The Centyrin of Attention

Improved standards of healthcare, treatments and hygiene control measures have been thrown at MRSA (methicillin-resistant Staphylococcus aureus) but it still continues to cause around 15,000 deaths a year in USA alone. It also costs over $3 billion a year in the USA to treat with a dwindling arsenal of effective therapeutic agents. Dr. Anthony Simon Lynch, Senior Scientific Director at Janssen Research and Development LLC in Spring House, PA, believes the lack of new therapeutic agents is largely due to a failure to properly appreciate the bacteria’s adaptive ability. “One of the problems with new biologic agents is that they typically only target a single molecular target – usually a cell surface marker on the bacteria,” he explains. “The argument we made in a review paper back in 2016 (1) is that, to tackle MRSA, you need to attack multiple targets simultaneously – and you really need to consider addressing both the extracellular space as well as the intracellular life cycle of the bacteria.”

Working with a team of researchers from New York University School of Medicine, Lynch is a contributor to a new paper published in Science Translational Medicine that incorporates such an approach to the identification of biologic agents capable of neutralizing MRSA (2).

One of the collaborators was Dr. Victor J. Torres, Associate Professor of Microbiology at New York University School of Medicine, New York. “There are a series of molecules – toxins to be more precise – that MRSA produces to promote its ability to cause infection,” he says. “We’ve known about them for over 100 years. Working with Anthony and his team at Janssen, the premise of our entire program is that we need to block these molecules to give the upper hand to the host.”

To that end, the team developed a new platform based on centyrins – small protein scaffolds derived from a human protein called tenascin-C that have previously been explored for diseases in oncology and immunology. The team got over a serious stumbling block – the short serum half-life of centyrins – by fusing the protein to an albumin-binding consensus domain. The result was a stable biomolecule with interesting properties. “These molecules are not just good at blocking purified toxin in a test tube,” explains Torres. “They also suppress the activity of MRSA in human cell models. Moreover, they also protect the host in different pre-clinical models of MRSA infections.”

Translational hopes? Another company – Arsanis – recently tried to take a similar approach using toxin-neutralizing antibodies, but failed to demonstrate meaningful efficacy in a Phase 2 trial.  One potential explanation is that the antibodies failed to penetrate the intracellular environment and protect key classes of immune cells from S. aureus residing in phagosomes. The Janssen/NYU team are more optimistic as their platform is much broader from a targeting perspective. Indeed, Lynch believes MRSA is just the start. “As you’ll see in subsequent manuscripts, using toxin-neutralizing centyrins tethered to monoclonal antibodies that also target the bacteria via multiple different mechanisms – we were able to target up to 10 virulence factors in the organism,” he explains. “We think this new platform ‘mAbtyrins’ (monoclonal antibody-centyrin fusion proteins) may be applicable to targeting a range of bacterial pathogens that deploy toxins as key virulence factor in invasive diseases”.

The unconventional approach excites Torres, who is confident that out-of-the-box thinking is required to tackle the problem of multi drug resistant bacteria, which has been recently recognized as a serious threat to human by the World Heath Organization (3). “This technology is quite adaptable, which gives it significant breadth,” he says. “Today we are rightly focused on MRSA, but we’ve got the idea that you could target whatever pathogen you want with the technique. Any target that scientists or companies can come up with, in theory could be used to identify new inhibitors. To do that with traditional antibodies is an Herculean effort. With the Centyrin platform, it is much more manageable.”