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Trehalose is enabling life-changing protein therapeutics and exosomes

Trehalose is vital to the biopharma industry. Manufacturers of monoclonal antibodies and other protein therapeutics use this saccharide to stabilize molecules that would otherwise be degraded during dehydration and freezing. However, the industry is yet to realize trehalose’s full potential. Nagase Viita, the first company to mass-produce trehalose, is unlocking new applications for the saccharide through research into exosomes and other emerging modalities.

Trehalose is found in plants, algae, fungi, bacteria and insects, but its industrial potential was unrealized until 1994, when Nagase Viita used its discovery of two enzymes as the foundation for a cost-effective method of mass production from starch. Almost 30 years later, Nagase Viita is continuing to innovate and expand the biopharmaceutical applications of trehalose.

Nagase Viita’s high-quality, low-endotoxin injectable product, Trehalose SG, is stable under heat and acidity and has been established as a way to enhance the stability of protein structures during dehydration and freezing by replacing water molecules. Trehalose SG is used to stabilize molecules including bevacizumab, which is an anti-vascular endothelial growth factor (VEGF) antibody, making it a key enabler of treatments for major, established diseases such as cancer and newer threats including coronavirus disease 2019 (COVID-19).

Overcoming exosome challenges

Having played a leading role in the industrialization of trehalose, Nagase Viita is now discovering ways to use the saccharide to support the success of new, potentially life-changing drug modalities. The very latest phase of Nagase Viita’s research has focused on exosomes, which are naturally occurring vesicles that encapsulate biological molecules, thereby facilitating drug delivery. Therefore, exosomes also mediate intercellular communication.

While highly promising, exosomes suffer from challenges related to stabilization. Exosomes are unstable even when stored at -80°C, with the properties of the vesicles changing and the quality of their payloads degrading over time. New stabilization methods are needed to realize the promise of exosomes.

Recognizing that, Nagase Viita has studied the effect of Trehalose SG on the stability of exosomes (Fig. 1). In one set of studies, the company’s researchers linked the use of the saccharide to improved exosome stability when kept at 4°C. Trehalose SG exosomes had a higher residual rate than vesicles formulated with glucose or sucrose. By protecting the lipid bilayer, Trehalose SG improved the residual rate after freeze–thaw cycles.

The impact of Trehalose SG on the stability of exosomes

Fig. 1 | Impact of Trehalose SG on the stability of exosomes. The addition of Trehalose SG increases exosome production from mesenchymal stem cells (MSCs). Furthermore, Trehalose SG can inhibit exosome aggregation and collapse due to various stresses such as long-term storage, freeze–thawing, and freeze–drying. Trehalose SG is expected to be a powerful tool for medical and therapeutic applications by increasing exosome yield during exosome production, purification, and storage processes.

Nagase Viita has also identified roles for Trehalose SG at other points in the exosome production and supply process. Adding Trehalose SG increased production of exosomes derived from mesenchymal stem cells, particularly when used in combination with another supplement. The saccharide acts on exosome production by elevating levels of Ras-related protein 7 (Rab7).

Trehalose SG also improves purification yields. Adding the saccharide suppresses exosome aggregation during purification, as shown by the increased yield of exosomes and by viewing the vesicles under a scanning electron microscope.

Nagase Viita ran another set of studies to assess the inhibitory effect of Trehalose SG on the aggregation of exosomes by lyophilization. Bovine milk exosomes were lyophilized overnight, both with and without Trehalose SG. In the absence of Trehalose SG, lyophilization caused the collapse and aggregation of exosomes, as shown by the presence of vesicles that were smaller and larger than those kept in refrigerators. The exosomes lyophilized with Trehalose SG were the same size as the refrigerated vesicles.

Supporting sustainability goals

The exosome studies are part of a broader effort by Nagase Viita to expand the use of Trehalose SG to new modalities such as nucleotide-based therapeutics. As Nagase Viita works toward that goal, it will build on the legacy of safe use of Trehalose SG in the stabilization of monoclonal antibodies and other protein-based therapeutics and its own legacy as the pioneer of the mass production of the saccharide.

Nagase Viita’s production of Trehalose SG aligns with its core focus on sustainable development goals. By using an environmentally friendly, enzyme-based trehalose-production process and taking other actions, Nagase Viita has emerged as a leader in the space, as shown by its ‘Gold Medal’ rating in the 2022 EcoVadis sustainability assessment—only the top 5% of companies receive this rating.

The sustainability focus is in keeping with Nagase Viita’s commitment to innovation and being a reliable, high-quality supplier to the global biopharmaceutical industry. With Nagase Viita continuing to invest in Trehalose SG and other products, the company is poised to retain the position at the cutting-edge of the industry that it established with its mass-production breakthrough and credible experiences gained throughout its long history after the first industrialization of trehalose.

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