Biologics articles within Nature Communications

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  • Article
    | Open Access

    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 Access

    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 Access

    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 Access

    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 Access

    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 Access

    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 Access

    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 Access

    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 Access

    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 Access

    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 Access

    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 Access

    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 Access

    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 Access

    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 Access

    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 Access

    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 Access

    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 Access

    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 Access

    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 Access

    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 Access

    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

  • Review Article
    | Open Access

    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 Access

    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 Access

    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 Access

    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 Access

    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 Access

    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 Access

    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 Access

    Cancers often harbor mutations in genes encoding important regulatory proteins, but therapeutic targeting of these molecules proves difficult due to their high structural similarity to their non-mutated counterpart. Here authors show the engineering of T cell engaging bispecific protein able to selectively target cancer cells with a high-frequency mutation in the KRAS oncogene.

    • Andrew Poole
    • , Vijaykumar Karuppiah
    •  & Chandramouli Chillakuri

  • Article
    | Open Access

    Low solubility and stability of Escherichia coli produced single chain variable fragments (scFvs) restrict their applications. Here the authors report a 33-residue peptide tag which simultaneously increases the solubility and thermostability of multiple scFvs produced in Escherichia coli SHuffle strain.

    • Yang Wang
    • , Wenjie Yuan
    •  & Yong-Xiang Wang

  • Article
    | Open Access

    Excess ketogenesis can lead to ketoacidosis, a serious complication in patients with diabetes. Here the authors report an insulin independent pathway, the hepatic nonparenchymal S100A9-TLR4-mTORC1 axis, that is able to normalize diabetic ketogenesis and pre-clinical data to suggest potential for development of S100A9 based adjunctive therapy to insulin.

    • Gloria Ursino
    • , Giorgio Ramadori
    •  & Roberto Coppari

  • Article
    | Open Access

    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

  • Article
    | Open Access

    CD28 costimulatory signalling can be suppressed by immune checkpoints, such as CTLA-4 and PD-1. Here the authors describe the design of the fusion therapeutic davoceticept (ALPN-202), based on a variant CD80 extracellular domain engineered to bind PD-L1 as well as CD28 and CTLA-4, providing direct T cell costimulation and dual checkpoint inhibition to enable anti-tumor immune responses.

    • Mark F. Maurer
    • , Katherine E. Lewis
    •  & Stanford L. Peng

  • Article
    | Open Access

    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

  • Article
    | Open Access

    In this in vitro, in silico, and in vivo study Nguyen and colleagues show that specific and stable viral gene delivery of engineered prokaryotic voltage-gated sodium channels (BacNav) to cardiomyocytes can directly augment cardiac tissue excitability and conduction.

    • Hung X. Nguyen
    • , Tianyu Wu
    •  & Nenad Bursac

  • Article
    | Open Access

    In vivo assessment of nuclease off-target activity has primarily been indirect or through ChIP-based detection of double-strand break DNA repair factors, which can be cumbersome. Here, the authors show that GUIDE-tag, enables one-step off-target genome editing analysis in mouse liver and lung.

    • Shun-Qing Liang
    • , Pengpeng Liu
    •  & Wen Xue

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