Researchers at the Karolinska Institute have succeeded in delivering targeted cancer treatment via extracellular vesicles (EVs), the small membrane bubbles that our cells use to communicate. Using molecular engineering tools, the team developed EVs that can bind the fragment crystallizable (Fc) portion of antibodies, so that the variable regions are displayed for antigen recognition. These Fc-binding EVs (Fc-EVs) can be decorated with different types of antibody, to potentially target tissues of interest. In their newly reported study in cancer-bearing mice, the team demonstrated reduced tumor growth and improved survival among animals treated using engineered Fc-EVs studded with tumor-targeting PD-L1 antibodies and loaded with a chemotherapy cargo.

“By attaching different antibodies to extracellular vesicles, we can target them to virtually any tissue and we can load them with other types of drugs as well,” said Oscar Wiklander, PhD, at the department of laboratory medicine, Karolinska Institute. “Therefore, the treatment has the potential to be used against other diseases and cancer types.” Wiklander is co-first author of the team’s published paper in Nature Biomedical Engineering, which is titled “Antibody-displaying extracellular vesicles for targeted cancer therapy.”

When our cells communicate, they send out small membrane bubbles known as extracellular vesicles, which contain various signaling molecules. “EVs contain lipids, proteins, and nucleic acid species from the source cell, and have the unique ability to convey these macromolecules via an advanced system of intercellular communication,” the authors explained. Interest in these nanovesicles, sometimes referred to as the body’s “message in a bottle,” has increased in recent years as they represent “promising nanocarriers for drug delivery,” the team continued. “Compared to other vehicles, such as liposomes and polymer-based synthetic nanoparticles, EVs are associated with high biocompatibility, minimal toxicity and enhanced drug potency, with improved pharmacokinetic profiles including improved tumor penetrance, and retention in tumor cells,” the team indicated. “Importantly, EVs benefit from the ability to cross biological barriers to reach distant organs and can be engineered to display targeting moieties and loaded with a wide variety of therapeutic cargo molecules.”

In recent years, EVs have gained increasing attention and there are currently numerous clinical trials being undertaken to evaluate the therapeutic potential of EVs, the investigators further noted. For their reported study the team set out to investigate whether Fc-EVs could be used as a delivery vehicle for targeted delivery of the chemotherapy drug doxorubicin (Dox) to tumor-bearing mice. They created a targeted cancer treatment by loading EVs with the chemotherapeutic drug and attaching tumor-targeting antibodies (Abs) to their surfaces, to create an Fc-Ev+Dox+PD-L1-Ab construct. In addition to targeting the tumor cells, the antibodies also act as a form of immunotherapy, resulting in an enhanced therapeutic effect.

The investigators focused on PD-L1, which is a key target for immune checkpoint inhibition (ICI) immunotherapy. “The hypothesis was that the PD-L1 targeting approach would result in a dual therapeutic role as it both directs the drug loaded Fc-EVs to the tumor and the PD-L1 antibody itself functions as a therapeutic intervention by blocking the immunosuppressive PD1/PD-L1 axis,” they explained.

The studies in mice confirmed that, when given as an injection to animals with breast cancer or melanoma, the treatment reduced tumor growth and improve survival, both at 20 day, and 35 day endpoints. “In fact, this combinational therapy displayed 100% survival at the measured endpoint of 20 days, compared to 35% survival in mock treated mice,” they wrote. When tested with a 35 day endpoint, “… Fc-EV+Dox+PD-L1-Ab treatment again showed a significantly improved disease course with decreased tumor size development over time, and a significantly improved survival.” By the 35 day timepoint median survival of mice treated using the Fc-EV+Dox+PD-L1-Ab nanovesicles had not yet been reached.

The hope is that the new treatment will be more specific and effective in eliminating tumor cells without affecting healthy tissue, compared to current treatment strategies. The researchers plan to investigate whether different combinations of antibodies and drugs can further improve treatment.

“Among other things, we want to investigate the possibility of delivering mRNA as an anticancer drug,” says the study co-author Samir EL Andaloussi, PhD, professor at the department of laboratory medicine, Karolinska Institute. “Ultimately, we hope this can lead to a new treatment platform that can improve treatment efficacy and reduce side effects in difficult-to-treat diseases, especially cancer.”

Writing in their paper, the team concluded, “… the Fc-EV technology offers a combined EV-antibody therapy in which targeting and/or therapeutic antibodies facilitate targeted EV delivery with therapeutic cargo that can generate a synergistic effect.”  In theory, they suggested, the technology could be applied to “a myriad of indications” and used to generate multiple combinations, including classical antibodies, but also, for example, Fc-fused proteins, antibody-drug conjugates or bispecific antibodies. “Subsequent studies on the Fc-EV concept will hopefully explore the therapeutic potential further and possibly translate it to clinical use.”

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