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Extracellular vesicles (EVs) are an emerging new class of nano-sized biological delivery systems involved in intercellular communication, immune responses, and tissue regeneration, that are increasingly being investigated for therapeutic potential. Since EVs are released by cells endogenously and naturally transfer genetic material and proteins, they offer a safer alternative for delivery of biologicals (e.g. RNAs, cytokines, monoclonal antibodies). In addition, EVs carry complex biological messages of the parental cell, and thus are being tested as safer alternatives to cell therapy (e.g. in lieu of mesenchymal stem cell therapy for heart tissue regeneration). Furthermore, in human clinical trials EVs have been used as cancer vaccines and for immunomodulation.
Significant opportunity for EV discovery and understanding remain. For the successful translational development of EVs there is a need for efficient, scalable processes for production, therapeutic enhancement, and purification. In addition to being scalable, these methods must retain the biological properties of EVs to avoid loss of their therapeutic activity. There are also opportunities to improve the use of EVs to treat disease. Administered EVs are rapidly cleared by the reticuloendothelial system (RES), especially by liver macrophages. The clearance of EVs by the RES decreases their delivery to desired target sites, including tumors. Consequently, there is a need for improved EVs, methods of producing EVs, and methods of improving delivery of EVs to a target site.
Researchers at the National Cancer Institute (NCI) have developed a method of scalable EV production and effective delivery, thereby representing a significant market opportunity. The NCI’s technology provides a fully scalable procedure for production and purification of extracellular vesicles enriched for hetIL-15, a molecule in clinical trials for treatment of metastatic cancer. The technology includes a novel, bioactive, fully human form of the cytokine (hetIL-15/Lactadherin) capable of more efficiently coating the surface of EVs. The invention also includes methods for producing large amounts of these EVs in a bioreactor, and ways of efficiently obtaining highly purified EV preparations using cGMP-compatible tools (namely, tangential flow filtration and size-exclusion chromatography). Moreover, the invention includes methods of blocking the rapid clearance of administered EVs by liver macrophages, which enables enhanced accumulation of EVs carrying the therapeutic molecule, hetIL-15 to tumors. Implementation of the NCI’s methods will allow interested commercial partners to proceed with large-scale production of EVs for therapeutic use. Additionally, commercial partners may expand on the scope of the invention, for example by developing more effective molecules for blocking liver uptake and using the hetIL-15/Lactadherin protein to coat EVs from primary human cells.
Watson DC, et al.
Researchers at the NCI seek licensing and/or co-development research collaborations for isolated or purified Extracellular Vesicles (EVs), a method of preparing isolated or purified EVs containing a therapeutic protein, for example, hetIL-15/Lactadherin fusion, methods of reducing liver uptake of EVs, methods of improving delivery of EVs to a target site, and methods of treating or preventing cancer by administering the isolated or purified EVs.
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