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Pathogen Capture Technology for Infectious Disease Therapeutics and Diagnostics

A broadly applicable pathogen capture platform based on a genetically engineered version of a natural human blood protein, suitable for multiple therapeutic and diagnostic applications

Microbial contamination is the cause of life-threatening cases of sepsis, meningitis and multiple other infectious diseases that are a major cause of death world-wide. Equally prevalent are pathogenic contaminants in our environment, food, and manufacturing processes. In each case, the presence of microbial contaminants must be confirmed, and when they are found, they need to be removed, identified or targeted with therapeutics.

This electron micrograph shows Staphylococcus aureus bacteria (artificially colored in yellow), whose surface has been bound by FcMBL protein coupled to magnetic beads after the enzyme-based method has exposed the sugar molecules that are recognized by FcMBL. Exposing the FcMBL-bead-covered bacteria to a magnetic field allows their rapid and efficient isolation for subsequent analysis. Credit: Wyss Institute at Harvard University.

The Wyss Institute’s pathogen capture platform is based on a genetically engineered version of the natural human blood protein, Mannose Binding Lectin (MBL), which is part of our body’s innate immune system. Native MBL binds to numerous pathogens from all microbial classes (Gram +/- bacteria, fungi, viruses and parasites). Wyss researchers created a genetically engineered form of MBL by deleting potentially complicating complement activation and coagulation-promoting domains, and fusing it to an antibody Fc fragment (FcMBL), which stabilizes the molecule and enables rapid purification. FcMBL retains the ability of native MBL to bind to the same broad spectrum of pathogens, can be easily coupled to surfaces for pathogen capture or biologically active therapeutics or diagnostic markers; it also can be produced with a thousand-fold lower cost and exhibits higher stability. Importantly, FcMBL not only captures live and intact pathogens, but also toxic fragments and toxins released by dead pathogens, known as Pathogen Associated Molecular Patterns (PAMPs), which trigger the inflammatory cascade that leads to organ injury and sepsis.

In the pathogen detection technology, engineered FcMBL proteins coupled to magnetic beads (grey) specifically bind to carbohydrate molecules on the surface of life pathogens, like infectious E.coli bacteria (colored in blue) in this electron micrograph, or on fragments of dead pathogens circulating in the blood-stream. After isolation in a magnetic field, the total pathogenic material is quantified with a second FcMBL protein that is linked to a color-producing enzyme. Credit: Wyss Institute at Harvard University.

The Wyss Institute’s first major application based on this strategy is a broad-spectrum, pathogen-extracting therapy in the form of an extracorporeal device that mimics the blood cleansing function of the human spleen by removing pathogens and pathogen-released toxins from the blood of patients with bloodstream infections or sepsis. A Wyss-launched start-up company, Opsonix Inc., is further developing and commercializing the pathogen-extracting therapy, while also developing a rapid companion diagnostic based on identification of the presence of PAMPs in blood, which was shown in a clinical study at the Beth Israel Deaconess Hospital to be able to determine whether patients have blood-borne infections within 1 hour after a blood draw.  This FcMBL-based PAMPs assay may be used to provide a more rapid and much higher sensitivity of infection detection than conventional blood cultures.

This video explains how sepsis induced by an overload of blood pathogens can be treated with the Wyss Institute’s improved pathogen-extracting, spleen-mimicking device. Blood is flown through a cartridge filled with hollow fibers that are coated with a genetically engineered blood protein inspired by a naturally-occurring human molecule called Mannose Binding Lectin (MBL). MBL is found in our innate immune system and binds to toxic invaders, marking them for capture by immune cells in the spleen. Credit: Wyss Institute at Harvard University.

Additional applications that remain open for licensing include use of FcMBL to capture circulating tumor cells for cancer diagnostics; FcMBL linked to an imaging reagent as a clinical diagnostic to localize infections in the body; injectable therapeutics for patients with opsonin deficiencies; and injectable therapeutics coupling FcMBL with anti-infectious agents, thereby targeting a payload directly to pathogens regardless of the site of infection. In addition, Wyss researchers are also leveraging FcMBL as a quality control and safety mechanism for pharmaceutical and food products, a cleansing strategy for agricultural and research products.

Other ongoing efforts at the Institute that also remain open for future licensing focus on opsonins that are different from MBL and have more restricted pathogen-binding affinities for specific therapeutic or diagnostic applications.

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