Trappe, Anne ORCID: 0000-0001-7349-9592 (2018) Development and application of charge variant profiling platforms for molecular triage of candidate monoclonal antibodies. PhD thesis, Dublin City University.
Abstract
Monoclonal antibodies (mAbs) are highly valued biopharmaceuticals. To patients, these
molecules are medicines for conditions that have previously been untreatable, improving
quality of life and saving lives. To pharmaceutical companies, a successful product can
be worth billions. For companies, however, the development of these therapies is a long
and expensive process. The patent protected, marketable “life”, of these molecules is
relatively short and so companies have only a few years to recoup the cost of
development. The cost of these treatments to health services and patients alike can,
therefore, be prohibitive. If the development process could be de-risked to identify
molecules that will be easily manufactured early in the process, this could lead to
significantly reduced costs.
MAbs are complex molecules produced by living organisms. Their production process
leads to inherent differences. The charge variant (CV) profile of a mAb is arguably one
of the most important critical quality attributes (CQAs) monitored during manufacturing.
The CV profile is constituted by mAb isoforms with heterogeneous net charge caused by
enzymatic and non-enzymatic processes. Strong cation exchange (SCX) represents the
predominant analytical procedure used in this project. The molecular composition of
each isoform is usually determined using a multifaceted analytical strategy consisting of
mass spectrometry (MS) analysis on many levels, peptide mapping and glycosylation
profiling in addition to other methods to evaluate structure and function. By hyphenation
of SCX to MS the main isoforms of the mAb can be identified in one analysis rather than
a longer and less reliable multi-step process.
To fully understand SCX in depth investigations into the fundamental absorption
mechanisms of salt and pH elution modes were performed. From this investigation the
optimum parameters were utilised to develop a rapid charge variant method. Finally, to
investigate the equivalence of SCX-MS to traditional characterisation studies a
comprehensive study of in-house produced Cetuximab was performed. These studies
combined to develop a platform for the rapid and in-depth characterisation of candidate
molecules by SCX-MS.
Metadata
Item Type: | Thesis (PhD) |
---|---|
Date of Award: | November 2018 |
Refereed: | No |
Supervisor(s): | Meleady, Paula and Bones, Jonathan |
Subjects: | UNSPECIFIED |
DCU Faculties and Centres: | DCU Faculties and Schools > Faculty of Science and Health > School of Biotechnology |
Use License: | This item is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 License. View License |
ID Code: | 22670 |
Deposited On: | 22 Nov 2018 16:34 by Paula Meleady . Last Modified 13 Sep 2022 03:30 |
Documents
Full text available as:
Preview |
PDF
- Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
7MB |
Downloads
Downloads
Downloads per month over past year
Archive Staff Only: edit this record