to RNA editing
CRISPR-Cas tools have shown exceptional promise in genome engineering over the past decade. Here the authors review the development of CRISPR-Cas9/Cas12/Cas13 nucleases, DNA base editors, prime editors, and RNA base editors, as well as their editing precision, off-target effects, and clinical considerations.
- Jianli Tao
- , Daniel E. Bauer
- & Roberto Chiarle
-
Article
| 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
-
Article
| Open AccessAn in silico method to assess antibody fragment polyreactivity
Off-target binding hinders the development of therapeutic antibodies and reproducibility in basic research settings. Here the authors develop a method to quantify and reduce the polyreactivity of antibody fragments based on protein sequence alone.
- Edward P. Harvey
- , Jung-Eun Shin
- & Andrew C. Kruse
-
Article
| Open AccessXNAzymes targeting the SARS-CoV-2 genome inhibit viral infection
RNA viruses have been responsible for large-scale epidemics and pandemics throughout the last few centuries. Here, the authors show the design, synthesis and screening of artificial RNA endonuclease XNAzymes capable of cleaving genomic SARS-CoV-2 RNA and self-assembling into enzymatic nanostructures inhibiting cellular viral replication.
- Pehuén Pereyra Gerber
- , Maria J. Donde
- & Alexander I. Taylor
-
Article
| Open AccessOptogenetic-controlled immunotherapeutic designer cells for post-surgical cancer immunotherapy
The induction of long-term systemic immunosurveillance can protect against post-surgery tumor recurrence. Here the authors describe the design of optogenetic-controlled cytokine secreting (IFN-β, TNF-α, and IL-12) engineered mesenchymal stem cells loaded into a hydrogel scaffold, eliciting long-term immune memory and preventing post-operative recurrence in preclinical cancer models.
- Yuanhuan Yu
- , Xin Wu
- & Haifeng Ye
-
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
-
Article
| 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
-
Article
| Open AccessCombined IgE neutralization and Bifidobacterium longum supplementation reduces the allergic response in models of food allergy
IgE is a critical component of the allergic response and therapeutic targeting can alleviate symptomology. Here the authors propose the combined use of Bifidobacterium longum and a FcεRIα extracellular domain linked to a IgD/IgG4 hybrid Fc domain fusion protein called IgETRAP and show reduction of mast cell and IgE levels in models of food allergy.
- Seong Beom An
- , Bo-Gie Yang
- & Myoung Ho Jang
-
Article
| 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
Browse broader subjects
Browse narrower subjects
- Antagomir and RNA sponge
- Antibody fragment therapy
- Antibody therapy
- Antisense oligonucleotide therapy
- Cell therapies
- DNA vaccines
- Gene therapy
- Locked nucleic acid
- Meganucleases
- Nucleic-acid therapeutics
- Peptide nucleic acid oligo
- Recombinant peptide therapy
- Recombinant protein therapy
- Recombinant vaccine
- RNA vaccines
- siRNAs
- TAL effector nuclease
- Triplex-forming oligonucleotide
- Zinc finger nuclease