ORCID Profile
0000-0002-2158-0601
Current Organisation
Technical University of Denmark
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Publisher: Springer Science and Business Media LLC
Date: 08-02-2023
DOI: 10.1038/S41467-023-36393-4
Abstract: Snakebite envenoming continues to claim many lives across the globe, necessitating the development of improved therapies. To this end, broadly-neutralizing human monoclonal antibodies may possess advantages over current plasma-derived antivenoms by offering superior safety and high neutralization capacity. Here, we report the establishment of a pipeline based on phage display technology for the discovery and optimization of high affinity broadly-neutralizing human monoclonal antibodies. This approach yielded a recombinant human antibody with superior broadly-neutralizing capacities in vitro and in vivo against different long-chain α-neurotoxins from elapid snakes. This antibody prevents lethality induced by Naja kaouthia whole venom at an unprecedented low molar ratio of one antibody per toxin and prolongs the survival of mice injected with Dendroaspis polylepis or Ophiophagus hannah whole venoms.
Publisher: Oxford University Press (OUP)
Date: 2022
DOI: 10.1093/GIGASCIENCE/GIAC121
Abstract: Venomous snakes are important parts of the ecosystem, and their behavior and evolution have been shaped by their surrounding environments over the eons. This is reflected in their venoms, which are typically highly adapted for their biological niche, including their diet and defense mechanisms for deterring predators. Sub-Saharan Africa is rich in venomous snake species, of which many are dangerous to humans due to the high toxicity of their venoms and their ability to effectively deliver large amounts of venom into their victims via their bite. In this study, the venoms of 26 of sub-Saharan Africa's medically most relevant elapid and viper species were subjected to parallelized toxicovenomics analysis. The analysis included venom proteomics and in vitro functional characterization of whole venom toxicities, enabling a robust comparison of venom profiles between species. The data presented here corroborate previous studies and provide biochemical details for the clinical manifestations observed in envenomings by the 26 snake species. Moreover, two new venom proteomes (Naja anchietae and Echis leucogaster) are presented here for the first time. Combined, the presented data can help shine light on snake venom evolutionary trends and possibly be used to further improve or develop novel antivenoms.
Publisher: Cold Spring Harbor Laboratory
Date: 31-08-2023
DOI: 10.1101/2023.08.30.555055
Abstract: Bottom-up mass spectrometry-based proteomics is challenged by the task of identifying the peptide that generates a tandem mass spectrum. Traditional methods that rely on known peptide sequence databases are limited and may not be applicable in certain contexts. De novo peptide sequencing, which assigns peptide sequences to the spectra without prior information, is valuable for various biological applications yet, due to a lack of accuracy, it remains challenging to apply this approach in many situations. Here, we introduce InstaNovo, a transformer neural network with the ability to translate fragment ion peaks into the sequence of amino acids that make up the studied peptide(s). The model was trained on 28 million labelled spectra matched to ~742k human peptides from the ProteomeTools project. We demonstrate that InstaNovo outperforms current state-of-the-art methods on benchmark datasets and showcase its utility in several applications. Building upon human intuition, we also introduce InstaNovo+, a multinomial diffusion model that further improves performance by iterative refinement of predicted sequences. Using these models, we could de novo sequence antibody-based therapeutics with unprecedented coverage, discover novel peptides, and detect unreported organisms in different datasets, thereby expanding the scope and detection rate of proteomics searches. Finally, we could experimentally validate tryptic and non-tryptic peptides with targeted proteomics, demonstrating the fidelity of our predictions. Our models unlock a plethora of opportunities across different scientific domains, such as direct protein sequencing, immunopeptidomics, and exploration of the dark proteome.
Publisher: Springer Science and Business Media LLC
Date: 22-06-2023
DOI: 10.1038/S41598-023-37056-6
Abstract: Antibodies with cross-reactive binding and broad toxin-neutralizing capabilities are advantageous for treating indications such as infectious diseases and animal envenomings. Such antibodies have been successfully selected against closely related antigens using phage display technology. However, the mechanisms driving antibody cross-reactivity typically remain to be elucidated. Therefore, we sought to explore how a previously reported phage display-based cross-panning strategy drives the selection of cross-reactive antibodies using seven different snake toxins belonging to three protein (sub-)families: phospholipases A 2 , long-chain α-neurotoxins, and short-chain α-neurotoxins. We showcase how cross-panning can increase the chances of discovering cross-reactive single-chain variable fragments (scFvs) from phage display c aigns. Further, we find that the feasibility of discovering cross-reactive antibodies using cross-panning cannot easily be predicted by analyzing the sequence, structural, or surface similarity of the antigens alone. However, when antigens share the (exact) same functions, this seems to increase the chances of selecting cross-reactive antibodies, which may possibly be due to the existence of structurally similar motifs on the antigens.
Publisher: Informa UK Limited
Date: 23-02-2023
Publisher: Frontiers Media SA
Date: 24-08-2023
DOI: 10.3389/FPHAR.2023.1249336
Abstract: Ion channels play a crucial role in erse physiological processes, including neurotransmission and muscle contraction. Venomous creatures exploit the vital function of ion channels by producing toxins in their venoms that specifically target these ion channels to facilitate prey capture upon a bite or a sting. Envenoming can therefore lead to ion channel dysregulation, which for humans can result in severe medical complications that often necessitate interventions such as antivenom administration. Conversely, the discovery of highly potent and selective venom toxins with the capability of distinguishing between different isoforms and subtypes of ion channels has led to the development of beneficial therapeutics that are now in the clinic. This review encompasses the historical evolution of electrophysiology methodologies, highlighting their contributions to venom and antivenom research, including venom-based drug discovery and evaluation of antivenom efficacy. By discussing the applications and advancements in patch-cl techniques, this review underscores the profound impact of electrophysiology in unravelling the intricate interplay between ion channels and venom toxins, ultimately leading to the development of drugs for envenoming and ion channel-related pathologies.
Publisher: Elsevier BV
Date: 04-2018
No related grants have been discovered for Anne Ljungars.