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- Aniander, Gustav
(författare)
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Improved candidate screening through tailored co-culture assays and precise tuning of protein expression
- 2024
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The field of biopharmaceuticals is a rapidly growing one. In the last ten years the number of approved biopharmaceuticals has more than doubled. A major hurdle to overcome for increased availability of all the new, effective biopharmaceuticals is the cost of treatment. Much of this can be attributed to the sheer time required for their development. Owing to this, interest in improvements to the biopharmaceuticals and their development process has also rapidly increased. As costs increase the further into development a drug candidate progresses, increasing the fidelity of screening at early stages could alleviate some of the exorbitant costs of development.In paper I, we showcase a novel way of targeting the tumor microenvironment (TME) to allow for TMElocalized CD40 activation. This is of interest as CD40 agonists have shown great potential for immune activation, but with systemic activation leading to severe adverse effects. The localized activation is achieved through the construction of an affinity fusion protein termed an AffiMab through fusion of a platelet derived growth factor receptor beta (PDGFRβ) targeting affibody to the heavy chain of a CD40 agonistic monoclonal antibody (mAb). We demonstrate PDGFRβ-dependent activation in a variety of assays, showing that the approach merits further investigation.Building on the activation assays set up in paper I, we aim to generate an in vitro screening platform for immune cell engagers in paper II. Screening candidates for on-target off-tumor activation is essential, as such activation would lead to adverse effects and be a doselimiting factor. To screen for this, we construct a series of plasmids which upon transfecting cells allow for different levels of a cell-surface target protein to be expressed, a so-called target density panel. This is achieved through the use of hairpin forming elements in the 5’ untranslated region of the mRNA dubbed regulatory elements (RgEs). Through use of different RgEs, we show that a target density panel can be generated and validate it in activation assays with the AffiMab developed in paper I. The platforms’ uniform cell surface background due to all different levels of target being expressed in the same host cell line and tunability through use of different RgEs are features that make it interesting for further research.Finally in paper III, we construct and test an improved translation initiation site (TIS) sequence. Using previous studies on the impact of the nucleotides in the sequence on the efficacy of the TIS, we constructed a novel sequence, TISNOV. This sequence enhanced titer and quality for recombinant production of IgG1 and IgG4 in both stable and transient settings. Further research into other TIS sequences and their uses in regulating protein expression, as well as usage of the TISNOV to improve expression of difficult to express proteins such as bispecifics remain interesting.In conclusion this thesis focuses on different manners to improve and hasten development of new biopharmaceuticals through usage of new workflows, platforms, and genetic engineering strategies.
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| 2. |
- Kuzmin, Leonid, 1958-
(författare)
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Investigation of the most essential factors influencing ski glide
- 2006
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There are many different parameters of a ski running surface (material, roughness, hydrophobicity, etc.). All the parameters have an influence on ski glide, some more and some less. Furthermore, some parameters with only minor relevance are commonly declared as critical, while truly critical parameters, as far as we know, never been investigated. In this thesis, we try to identify and structure the different stages of ski running surface preparation. In our experiments, we have applied well-established, commonly used treatments parallel with alternative preparations. The unexpected result of our experiments is that the treatments commonly used today are not as good as alternative treatments, namely; stone grinding and glide wax application are far from an optimal ski treatment if minimising friction over a given distance is the major goal.
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| 3. |
- Larsson, Carina, 1969-
(författare)
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Communicating performance measures : Supporting continuous improvement in manufacturing companies
- 2017
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Manufacturing enterprises are a key driver of economic growth (Eurostat, 2016). Implementing continuous improvement (CI) is commonly used to increase competitiveness (Hyland et al., 2007), but despite the well-known theory of CI, many manufacturing companies fail in implementing it (Bhasin, 2012; Nordin et al., 2012; Tiwari et al., 2007).An identified critical success factor in CI implementation is the evaluation of performance, including the performance evaluation system itself, the linkage between targets at different company levels, and continual evaluation of performance (Bakås et al., 2011; Scherrer-Rathje et al., 2009; Ukko et al., 2009). Another critical success factor in CI implementation is the communication of performance measures (Bakås et al., 2011; Ukko et al., 2009).This research explores the communication of performance measures. The aim is to support CI by improving the communication of performance measures, and to this end, this thesis concentrates on identifying the main challenges in the communication of performance measures supporting CI. The research scope is manufacturing companies in general, and manufacturing SMEs in particular. The relevant literature concerning the communication of performance measures in manufacturing companies is identified and summarized. Also, current practice is explored, focusing on how performance measures are communicated in manufacturing companies, and whether and how the communication supports CI. This has been done to identify divergences between current practice and theory. Finally, theory and empirical findings are synthesized to identify some of the main challenges to be addressed in order to succeed in CI.The main task is to support CI efforts in manufacturing SMEs, eliminating the identified divergences in the communication of performance measures by adapting these measures to these manufacturing SMEs. These challenges can be summarized as follows: - using both financial performance measures as well as objective and subjective, non-financial performance measures - aligning performance measures with strategy and targets - integrating all performance measure communication, as related to both daily performance and CI, in the same communication loop. - forming two-way communication channels between managers and operators - aligning oral and written communication channels - exploring how information systems can facilitate the communication of performance measures - using and optimizing the visual communication of performance measures
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