MetrioPharm’s MP1032 has anti-viral effects on different SARS-CoV-2 Variants of Concern
By Dr. Christian Setz, Scientific Managing Director of ImmunoLogik
This is the third article within our series of six covering different aspects of work behind the scenes in the iMPAct project. In today’s article, we will explore pre-clinical studies performed to test the efficacy of MetrioPharm’s MP1032 drug on different variants of concern of SARS-CoV-2, how these variants of concern were obtained, and how to interpret these results.
Viruses sometimes change through mutation, an event involving alterations to their genes. Accumulating mutations over time is expected of viruses and often does not affect how the virus behaves, or even negatively effects the virus’ ability to replicate or infect hosts. However, there are instances where viral mutation can enhance its ability to replicate and lead to increased numbers of infection. The SARS-CoV-2 that is responsible for the pandemic we are currently in, also undergoes mutations and has produced concerning variants classified into different ‘Variants of Concern (VOC)’ categories by the World Health Organization (WHO).
Based on MetrioPharm’s previous work, MetrioPharm’s MP1032 compound has shown anti-viral effects against the original SARS-CoV-2 VOC. However, it was not known whether it had the same efficacy on different emerging VOC. Dr. Christian Setz is leading the experiments to tackle this question.
Testing of MP1032 in pre-clinical experiments
When a patient is infected with a new VOC of SARS-CoV-2, a sample can be collected.
The virus is then isolated from the sample and its RNA is sequenced to determine what VOC it is. Through a collaboration with the institutes of virology at the university hospital of Tuebingen and Erlangen Dr. Christian Setz and his colleagues received different viral VOCs for their pre-clinical studies.
In highly secure and restricted labs the virus is then allowed to replicate under strict laboratory conditions. Large viral stocks of the virus will then be frozen and stored at -80 degrees Celsius. This is to ensure that the investigators will have viable virus to work with for subsequent lab testing.
In order to test whether MP1032 has an effect on different SARS-CoV-2 VOC Dr. Christian Setz and his colleagues use state-of-the-art models and protocols. First, they infect specific human cell lines with a predetermined amount of virus via the determination of the so called TCID50. The TCID50 is a value which classifies the number of infectious virus particles needed to infect cells and which enables them to infect cells with the same multiplicity of infection (MOI). The cell lines they primarily use in such experiments are immortalized cancer cells which were originally isolated from human lungs and have been extensively characterized and standardized to be grown in the lab. After they infect a predetermined amount of the cells grown in culture dishes with the known amount of virus, the virus undergoes replication within its host cells. Eventually the infected cells release new viruses into the culture medium where the cells are grown (the supernatant).
Now the drug candidate MP1032 is introduced. The cell lines are treated with different quantities of MP1032 after infection with the virus and the supernatant is analyzed for viruses after 3 days. Depending on how many viruses can be detected in the supernatants Dr. Christian Setz and his colleagues can then calculate the ‘effective dose’ of the compound. A negative control – untreated cells – is used as a comparison to calculate how potent the anti-viral effect of MP1032 is for different viral VOC.
This graph demonstrates the basic principles of the pre-clinical experiments conducted by Dr. Christian Setz and his colleagues in the laboratory
Testing against different viral Variants of Concern
In such experiments Dr. Christian Setz and his colleagues have discovered that MP1032 has potent anti-viral effects against the original SARS-CoV-2 variant (Wuhan Type), as well as for all VOCs such as the now predominant Omicron variant, as well as Alpha, Beta, Gamma and Delta variants. Dr. Christian Setz and his colleagues are now investigating the specific time point in viral replication that MP1032 acts on. Based on whether the compound works best at viral entry or at a later time point, the mechanism of action can be assessed.
Dr. Christian Setz and his colleagues have promising results from their pre-clinical experiments and are currently preparing a scientific publication about their findings. However, Dr. Christian Setz stresses that even the best pre-clinical data is no guarantee that these findings can be extrapolated to the clinical setting in which patients receive the drug. But these experiments are an important component of the long trajectory each drug must take before it can reach the market and prove an effective treatment for COVID-19 in patients who need it most.
Our next article: A phase2a clinical trial during the COVID-19 pandemic
In our next article Petra Schulz, the head of drug development at MetrioPharm walks us through her role in managing the iMPact project’s clinical trial. Learn about the fundamentals of clinical trials, their phases, and the challenges of running one during a pandemic.
Posted on the 7th of December 2022.