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  • 51.
    Wikman, Maria
    KTH, School of Biotechnology (BIO).
    Rational and combinatorial protein engineering for vaccine delivery and drug targeting2005Doctoral thesis, comprehensive summary (Other scientific)
    Abstract [en]

    This thesis describes recombinant proteins that have been generated by rational and combinatorial protein engineering strategies for use in subunit vaccine delivery and tumor targeting.

    In a first series of studies, recombinant methods for incorporating immunogens into an adjuvant formulation, e.g. immunostimulating complexes (iscoms), were evaluated. Protein immunogens, which are not typically immunogenic in themselves, are normally administered with an adjuvant to improve their immunogenicity. To accomplish iscom incorporation of a Toxoplasma gondii surface antigen through hydrophobic interaction, lipids were added either in vivo via E. coli expression, or in vitro via interaction of an introduced hexahistidyl (His6) peptide and a chelating lipid. The possibility of exploiting the strong interaction between biotin and streptavidin was also explored, in order to couple a Neospora caninum surface antigen to iscom matrix, i.e. iscom particles without any antigen. Subsequent analyses confirmed that the immunogens were successfully incorporated into iscoms by the investigated strategies. In addition, immunization of mice with the recombinant Neospora antigen NcSRS2, associated with iscoms through the biotin-streptavidin interaction, induced specific antibodies to native NcSRS2 and reduced clinical symptoms following challenge infection. The systems described in this thesis might offer convenient and efficient methods for incorporating recombinant immunogens into adjuvant formulations that might be considered for the generation of future recombinant subunit vaccines.

    In a second series of studies, Affibody® (affibody) ligands directed to the extracellular domain of human epidermal growth factor receptor 2 (HER2/neu), which is known to be overexpressed in ∼ 20-30% of breast cancers, were isolated by phage display in vitro selection from a combinatorial protein library based on the 58 amino acid residue staphylococcal protein A-derived Z domain. Biosensor analyses demonstrated that one of the variants from the phage selection, denoted His6-ZHER2/neu:4, selectively bound with nanomolar affinity (KD ≈ 50 nM) to the extracellular domain of HER2/neu (HER2-ECD) at a different site than the monoclonal antibody trastuzumab. In order to exploit avidity effects, a bivalent affibody ligand was constructed by head-to-tail dimerization, resulting in a 15.6 kDa affibody ligand, termed His6-(ZHER2/neu:4)2, that was shown to have an improved apparent affinity to HER2-ECD (KD ≈ 3 nM) compared to the monovalent affibody. Moreover, radiolabeled monovalent and bivalent affibody ligands showed specific binding in vitro to native HER2/neu molecules expressed in human cancer cells. Biodistribution studies in mice carrying SKOV-3 xenografted tumors revealed that significant amounts of radioactivity were specifically targeted to the tumors in vivo, and the tumors could easily be visualized with a gamma camera. These results suggest that affibody ligands would be interesting candidates for specific tumor targeting in clinical applications, such as in vivo imaging and radiotherapy.

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  • 52.
    Wikman, Maria
    et al.
    KTH, Superseded Departments (pre-2005), Biotechnology.
    Steffen, Ann Charlott
    Gunneriusson, Elin
    Tolmachev, Vladimir
    Adams, Gregg
    Carlsson, Jörgen
    Ståhl, Stefan
    KTH, Superseded Departments (pre-2005), Biotechnology.
    Selection and characterization of HER2/neu-binding affibody ligands2004In: Protein Engineering Design & Selection, ISSN 1741-0126, E-ISSN 1741-0134, Vol. 17, no 5, p. 455-462Article in journal (Refereed)
    Abstract [en]

    Affibody® (affibody) ligands that are specific for the extracellular domain of human epidermal growth factor receptor 2 (HER2/neu) have been selected by phage display technology from a combinatorial protein library based on the 58 amino acid residue staphylococcal protein A-derived Z domain. The predominant variants from the phage selection were produced in Escherichia coli, purified by affinity chromatography, and characterized by biosensor analyses. Two affibody variants were shown to selectively bind to the extracellular domain of HER2/neu (HER2-ECD), but not to control proteins. One of the variants, denoted His6-ZHER2/neu:4, was demonstrated to bind with nanomolar affinity (∼50 nM) to the HER2-ECD molecule at a different site than the monoclonal antibody trastuzumab. Furthermore, radiolabeled His 6-ZHER2/neu:4 affibody showed specific binding to native HER2/neu, overexpressed on the SKBR-3 tumor cell line. Such affibody ligands might be considered in tumor targeting applications for radionuclide diagnostics and therapy of adenocarcinomas such as breast and ovarian cancers.

  • 53.
    Zhang, Chuan
    et al.
    Center for Optical and Electromagnetic Research, College of Optical Science and Engineering, Zhejiang University, Hangzhou, 310052, China.; Taizhou Hospital, Zhejiang University, Taizhou, 318000, China..
    Yang, Anqi
    Center for Optical and Electromagnetic Research, College of Optical Science and Engineering, Zhejiang University, Hangzhou, 310052, China..
    He, Sailing
    KTH, School of Electrical Engineering and Computer Science (EECS), Electrical Engineering, Electromagnetic Engineering and Fusion Science. Center for Optical and Electromagnetic Research, College of Optical Science and Engineering, Zhejiang University, Hangzhou, 310052, China.; Taizhou Hospital, Zhejiang University, Taizhou, 318000, China.; National Engineering Research Center for Optical Instruments, Zhejiang University, Hangzhou, 310052, China.
    Lateral Flow Immunoassay Strip Based on Confocal Raman Imaging for Ultrasensitive and Rapid Detection of COVID-19 and Bacterial Biomarkers2023In: Progress In Electromagnetics Research M, ISSN 1937-8726, Vol. 120, p. 41-54Article in journal (Refereed)
    Abstract [en]

    Rapid and sensitive analysis of proteins in complex biological environments is crucial for the screening and defense against infectious diseases. Here, we show that the lateral flow immunoassay strip based on confocal Raman imaging can achieve immune analysis at pM and ∼ 104 cfu/mL molecular level for the rapid detection of COVID-19 virus and bacteria. Fluorescent dyes of Alexa 647 were used as Raman markers in the Raman silent region of 1800 cm−1 and 2800 cm−1, and colloidal gold nanospheres were used to enhance the Raman signal. Raman imaging was performed with our self-developed confocal Raman microscopy for COVID-19 and Escherichia coli O157: H7 on lateral flow immunoassay strip. Compared to traditional colloidal gold test strips, the sensitivity of this technology has been significantly improved. This work will promote the widespread application of surface enhanced Raman detection for bacteria and virus, which is of great significance for in vitro screening and disease diagnosis.

  • 54. Šket, Robert
    et al.
    Treichel, Nicole
    Kublik, Susanne
    Debevec, Tadej
    Eiken, Ola
    KTH, School of Technology and Health (STH), Environmental Physiology. KTH, School of Technology and Health (STH), Centres, Swedish Aerospace Physiology Centre, SAPC.
    Mekjavić, Igor
    Schloter, Michael
    Vital, Marius
    Chandler, Jenna
    Tiedje, James M.
    Murovec, Boštjan
    Prevoršek, Zala
    Likar, Matevž
    Stres, Blaž
    Hypoxia and inactivity related physiological changes precede or take place in absence of significant rearrangements in bacterial community structure: The PlanHab randomized trial pilot study2017In: PLOS ONE, E-ISSN 1932-6203, Vol. 12, no 12, article id e0188556Article in journal (Refereed)
    Abstract [en]

    We explored the assembly of intestinal microbiota in healthy male participants during the randomized crossover design of run-in (5 day) and experimental phases (21-day normoxic bed rest (NBR), hypoxic bed rest (HBR) and hypoxic ambulation (HAmb) in a strictly controlled laboratory environment, with balanced fluid and dietary intakes, controlled circadian rhythm, microbial ambiental burden and 24/7 medical surveillance. The fraction of inspired O2 (FiO2) and partial pressure of inspired O2 (PiO2) were 0.209 and 133.1 ± 0.3 mmHg for NBR and 0.141 ± 0.004 and 90.0 ± 0.4 mmHg for both hypoxic variants (HBR and HAmb; ~4000 m simulated altitude), respectively. A number of parameters linked to intestinal environment such as defecation frequency, intestinal electrical conductivity (IEC), sterol and polyphenol content and diversity, indole, aromaticity and spectral characteristics of dissolved organic matter (DOM) were measured (64 variables). The structure and diversity of bacterial microbial community was assessed using 16S rRNA amplicon sequencing. Inactivity negatively affected frequency of defecation and in combination with hypoxia increased IEC (p < 0.05). In contrast, sterol and polyphenol diversity and content, various characteristics of DOM and aromatic compounds, the structure and diversity of bacterial microbial community were not significantly affected over time. A new in-house PlanHab database was established to integrate all measured variables on host physiology, diet, experiment, immune and metabolic markers (n = 231). The observed progressive decrease in defecation frequency and concomitant increase in IEC suggested that the transition from healthy physiological state towards the developed symptoms of low magnitude obesity-related syndromes was dose dependent on the extent of time spent in inactivity and preceded or took place in absence of significant rearrangements in bacterial microbial community. Species B. thetaiotamicron, B. fragilis, B. dorei and other Bacteroides with reported relevance for dysbiotic medical conditions were significantly enriched in HBR, characterized with most severe inflammation symptoms, indicating a shift towards host mucin degradation and proinflammatory immune crosstalk.

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