Milton protein scaffold6/23/2023 Glycoproteins that sit at the surface of the virus can act as ‘keys’ that recognize and unlock the cells of certain organisms, leading to viral infection. To do so, many vaccines contain viral molecules called glycoproteins, which are specific to each type of virus. Vaccines train the immune system to recognize a specific virus or bacterium so that the body can be better prepared against these harmful agents. This work demonstrates that antigen-displaying protein nanoparticles can be designed from scratch, and provides a systematic way to investigate the influence of antigen presentation geometry on the immune response to vaccination. Electron microscopy and antibody binding experiments demonstrated that the designed nanoparticles presented antigenically intact prefusion HIV-1 Env, influenza hemagglutinin, and RSV F trimers in the predicted geometries. Trimers that experimentally adopted their designed configurations were incorporated as components of tetrahedral, octahedral, and icosahedral nanoparticles, which were characterized by cryo-electron microscopy and assessed for their ability to present viral glycoproteins. We first de novo designed trimers tailored for antigen fusion, featuring N-terminal helices positioned to match the C termini of the viral glycoproteins. To enable a new generation of anti-viral vaccines, we designed self-assembling protein nanoparticles with geometries tailored to present the ectodomains of influenza, HIV, and RSV viral glycoprotein trimers. Multivalent presentation of viral glycoproteins can substantially increase the elicitation of antigen-specific antibodies. Howard Hughes Medical Institute, University of Washington, United States.Center for Advanced Mathematics in Energy Research Applications, Computational Research Division, Lawrence Berkeley Laboratory, United States.Amsterdam UMC, Department of Medical Microbiology, Amsterdam Infection & Immunity Institute, University of Amsterdam, Netherlands.Berkeley Center for Structural Biology, Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley Laboratory, United States.Electron Microscopy Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, United States.Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, United States.Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States.International AIDS Vaccine Initiative Neutralizing Antibody Center, the Collaboration for AIDS Vaccine Discovery (CAVD) and Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, United States.Department of Integrative Structural and Computational Biology, The Scripps Research Institute, United States.Institute for Protein Design, University of Washington, United States.Department of Biochemistry, University of Washington, United States.Here we review the current state and clinical validation of these next-generation therapeutics.Īdnectin Affibody Anticalin DARPin antibody immunoglobulin. This includes the abovementioned pioneering examples as well as designed ankyrin repeat proteins (DARPins). However, despite strong interest from basic science, only a handful of those protein scaffolds have undergone biopharmaceutical development up to the clinical stage. In fact, engineered protein scaffolds with useful binding specificities, mostly directed against targets of biomedical relevance, constitute an area of active research today, which has yielded versatile reagents as laboratory tools. Since then, this concept has expanded considerably, including many other protein templates. Early examples were the Affibody, Monobody (Adnectin), and Anticalin proteins, which were derived from fragments of streptococcal protein A, from the tenth type III domain of human fibronectin, and from natural lipocalin proteins, respectively. The concept of engineering robust protein scaffolds for novel binding functions emerged 20 years ago, one decade after the advent of recombinant antibody technology.
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