Biologics articles within Nature Communications

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  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    Production of reactive oxygen species is an ancient antimicrobial mechanism, but its role in antiviral defense in mammals is unclear. Here, To et al. show that virus infection activates endosomal NOX2 oxidase and restricts TLR7 signaling, and that an endosomal NOX2 inhibitor decreases viral pathogenicity.

    • Eunice E. To
    • , Ross Vlahos
    •  & Stavros Selemidis

  • Article
    | Open Access

    Humans are less sensitive to the therapeutic effects of botulinum neurotoxin B (BoNT/B) than the animal models it is tested on due to differences between the human and the mouse receptors. Here, the authors engineer BoNT/B to improve its affinity to human receptors and enhance its therapeutic efficacy.

    • Liang Tao
    • , Lisheng Peng
    •  & Min Dong

  • Article
    | Open Access

    Inhibition of GDF8 increases muscle mass in mice, but is less effective in monkeys and humans. Here the authors show that activin A also inhibits muscle hypertrophy and that concomitant inhibition of activin A and GDF8 synergistically increases muscle mass in mice and non-human primates.

    • Esther Latres
    • , Jason Mastaitis
    •  & Jesper Gromada

  • Article
    | Open Access

    The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) is a promising therapeutic target. Here the authors characterize the assembly mechanism of the receptor complex driven by human TSLP, and its antagonism by the monoclonal antibody Tezepelumab and a fusion protein comprising the TSLP receptors.

    • Kenneth Verstraete
    • , Frank Peelman
    •  & Savvas N. Savvides

  • Article
    | Open Access

    The Zika virus outbreak is a global health threat and there is an urgent need for drugs against the virus. Here the authors present the structure of the RNA-dependent RNA-polymerase domain from Zika non-structural protein 5, which is a template for the design of non-nucleoside polymerase inhibitors.

    • Andre S. Godoy
    • , Gustavo M. A. Lima
    •  & Glaucius Oliva

  • Article
    | Open Access

    Retinal vascular disease treatments involve frequent pharmacological intraocular administrations. Here the authors present a method to increase the half-life of injected drugs by fusing these to a hyaluronan-binding peptide, which might lead to less frequent retinal disease treatments.

    • Joy G. Ghosh
    • , Andrew A. Nguyen
    •  & Michael Roguska

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