by Maurizio Muroni, Ph.D.
Senior Principal Scientist
Overcoming the analytical challenges that post-translational modifications present, getting our customers’ molecules to the clinic and market to start improving patient lives.
Revolutionizing Analytics Method Development for Minimizing the Risk of Post-Translational Modifications
While the majority of biologic drugs in development continue to be monoclonal antibodies (mAbs) or antibody-based therapeutics, innovation in the biopharmaceutical industry is continuously evolving. This is leading to novel recombinant protein formats with the potential to address unmet needs for many patients.
Although these more complex formats are promising as new therapies, they can present unique challenges to drug developers. This includes developing analytical methods that can ensure full characterization of not only the desired products, but potential process and product-related impurities.
One of the biggest analytical challenges for these non-conventional formats is the identification and quantification of uncommon post-translational modifications (PTMs) that may be present in these complex molecules. Degradation profiles can also be difficult to interpret given their unusual structures.
Tackling challenges associated with post-translational modifications
At Lonza, my team and I tackle the challenges presented by multi-specifics and other non-mAb protein-based biologics head-on. With my experience in the analysis of small molecules, peptides, and many types of proteins, I am able to look at the product quality attributes of molecules from both chemical and biological perspectives, including any post-translational modifications impacting a molecule (Figure 1).
This approach allows me to identify potential method development approaches not typically adopted for biopharmaceuticals that may tackle shortcomings of traditional mAb-based strategies. Methods for the analysis of biological samples such as plasma are one example.
Figure 1: Typical workflow for method development
In the course of my work, the collaborative environment of Lonza enables cross-functional interactions and ensures successful outcomes. My team also has access to the extensive Lonza network of experts who have experience in every type of therapeutic format – from small molecules to gene therapies and mRNA products. These teams are always keen to share their knowledge.
A bespoke approach to method development
Another approach we take at Lonza to help accelerate method development for these complex modalities is the use of a design-of-experiment (DoE) approach (Figure 2). For many of these molecules, there are few or no literature references on what methods to use, so it is often necessary to start method development from scratch. That requires the evaluation of many different parameters to identify and optimize the most important ones.
DoE provides a mechanism for investigating multiple parameters at once, significantly shortening the time it takes to develop new methods. Often, an initial DoE study helps us identify the critical parameters that must be considered during method development. A second DoE study then enables optimization of the method.
Collaboration is important here too; Lonza’s statistical analysis team helps with the design of the DoE studies.
Figure 2: Examples of design space (top left), interaction plots (bottom) and response surface plot (top right)
How our post-translational modification expertise helps our customers to meet their timelines
What does all of this mean for Lonza’s customers? First, analytical strategies are tailored to their molecules, rather than being based on a set of assays previously developed for mAbs that might not fit the molecule.
Second, our fit-for-purpose methods are optimized and developed within an accelerated timeframe, to rapidly address unmet clinical needs.
Last but not least, methods developed using this customized and detailed approach support successful Investigational New Drug (IND) filings for new modalities, with fewer questions from regulatory authorities.
Helping customers complete successful IND filings provides the greatest reward for my team and I, because the clinical studies that result have the potential to lead to novel medicines with real impact on patients’ lives.
About the author:
Maurizio Muroni attained a Laurea in Chimica from University of Sassari. He then moved to Cardiff, where he obtained a PhD in Biochemistry from the School of Chemistry at Cardiff University. In 2011 Maurizio moved to London to start his career in the Industry at PolyTherics (now Abzena) leading the Analytical Team. In 2014 he joined MedImmune (now AstraZeneca) as scientist working on the characterisation of therapeutic proteins in the Physiochemical Development department. Maurizio Joined Lonza in 2021 as Principal Scientist in the Analytical Development team working on CMC analytical development strategies for complex molecules.