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Developing Synthetic Affinity Reagents for Improved Diagnostics

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As the COVID-19 pandemic highlighted, effective diagnostic technologies are an essential part of the response to a disease outbreak. However, developing diagnostics rapidly and on a large scale using traditional approaches can be challenging. MIP Discovery is working to address these issues, by designing molecularly imprinted polymers (MIPs) – synthetic affinity reagents that offer several advantages over antibodies.

To learn more about MIPS and why they are particularly suited for use in in vitro diagnostic assays, we spoke to Dr. Francesco Canfarotta, head of chemistry at MIP Discovery. In this interview, Dr. Canfarotta also tells us about MIP Discovery’s nanoMIP™ technology and how recent funding from the Bill & Melinda Gates Foundation will be used by the company to develop nanoMIPs for use in a future pandemic response.

Anna MacDonald (AM): Can you explain what MIPS are and how they are produced?

Dr. Francesco Canfarotta (FC): MIPS are synthetic affinity reagents that are designed and manufactured around a biomarker, or target of interest, to mimic its shape and surface functionality. In essence, they are polymers with a functional binding pocket that can be utilized in applications that require a binding event.

AM: Can you tell us more about MIP Discovery’s nanoMIP technology and how it compares to other approaches?

FC: Molecular imprinting techniques are well established but have seen little practical use in the past due to limitations with the size of the resultant “imprint” molecule and inconsistency of recognition. This is largely down to how the imprints are created, which is often in solution and with no specific strategy as to how such imprints are generated. MIP Discovery has developed a proprietary technology – nanoMIPs – which overcomes these problems. Our approach is based on actively designing the recognition qualities that we want. Our team uses high-end molecular modeling software to model interactions between the target molecule and individual monomers (the building blocks of nanoMIPs). This allows us to design and control a polymerization reaction around the immobilized target, which can be anything from a small molecule to a protein or whole virus. This results in the formation of a nanoMIP affinity reagent, which is then eluted from the immobilized target and evaluated for performance in a chosen application. The outcome is a high-performing affinity reagent, tightly controlled (typically 10–60 nm in size), which can specifically bind a chosen target in a given orientation.

The main technology we benchmark against is antibodies, although we are aware of alternative technologies such as aptamers and affimers. A common difference between nanoMIPs and any of the other technologies is the sheer number of building blocks we can use to create a nanoMIP with the correct physicochemical and binding properties. MIP Discovery relies on over 600 carefully selected monomers versus the ~20 amino acids used for antibodies/affimers, or the 50–100 nucleotides used for aptamers. This enlarged design space gives nanoMIPs a distinct advantage that is further enhanced by the potential for a greater number of contact points with the target (nominally 5–6 contact points for an antibody versus 10 or more contact points for a nanoMIP, depending on the size of the target).

With regards to antibodies, their production is reliant on animal subjects or components to varying degrees. Aside from the ethical dimension, it creates challenges around sterility and contamination, not to mention significant timelines driven by animal husbandry/cell culture expansion. nanoMIPs are entirely synthetic, chemically defined and animal component free. Moreover, they can be exposed to extreme conditions of temperature, pressure and pH, allowing sterilization while retaining their functionality.

While antibodies are well established for recognizing proteins, and have become the reagent of choice in this respect, they are less well suited to other target classes. nanoMIPs have been shown to have a broad range for recognition, from differentiating individual ions separated only by valency, to small molecules such as drugs of abuse and through to peptides and proteins.

AM: What makes nanoMIPs well-suited for use in in vitro diagnostic assays? Are there any other applications that MIPs are used in?

FC: nanoMIPs have a plethora of unique characteristics that are of interest to diagnostic assay developers. The first is their robustness: their polymer structures mean they can withstand harsh environments and fluctuating temperatures, making them ideal for in-field devices. Imagine a drug testing device in a Canadian police car: it needs to withstand extreme seasonal temperatures plus everyday handling without impacting performance. This can be difficult to achieve with biological reagents, but nanoMIPs can overcome this. Another feature of nanoMIPs that has gained a lot of interest is their scalability and reproducibility, which inevitably leads to supply security. The chemical production method means that batch-to-batch consistency can easily be achieved, and supply chain risks, such as an antibody clone no longer producing, can be eliminated. Beyond diagnostic assays, we are working with a number of partners to develop nanoMIPs for use in bioprocessing, particularly around sensing and chromatography applications. The needs here are driven by cell and gene therapy in particular.

AM: What advantages do MIPs offer over antibodies?

FC: Antibodies are an amazing technology platform, and this is very much reflected in their use through R&D, diagnostics and other applications. However, by their very nature, antibodies do have limitations. The majority of antibodies sold commercially have been generated through an immune response, which cannot be controlled and is ultimately influenced by millions of years of biology. This makes recognizing certain classes of molecule, or certain features of a given molecule, very difficult. nanoMIPs can be designed against almost any target of interest, from ions, small organic molecules, proteins and even a full virus. This makes them an ideal option for targeting species like toxic substances, drugs and their metabolites.

From a product profile perspective, nanoMIPs are chemically defined and animal component-free, allowing for rapid generation at scale. This is of course one of the key features that has attracted interest from the Bill & Melinda Gates Foundation in tackling mass-scale infectious testing in low- and middle-income countries.

AM: MIP Discovery recently received funding from the Bill & Melinda Gates Foundation. Can you explain how this funding will be used and some of the expected impacts the project will have?

FC: The grant from the Bill & Melinda Gates Foundation is supporting an innovative project to develop nanoMIPs for use in a future pandemic response. This project is alongside funding to other partners such as Sapphiros, as an improvement over antibodies, to quickly enable low-cost, high volume diagnostic tests, for low- and middle-income countries during endemic or pandemic outbreaks. Key objectives of the project include reducing current timelines to enable design and scale-up of novel detection reagents in under four weeks. nanoMIP detection reagents can then be deployed using high-throughput diagnostic platforms on a global scale. Our “scale out” approach will allow MIP Discovery to tackle multiple diagnostic markers at once, whilst still achieving the volumes required for mass-scale diagnostics.

We expect this project to impact the speed at which the industry can respond to pandemic and endemic situations, whether natural or otherwise.

AM: Do you have plans to develop NanoMIPs for diagnostics for non-communicable diseases? What further innovations do you envisage for MIPs?

FC: Our focus in the coming 24 months, beyond infectious disease, is on solving problems with a significant unmet need that can impact quality of life. The first area of focus is on drugs of abuse, particularly the North American fentanyl pandemic. Creating reagents to enable better in-field testing is one of the key steps in the fight against this chemical epidemic.

Our second area of focus is on bioprocessing, particularly around cell and gene therapy. Cell and gene therapy treatments are among the most expensive in any health care service. They are complex and costly to produce. nanoMIPs are ideally suited to in-line sensing and chromatography processes in industrial settings, potentially allowing the generation of higher quality therapies at a lower cost.

Dr. Francesco Canfarotta was speaking to Anna MacDonald, Interim Managing Editor for Technology Networks.