Therapeutics

Exosomes are nano-sized vesicles secreted by cells that contain proteins, RNAs, polysaccharides, and lipids, playing a key role in cellular communication and holding promise for diagnostic and therapeutic applications. Tumor-derived exosomes facilitate tumor progression and metastasis by transporting molecular messages and contribute to the immunosuppressive tumor microenvironment. They can penetrate blood vessels and circulate in the bloodstream, making them potential markers for cancer diagnosis. Exosomes also serve as a source of tumor antigens for cancer vaccines, which aim to generate antigen-specific immune responses. However, identifying tumor-specific antigens is complex and costly. Tumor exosome-based vaccines have shown promise in clinical trials but face challenges in effectively activating dendritic cells (DCs) and generating strong cytotoxic T lymphocyte (CTL) responses. The integration of adjuvants with tumor exosomes has not significantly improved vaccine potency due to differing trafficking and uptake profiles. There is a need for effective methods to conjugate adjuvants to exosomes to enhance their synergistic effects.

This technology is a method for development of personalized cancer vaccines using cancer cell-derived exosomes. Cancer cells collected from a patient can be labeled with unnatural sugars displaying the azide functional group. Exosomes generated from these cancer cells can be conjugated to adjuvants (or other tags or fluorescent dyes for diagnostic or research purposes) via click chemistry and reintroduced into the patient. Components of the exosome can be recognized as antigens and help the immune system in producing antigen-specific T cells and antibodies, showing a lower concentration of adjuvant is required to trigger the immune response.

Benefits

Conjugating adjuvant to exosomes improves immune response against cancer cells.

Lower concentration of potentially toxic adjuvant is required to trigger the immune response.
 

Publication
Bhatta, R., Han, J., Liu, Y. et al. Metabolic tagging of extracellular vesicles and development of enhanced extracellular vesicle based cancer vaccines. Nat Commun 14, 8047 (2023). https://doi.org/10.1038/s41467-023-43914-8
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Amyotrophic lateral sclerosis (ALS) is a  fatal neurogenerative disorders that affect 5,000 people in the U.S. each year. Huntington’s disease (HD) is another progressive and fatal neurogenerative disorder that affects nearly 30,000 people in the U.S. Both of these neurodegenerative disorders are associated with abnormal protein accumulation, such as SOD1 and HTT. CRISPR-Cas13 targets the genes of interest (i.e., SOD1 and HTT) and ultimately reduces the gene expression that are related to ALS and HD. Previous CRISPR technologies often use the Cas9 enzyme, which presents multiple problems with ease of delivery, size, and potential genomic damage to cells. Cas13 is smaller in size, making it easier to deliver. Furthermore, Cas13 targets the RNA—not the DNA, which means Cas13 downregulates gene expression without having to change the DNA sequence.

Antibodies serve as both therapeutic and research tools due to their high specificity and low immunogenicity. Therapeutically, they target specific antigens to treat diseases like cancer and diabetes. In research, they aid in protein localization, isolation, and cell separation. Their reproducibility and scalability make them valuable, but the need for diverse antibodies necessitates ongoing discovery and testing. Limiting focus to human antibodies restricts availability, while chimeric and humanized antibodies expand the range to include non-naturally occurring types, enhancing their application and functionality. 

This technology is a chimeric antibody engineered by joining immunoglobulin M (IgM) fragments from humans and teleost fish, which does not encode a Joining-Chain (JC) to assemble polymeric immunoglobulins. The resulting structure is distinct from mammalian IgM. Receptor binding sections of the chimeric antibody are from the human sequences, and therefore they react with human antigens. This undiscovered chimeric class of human tetrameric antibodies widen the variety and potential applications of antibodies for therapeutic and research purposes.  

Lyu, M., Malyutin, A.G. & Stadtmueller, B.M. The structure of the teleost Immunoglobulin M core provides insights on polymeric antibody evolution, assembly, and function. Nat Commun 14, 7583 (2023). https://doi.org/10.1038/s41467-023-43240-z

Bacteria-based therapeutics are engineered live microbial cells that produce a drug or perform a metabolic function while inhabiting a specific physiological niche on or within the host. This targeted therapeutic approach can help minimize negative side effects associated with many drugs (e.g., off-target toxicity from intravenous chemotherapy distributed throughout the entire body). Antibody therapies are also traditionally administered intravenously, but do not accumulate to high levels in the gut and thus have limited impact on gut disease. On the other hand, bacterial therapeutics allow production of antibodies directly within the gut. Current bacterial therapies utilize transient colonizers of the human body (e.g., Escherichia coli, Lactococcus lactis, Salmonella typhimurium), limiting applications in long-term disease treatment and monitoring. Bacteroides species, are long-term stable colonizers of the human gut and are thus a promising for developing long-term bacterial therapeutics and diagnostics. Bacteroides also benefit from already being highly abundant and prevalent in the human gut microbiota. However, more work is required in identifying and optimizing protein secretion machinery for Bacteroides species.

This technology is a molecular toolkit for engineering of the stable gut colonizing bacteria Bacteroides thetaiotaomicron. The system allows expression and secretion of protein cargos from multiple Bacteroides species. In contrast to transient colonizers such as E. coli, Bacteroides can be better leveraged for long-term therapeutic and diagnostic applications, providing a platform for targeted approaches to the treatment of ailments such as cancer and gut-related diseases.

Benefits

Effective secretion achieved in multiple Bacterioides speices. Preserved function for the secreted cargo.

Application

Bacterial-based therapeutics, Gut microbiome

Publication

Yeh, YH., Kelly, V.W., Rahman Pour, R. et al. A molecular toolkit for heterologous protein secretion across Bacteroides species. Nat Commun 15, 9741 (2024). https://doi.org/10.1038/s41467-024-53845-7