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Coming dissertations at Uppsala university

  • Development and evaluation of analytical techniques for antibodies and antibody-drug conjugates : From verification of conjugation to stability testing Author: Malin Källsten Link: Publication date: 2020-02-26 12:57

    Antibody-drug conjugates (ADCs) are becoming increasingly important in oncology. ADCs are inherently heterogeneous analytes. For a successful drug candidate to go through to the clinic, extensive characterization and evaluation of the constructs are necessary. The drug-to-antibody ratio (DAR) directly determines the toxicity and efficacy of the product and has to be closely monitored during the entire process.

    In this thesis, several analytical techniques suitable for DAR determination in early-stage development have been evaluated against two more readily available options. The main focus in all studies has been on cysteine-linked ADCs, due to their prevalence in successful designs and their higher demand on the analytical set-up.

    The comparisons showed that mass spectrometry (MS) derived DAR values did conform well with hydrophobic interaction chromatography derived values, irrespective of which MS instrument was used. For MS instruments, overall the desolvation was found to have a bigger impact on the apparent DAR values than the resolution of the instrument and low-resolution instruments, such as triple quadrupoles, can be viable options for DAR determination in early-stage development. Furthermore, it also could be concluded that MS-derived DAR values are susceptible to alterations in the sample preparation workflow.

    Stability testing is vital to ensure a safe product. In this thesis, different compositions of mobile phases in size exclusion chromatographic (SEC) were tested for their ability to elute ADC aggregates. It was concluded that sufficient ionic strength to elute ADC aggregates from a SEC column purely by adding ammonium acetate cannot be achieved without exceeding salt concentrations compatlible with MS sources.

    Finally, two new analytical workflows have been designed by applying a proteomic desalting protocol and supercharging reagents to mAb and ADC samples. Both techniques showed promise; the magnetic beads as a more flexible desalting alternative for mAbs and ADCs and the addition of selective supercharging reagents for improved sensitivity and peak shapes in MS spectra (without significant alterations of the derived DAR values).

    Taken together, this thesis provides guidance on many aspects of ADC analysis from DAR determination to aggregate detection. The gathered knowledge can help setting up faster or more reliable quality checks for new candidates.

  • Avtalets räckvidd I : Om avtals tredjemansverkningar, särskilt vid tredjemansavtal och direktkrav Author: Oskar Mossberg Link: Publication date: 2020-02-24 12:39

    The idea that a contract should affect other people than the parties has seemingly always been a provocative notion. A contract binds the contracting parties – and only them – together in a legal relationship, and yet according to contemporary law a contract can have various legal effects for third parties, i.e. non-parties. The parties can conclude a contract for the benefit of a third party, and third parties can be affected by the contracts of others pursuant to both statutory law and uncodified general principles of law.

    The legal theme of contractual third party effects involves both theoretical and practical challenges. This doctoral dissertation addresses a number of these challenges, by examining (mainly) Swedish and Nordic private law sources. The study explores third party contracts and direct claims, as well as the relationship between these two legal figures, by placing them in a historical and theoretical context and by performing a series of contextualizing readings of sources revealing developments in both case law and legal scholarship.

    The research is based on a legal scientific methodology, enriched by theoretical and methodological imports pillaged from the classical teachings and contemporary scholarship on rhetoric. The result can be characterized as a form of rhetorically infused, topically oriented, hermeneutic study of contemporary legal discourse on third party effects of contract.

  • Legal Interpretation and Standards of Proof : Essays in Philosophy of Law and Evidence Law Theory Author: Sebastián Reyes Molina Link: Publication date: 2020-02-20 14:53

    This dissertation addresses the issues of the indeterminacy of law and judicial discretion in the decision of the quaestio facti. It is composed of four papers:

    In the first paper, I develop an account of legal indeterminacy called the ‘systemic indeterminacy’ thesis. This thesis claims that legal indeterminacy and judicial discretion are the results of features of the structure of typical rational legal systems such as interpretative codes with a plurality of interpretative directives, the non-redundancy clause, and the non-liquet rule. 

    In the second paper, I criticise two approaches that support the thesis that law ought to ascertain the truth of the quaestio facti: the motivation approach and the legal approach. First, I advance two objections to a version of the motivation approach that I call the ‘behaviour-guidance’ theory. The first objection claims that the appearance of ascertaining the truth is enough to produce the psychological state of compliance. The second objection claims that the indeterminacy of law brings about the impossibility of an ex ante knowledge of the content of the law, thus, the governed cannot gain knowledge of the law’s efforts to ascertain the truth. Second, I explore if the legal approach is plausible. I provide five different legal reasons to support the claim that the law ought to ascertain the truth of the quaestio facti. However, I show that none of these reasons are particularly convincing.

    In the third paper, I advance three objections to the idea of reducing the indeterminacy of the standard of proof rules by adding new legal rules for their interpretation. The first objection claims that these interpretative rules, do not provide any guidance to the trier of fact to set the quantum of evidence. The second objection claims that insofar as these interpretative rules are posited in a natural language they are also indeterminate. The third objection claims that these interpretative rules are redundant legal rules.

    In the fourth paper, I develop the thesis that standards of proof are competence norms that grant competence to triers of fact to set the quantum of evidence in a case-by-case manner.