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| Open AccessAn in vivo platform to select and evolve aggregation-resistant proteins
Protein aggregation remains a significant challenge for manufacturing of protein biopharmaceuticals. Here, the authors demonstrate the use of directed evolution and an assay for in vivo innate protein aggregation-propensity to generate aggregation-resistant scFv fragments.
- Jessica S. Ebo
- , Janet C. Saunders
- & David J. Brockwell
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Article
| Open AccessAn amber obligate active site-directed ligand evolution technique for phage display
Most epigenetic regulator inhibitors target tunnels of active sites, rather than the peptide binding groove, leading to concerns with low selectivity. Here the authors use an amber obligate phage library to rapidly identify isoform-selective inhibitors of SIRT2.
- Jeffery M. Tharp
- , J. Trae Hampton
- & Wenshe Ray Liu
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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 AccessCD229 CAR T cells eliminate multiple myeloma and tumor propagating cells without fratricide
CD229 is expressed on the surface of multiple myeloma cells, as well as B and T lymphocytes. Here, the authors engineer CD229-specific CAR T cells and, using patient samples and mouse models, show that treatment with these cells reduces tumour burden and results in limited targeting of T cells.
- Sabarinath V. Radhakrishnan
- , Tim Luetkens
- & Djordje Atanackovic
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Article
| Open AccessStructure-guided design of pure orthosteric inhibitors of αIIbβ3 that prevent thrombosis but preserve hemostasis
Current inhibitors of platelet integrin αIIbβ3 cause excessive bleeding, which limited their clinical use in cardiac patients. Here the authors design pure orthosteric αIIbβ3 inhibitors that prevent platelet aggregation and thrombosis without causing bleeding in humanized mouse models of thrombosis
- Brian D. Adair
- , José L. Alonso
- & M. Amin Arnaout
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Article
| Open AccessRational design of universal immunotherapy for TfR1-tropic arenaviruses
New World arenaviruses utilize the cellular transferrin receptor 1 (TfR1) to enter host cells. Here, the authors develop a TfR1-mimetic immunoadhesin, Arenacept, that targets viral spike complexes and exerts effective pan-reactive neutralization against pathogenic mammarenaviruses.
- Hadas Cohen-Dvashi
- , Ron Amon
- & Ron Diskin
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Article
| Open AccessCRISPR-Cas3 induces broad and unidirectional genome editing in human cells
Class 1 CRISPR systems are not as developed for genome editing as Class 2 systems are. Here the authors show that Cas3 can be used to generate functional knockouts and knock-ins, as well as Cas3-mediated exon-skipping in DMD cells.
- Hiroyuki Morisaka
- , Kazuto Yoshimi
- & Tomoji Mashimo
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Article
| Open AccessCrystal structure and receptor-interacting residues of MYDGF — a protein mediating ischemic tissue repair
Myeloid-derived growth factor (MYDGF) is an angiogenic growth factor with therapeutic potential for ischemic tissue repair and the receptor is still unknown. Here the authors present the crystal structure of human MYDGF and identify its functional epitope through mutagenesis studies.
- Rebecca Ebenhoch
- , Abbas Akhdar
- & Herbert Nar
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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 AccessInhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford Progeria Syndrome
Hutchinson–Gilford progeria syndrome causes premature aging. Here the authors show that activation of the DNA damage response at dysfunctional telomeres and transcription of telomeric non-coding RNAs contributes to the pathogenesis, which can be ameliorated by treatment with sequence-specific telomeric antisense oligonucleotides.
- Julio Aguado
- , Agustin Sola-Carvajal
- & Fabrizio d’Adda di Fagagna
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Article
| Open AccessDevelopment of a forward-oriented therapeutic lentiviral vector for hemoglobin disorders
Vectors used in gene therapy for hemoglobin disorders carry globin in a reverse-orientation to prevent the loss of key regulatory elements by RNA splicing, but this limits their efficiency. Here, the authors develop a vector carrying β-globin in a forward orientation and show that it has improved titers and transduction efficiency in humanized mice and nonhuman primates.
- Naoya Uchida
- , Matthew M. Hsieh
- & John F. Tisdale
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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 AccessHorse immunization with short-chain consensus α-neurotoxin generates antibodies against broad spectrum of elapid venomous species
Antivenoms, obtained by venom immunization, have narrow species coverage due to low immunogenicity of venom neurotoxins. Here the authors immunize horses with a designed recombinant consensus neurotoxin, and the resulting antisera protect mice from envenomation by a broad spectrum of elapid snakes.
- Guillermo de la Rosa
- , Felipe Olvera
- & Gerardo Corzo
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Article
| Open AccessMultifunctional cationic nanosystems for nucleic acid therapy of thoracic aortic dissection
Thoracic aortic dissection has a high fatality rate and no effective treatment. Here, the authors develop cationic nanoparticles for the delivery of miR-145 and show that they stabilize vascular structures and prevent further deterioration of the aorta in mouse models of the disease.
- Chen Xu
- , Yanzhenzi Zhang
- & Fu-Jian Xu
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Article
| Open AccessBone-targeting AAV-mediated silencing of Schnurri-3 prevents bone loss in osteoporosis
The adaptor protein SHN3 suppresses new bone formation by controlling osteoblast activity. Here, the authors show that ablation of SHN3 function, either genetically or by delivering an artificial miRNA via AAV9, rescues bone loss in osteoporotic mice, and show that engineering of the AAV9 capsid improves targeting to bone
- Yeon-Suk Yang
- , Jun Xie
- & Jae-Hyuck Shim
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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 AccessSynthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response
Supraphysiological T cell activation by chimeric antigen receptor (CAR) contributes to T cell exhaustion and adverse events in CAR T cell therapies. Here the authors engineer a synthetic antigen receptor that integrates into the endogenous TCR complex, preserving natural regulatory circuits and achieving improved performance in mouse tumor models.
- Patrick A. Baeuerle
- , Jian Ding
- & Robert Hofmeister
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Article
| Open AccessThe glycosylation design space for recombinant lysosomal replacement enzymes produced in CHO cells
Lysosomal replacement enzymes are taken up by cell surface receptors that recognize glycans, the effects of different glycan features are unknown. Here the authors present a gene engineering screen in CHO cells that allows custom N-glycan-decorated enzymes with improved circulation time and organ distribution.
- Weihua Tian
- , Zilu Ye
- & Zhang Yang
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Article
| Open AccessNeutrophil extracellular traps in the central nervous system hinder bacterial clearance during pneumococcal meningitis
Neutrophils play critical roles in the host response to bacteria, including the production neutrophil extracellular traps (NET). Here the authors show that NET formation in the context of pneumococcal meningitis impairs bacterial clearance and targeting NET formation in this context could be a potential therapeutic option.
- Tirthankar Mohanty
- , Jane Fisher
- & Adam Linder
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Article
| Open AccessA platform for glycoengineering a polyvalent pneumococcal bioconjugate vaccine using E. coli as a host
Bioconjugation is a promising process to manufacture conjugate vaccines, but currently employed enzymes cannot generate the full spectrum of bacterial glycoproteins. Here, the authors use an O-linking oligosaccharyltransferase to generate a polyvalent pneumococcal bioconjugate vaccine with polysaccharides containing glucose at their reducing end.
- Christian M. Harding
- , Mohamed A. Nasr
- & Mario F. Feldman
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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 AccessAnti-LRP5/6 VHHs promote differentiation of Wnt-hypersensitive intestinal stem cells
Enhanced Wnt receptor activity is a major cause of cancer development. Here the authors identify camelid single-domain antibody fragments (VHHs) that bind to the Wnt receptor LRP5/6 ectodomain, determine the crystal structures and show that these VHHs selectively inhibit Wnt3- mediated cellular responses and block the growth of mutant Wnt-hypersensitive intestinal tumor organoids.
- Nicola Fenderico
- , Revina C. van Scherpenzeel
- & Madelon M. Maurice
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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 AccessLocally anchoring enzymes to tissues via extracellular glycan recognition
The use of enzymes as drugs requires that they persist within target tissues over therapeutically relevant time frames. Here the authors use a galectin-3 fusion to anchor enzymes at injection sites for up to 14 days.
- Shaheen A. Farhadi
- , Evelyn Bracho-Sanchez
- & Gregory A. Hudalla
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Article
| Open AccessCell specific delivery of modified mRNA expressing therapeutic proteins to leukocytes
Therapeutic alteration of protein expression using modified mRNA is limited by immunogenicity and instability in vivo. Here the authors use antibody-coated lipid nanoparticles to deliver mRNA to leukocytes and drive expression of anti-inflammatory cytokines in an inflammatory bowel disease mouse model.
- Nuphar Veiga
- , Meir Goldsmith
- & Dan Peer
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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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Article
| Open AccessArgininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer
Patients with mutations in the ASL gene present with argininosuccinic aciduria characterised by hyperammonaemia and cognitive impairment. Here, the authors show that cerebral disease involves neuronal nitrosative/oxidative stress that is not induced by hyperammonaemia, and that it can be reversed using AAV-ASL directed to liver and brain in mice.
- Julien Baruteau
- , Dany P. Perocheau
- & Simon N. Waddington
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Article
| Open AccessDirect quality control of glycoengineered erythropoietin variants
Several therapeutics are glycosylated proteins, yet the analysis of their specific glycosylation patterns remains challenging. Here the authors demonstrate an approach for the detailed characterization of glycosylated biopharmaceuticals applied to the determination of the glycoproteoform profile of glycoengineered variants of erythropoietin.
- Tomislav Čaval
- , Weihua Tian
- & Albert J. R. Heck
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Article
| Open AccessA biodegradable hybrid inorganic nanoscaffold for advanced stem cell therapy
The promise of stem cell therapy for treating central nervous system disease is limited by low stem cell transplantation survival rates and poorly controlled cell fate. Here, the authors develop a biodegradable nanoscaffold for spinal cord injury that enhances transplantation and differentiation of neural stem cells and delivers drugs.
- Letao Yang
- , Sy-Tsong Dean Chueng
- & Ki-Bum Lee
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Article
| 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 AccessmiR-23b and miR-218 silencing increase Muscleblind-like expression and alleviate myotonic dystrophy phenotypes in mammalian models
Depletion of the splicing factors MBNL 1 and 2 causes myotonic dystrophy. Here, the authors show that miR-23b and miR-218 target MBNL proteins, and that antagonists to these miRNAs rescue mis-splicing events in myoblasts and boost MBNL expression and rescue pathology in mouse models.
- Estefania Cerro-Herreros
- , Maria Sabater-Arcis
- & Ruben Artero
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Article
| Open AccessOxidation-specific epitopes restrain bone formation
Atherosclerosis and osteoporosis are epidemiologically associated, and oxidation specific epitopes (OSEs), which can be neutralized by innate antibodies, are pathogenic for both. Here, the authors show that mice expressing antibody fragments targeted to OSEs are protected from the bone loss induced by high-fat diet and have increased bone mass when fed a normal diet, and that levels of innate antibodies to OSEs decrease with ageing.
- Elena Ambrogini
- , Xuchu Que
- & Robert L. Jilka
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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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Article
| Open AccessNative mass spectrometry combined with enzymatic dissection unravels glycoform heterogeneity of biopharmaceuticals
The specific glycosylation patterns of biological drugs often impact the efficacy and safety of the therapeutic product. Here the authors describe a native mass spectrometry approach that allows the resolution of highly complex glycosylation patterns on large proteins, which they apply to the therapeutic Fc-fusion protein Etanercept.
- Therese Wohlschlager
- , Kai Scheffler
- & Christian G. Huber
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Article
| 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
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Article
| Open AccessHSP27 is a partner of JAK2-STAT5 and a potential therapeutic target in myelofibrosis
Myelofibrosis is a chronic degenerative disorder characterized by progressive bone marrow fibrosis. Here, the authors show that the chaperone HSP27 contributes to myelofibrosis via regulation of the JAK2/STAT5 pathway, and that antisense oligonucleotides targeting HSP27 are effective in two mouse models of the disease
- Margaux Sevin
- , Lucia Kubovcakova
- & Aurélie de Thonel
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Article
| Open AccessSmall tumor necrosis factor receptor biologics inhibit the tumor necrosis factor-p38 signalling axis and inflammation
Anti-TNF therapy has improved the treatment of inflammatory disease but can predispose to infection and malignancy. Here the authors show an anti-TNF biologic peptide that functionally and selectively targets the TNF-p38 pathway in multiple models of inflammation.
- Violet R. Mukaro
- , Alex Quach
- & Antonio Ferrante
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Article
| Open AccessExpansion of functional personalized cells with specific transgene combinations
Personalised medicine requires cell cultures from defined genetic backgrounds, but providing sufficient numbers of cells is a challenge. Here the authors develop gene cocktails to expand primary cells from a variety of different tissues and species, and show that expanded endothelial and hepatic cells retain properties of the differentiated phenotype.
- Christoph Lipps
- , Franziska Klein
- & Tobias May
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Article
| Open AccessRational design of a trispecific antibody targeting the HIV-1 Env with elevated anti-viral activity
Broadly neutralizing antibodies targeting HIV Env could potentially be utilized as therapeutics. Here, Steinhardt et al. engineer a trispecific antibody with specificity for the receptor-binding site, a conserved Env glycan patch and the Env membrane proximal region with nearly pan-isolate neutralization breadth and high potency.
- James J. Steinhardt
- , Javier Guenaga
- & Yuxing Li
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Article
| Open AccessActivin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva
Fibrodysplasia ossificans progressiva is a severe disorder characterized by heterotopic ossification, and is caused by mutations in ACVR1. Here, the authors show that expression of mutant ACVR1 in fibro/adipogenic progenitors recapitulates disease progression, and that this can be halted by systemic inhibition of activin A in mice.
- John B. Lees-Shepard
- , Masakazu Yamamoto
- & David J. Goldhamer
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Article
| Open AccessVersatile and on-demand biologics co-production in yeast
The ability to combine the production of multiple biologics into a single ‘on demand’ system could help in situations where resources are limited. Here the authors demonstrate a proof-of-concept approach for the co-production of three biologics, allowing singular, mixed and combination drug products.
- Jicong Cao
- , Pablo Perez-Pinera
- & Timothy K. Lu
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Article
| Open AccessTrapping IgE in a closed conformation by mimicking CD23 binding prevents and disrupts FcεRI interaction
IgE is linked to allergic diseases and there is a great interest in developing anti-IgE therapeutics. Here the authors characterize the binding of human IgE Fc to a single domain antibody (sdab) and show that the sdab induces a closed conformation, which prevents and disrupts IgE binding to its receptor FcεRI and abrogates allergen mediated activation.
- Frederic Jabs
- , Melanie Plum
- & Edzard Spillner
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Article
| Open AccessMammalian display screening of diverse cystine-dense peptides for difficult to drug targets
Pathologies related to protein:protein interaction are hard to treat but cystine-dense peptides have the potential to disrupt such interactions. Here the authors develop a high-diversity mammalian cell screen for cystine-dense peptides with drug potential and use it to identify a YAP:TEAD inhibitor.
- Zachary R. Crook
- , Gregory P. Sevilla
- & James M. Olson
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Article
| Open AccessStructural basis of respiratory syncytial virus subtype-dependent neutralization by an antibody targeting the fusion glycoprotein
Monoclonal antibodies to prevent respiratory syncytial virus (RSV) disease are under development, but the molecular requirements for cross-subtype neutralization are unclear. Here, the authors show that residue 201 in RSV fusion protein determines subtype specific neutralization for the clinically-relevant monoclonal antibody, 5C4.
- Daiyin Tian
- , Michael B. Battles
- & Barney S. Graham
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Article
| Open AccessSelenoprotein P-neutralizing antibodies improve insulin secretion and glucose sensitivity in type 2 diabetes mouse models
Selenoprotein P is secreted by the liver and when present in excess it promotes development of type 2 diabetes. Here the authors develop neutralizing antibodies to target human and mouse selenoprotein P, and show that they improve insulin secretion and glucose tolerance in mouse models.
- Yuichiro Mita
- , Kaho Nakayama
- & Yoshiro Saito
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Article
| Open AccessHarnessing a catalytic lysine residue for the one-step preparation of homogeneous antibody-drug conjugates
Current strategies for producing antibody-drug conjugates often rely on inefficient conjugation chemistry or on generating mutations in the antibody sequence. Here the authors demonstrate a mutation-free, single-step conjugation platform utilizing a buried lysine residue.
- Alex R. Nanna
- , Xiuling Li
- & Christoph Rader
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Article
| Open AccessAlveolar macrophages are critical for broadly-reactive antibody-mediated protection against influenza A virus in mice
Broadly reactive antibodies that recognize influenza A virus HA can be protective, but the mechanism is not completely understood. Here, He et al. show that the inflammatory response and phagocytosis mediated by the interaction between protective antibodies and macrophages are essential for protection.
- Wenqian He
- , Chi-Jene Chen
- & Gene S. Tan
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Article
| Open AccessGenetically engineered red cells expressing single domain camelid antibodies confer long-term protection against botulinum neurotoxin
The therapeutic use of single-chain antibodies (VHHs) is limited by their short half-life in the circulation. Here the authors engineer mouse and human red blood cells to express VHHs against botulinum neurotoxin A (BoNT/A) on their surface and show that an infusion of these cells into mice confers long lasting protection against a high dose of BoNT/A.
- Nai-Jia Huang
- , Novalia Pishesha
- & Harvey F. Lodish
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Article
| Open AccessA peptide-based viral inactivator inhibits Zika virus infection in pregnant mice and fetuses
Zika virus (ZIKV) has spread rapidly in recent years and there is a need for antiviral treatments. Here, the authors develop an antiviral peptide, based on the stem region of ZIKV envelope protein, and show that it is safe in pregnant mice and inhibits ZIKV infection in pregnant mice and fetuses.
- Yufeng Yu
- , Yong-Qiang Deng
- & Lu Lu
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