Exosome Therapeutics: The Next Frontier in Targeted Drug Delivery Attracting Roche, Eli Lilly, and Takeda

Reposted from: Medicine Panorama

Within the human body, fundamental life processes such as intercellular energy conversion, information recognition and transmission, and substance transport are continuously occurring. The precise execution of these processes relies on the intracellular “logistics system”—vesicles, of which exosomes are a type. Vesicles act like “couriers,” packaging molecules destined for transport (such as proteins and nucleic acids) and delivering them to the correct location at the right time. In 2013, scientists who discovered the “mechanisms regulating vesicular traffic in cells” were awarded the Nobel Prize in Physiology or Medicine. This groundbreaking discovery sparked a surge of research interest in exosomes.

Currently, exosomes have become one of the ideal candidates for researchers to develop drug delivery vehicles and targeted drug administration. Many emerging companies such as Evox, Codiak BioSciences, and Capricor are focusing on the development of exosome therapies. Large pharmaceutical companies have also begun to pay attention to this field. In recent years, Roche, Takeda, and Eli Lilly and Company have respectively reached multiple high-value collaborations with companies possessing this innovative technology platform to develop exosome-targeted therapies.

So, what exactly are exosomes? Why have they garnered such significant attention?

Delivering Drugs via Cellular Signal “Messengers”

Exosomes were first discovered in 1983. They are extracellular membrane-bound lipid vesicles secreted by cells, with a size ranging from 30 nm to 120 nm. Nearly all cells in the human body secrete exosomes, which are distributed in almost all bodily fluids, including blood, saliva, cerebrospinal fluid, and breast milk.

Initially, exosomes were considered cellular “waste,” representing a mechanism for cells to excrete waste products. With extensive research, scientists have gradually discovered that exosomes act as intercellular signaling “messengers.” They can carry various biomacromolecules, including nucleic acids (DNA, RNA), soluble proteins, and lipids. By binding surface molecules to receptors on target cells, exosomes deliver their cargo into recipient cells, thereby facilitating intercellular communication.

As natural intercellular information carriers, exosomes have become one of the ideal candidates for researchers to develop drug delivery vehicles due to their inherent advantages, such as small size (nanoscale), stability, biocompatibility, permeability, low toxicity, and low immunogenicity. Various therapeutic agents, including small-molecule drugs, gene therapies such as mRNA, miRNA, and siRNA, as well as protein-based drugs, can be loaded into exosomes.

Exosome-based therapeutics have the potential to reach cells and tissues that are inaccessible to current drug delivery technologies, thereby addressing some of the limitations associated with protein-, antibody-, and nucleic acid-based therapies. Furthermore, the brain represents a particularly challenging target for drug development due to the blood-brain barrier, which prevents molecules in the bloodstream from entering the brain. Exosomes may offer a means to bypass this barrier.

Advantages of Exosomes in Drug Delivery

As cell-derived "natural nanoparticles," exosomes possess the dual advantages of cell-mediated drug delivery and the efficient transport capabilities of nanocarriers. Compared with traditional nanocarriers, exosomes offer numerous additional benefits in drug and gene delivery, including:

Exosomes from different sources exhibit distinct surface molecules and demonstrate selective targeting of recipient cells, offering therapeutic advantages.

Exhibits enhanced stability in the bloodstream, enabling exosomes to undergo long-distance transport in vivo under both physiological and pathological conditions.

Liposomes exhibit low encapsulation efficiency for hydrophilic substances, limiting their application in nucleic acid delivery. Exosomes possess a hydrophilic core, enabling them to encapsulate soluble drugs.

Their nanoscale size enables them to traverse various biological barriers, such as the plasma membrane and the blood-brain barrier (BBB), and selectively accumulate in pathological sites like tumors or inflamed tissues via the enhanced permeability and retention (EPR) effect. For instance, studies have demonstrated that dendritic cell-derived exosomes conjugated with targeting peptides can cross the BBB—the primary obstacle to drug delivery to the nervous system—thereby safely and effectively delivering therapeutic siRNA to the brain.

Compared with artificially manufactured drug carriers, exosomes derived from specialized cells can avoid interactions with opsonin proteins, antibodies, coagulation factors, and other substances due to their unique surface molecules, thereby preventing immune responses in vivo.

Pioneering the Way: Eli Lilly, Takeda, and Roche Join Through Partnerships

Currently, many companies are developing exosome-based carriers to deliver a variety of drugs for the treatment of cancer, central nervous system disorders, and other diseases. Major pharmaceutical companies such as Eli Lilly, Roche, and Takeda are also leveraging this innovative drug delivery platform through collaborations to develop novel therapies. The following provides an overview of selected companies’ strategic initiatives in this field for readers’ reference.

1. Eli Lilly and Company

On June 9, 2020, Eli Lilly and Company entered into a $1.2 billion collaboration agreement with Evox to leverage its exosome technology platform for the development and delivery of RNA interference therapeutics and antisense oligonucleotide (ASO) drugs for the treatment of central nervous system disorders.

Evox is a company dedicated to harnessing and engineering the natural delivery capabilities of exosomes to develop novel biotherapeutics. Its DeliverEX technology platform enables the design and modification of exosomes, loading them with therapeutic agents for targeted delivery to specific organs, including the central nervous system, as well as to cells and tissues that are inaccessible to other drug delivery technologies.

It is reported that in the collaboration between Eli Lilly and Evox, Evox will be responsible for exosome engineering design to achieve brain/central nervous system (CNS) targeting, drug loading and characterization, as well as the development of certain in vitro assays, and will provide materials for initial in vivo studies. Upon completion of preclinical proof-of-concept studies, Evox will transfer any candidate drugs and related technologies to Eli Lilly.

2. Takeda

In March 2020, Takeda also reached an $882 million collaboration agreement with Evox Therapeutics to leverage its exosome drug delivery technology for the development of five protein replacement therapies and mRNA therapies targeting rare diseases, including Niemann-Pick disease type C. Evox will be responsible for advancing the projects toward Investigational New Drug (IND) applications and for the manufacturing of exosomes through Phase 1 clinical trials and prior stages.

Under the terms of this agreement, Evox is poised to receive up to $44 million in upfront payments, near-term milestones, and research funding. If all five products are successfully commercialized, Takeda will pay Evox up to $882 million. Additionally, Evox will be eligible to receive tiered royalties on post-launch sales of the products developed under this agreement.

3. Roche

In July 2018, Roche entered into a multi-year collaboration agreement with PureTech Health, valued at over $1 billion, to leverage PureTech’s milk-derived exosome platform technology—which facilitates the oral delivery of complex cargoes such as nucleic acids, peptides, and small molecules—for the delivery of drugs developed using Roche’s antisense oligonucleotide (AON) platform. Under the terms of the agreement, PureTech received upfront payments, research support, and early clinical milestone payments totaling $36 million, and is eligible for more than $1 billion in milestone payments as well as royalties on an undisclosed number and types of products.

According to reports, PureTech Health’s milk-derived exosome technology features a highly unique design that facilitates the oral administration of complex payloads, such as nucleic acids, peptides, and small molecules. These exosomes are believed to be delivered via the lymphatic system and may target immune cells through novel mechanisms. This technology holds promise for addressing the challenges associated with the oral delivery of nucleic acids in oligonucleotide-based drug development.

4、Codiak BioSciences

Codiak BioSciences, founded in 2015, leverages its proprietary multifunctional exosome engineering and manufacturing platform, engEx®, to exploit the carrier properties of exosomes. This platform enables the integration of a range of therapeutic molecules—including small molecules, peptides, and cytokines—onto the exosome surface or within the vesicle interior for targeted delivery. Furthermore, this technology platform allows for precise modification of engineered exosomes to optimize transport to specific cell types, targeting particular drug targets and desired sites of action.

exoSTING is one of the primary exosome-based therapeutic candidates developed by Codiak, containing a potent small-molecule STING (stimulator of interferon genes) agonist specifically targeting the STING pathway in antigen-presenting cells (APCs). exoSTING has been evaluated in various preclinical studies, including syngeneic tumor models that are refractory to checkpoint inhibitor therapy.

Codiak’s technology platform has also garnered interest from other companies. In January 2019, Jazz Pharmaceuticals and Codiak entered into a collaboration valued at over $1 billion. Under the agreement, the two companies will develop exosome-based therapeutic candidates targeting five specific targets. These targets focus on well-validated oncogenes in hematologic malignancies and solid tumors that are currently considered undruggable by existing methods, including NRAS and STAT3.

5 、ExoCoBio

ExoCoBio was established in January 2017 as a company dedicated to developing innovative biopharmaceuticals and other products based on stem cell-derived exosomes. Since its inception, ExoCoBio has completed multiple rounds of financing, including a $11 million Series A round and a $27 million Series B round.

The company has opted for stem cell-derived exosomes. Research has demonstrated that exosomes secreted by stem cells can stimulate cellular or tissue regeneration, with broad applications in areas such as skin and hair care. These exosomes exhibit the following characteristics: they serve as a mediator of the paracrine effects of stem cells; they can be combined with existing developed formulations or methods; they can be engineered to contain specific components; they can be designed to target specific cell types or tissues; and they offer a higher safety profile compared to cell-based therapies. According to a scientific paper previously published by ExoCoBio in the journal Stem Cell Research and Therapy, stem cell-derived exosomes can significantly improve atopic dermatitis by inhibiting multiple inflammatory targets.

6、 Capricor Therapeutics

Capricor is a clinical-stage biotechnology company focused on the discovery, development, and commercialization of first-in-class cell therapies and exosome therapies for the treatment and prevention of diseases. The company possesses technology for isolating and purifying exosomes from cardiosphere-derived cells (CDCs). Their engineered exosome, CAP-2003, offers unique potential not only as a therapeutic delivery vehicle but also as a therapeutic agent itself. Preclinical studies have demonstrated that CAP-2003 has the potential to treat inflammatory and fibrotic diseases, as well as Duchenne muscular dystrophy, by reducing cell death and mitigating fibrosis or scarring.

Exosomes as Drug Carriers Still Face Challenges

Although exosomes hold significant potential as drug delivery vehicles, numerous challenges remain. Due to variations in the composition of exosomes derived from different cell sources, their potential biological functions differ substantially; therefore, selecting the appropriate source cells is a prerequisite for achieving optimal therapeutic efficacy. Furthermore, tumor-derived exosomes contain tumor-associated antigens and immunosuppressive molecules that can downregulate immune responses and transmit certain inhibitory signals. Consequently, the use of tumor-derived exosomes as drug delivery carriers may pose certain safety risks, necessitating systematic evaluation in future studies. In addition, the scalability and universality of exosome production remain problematic.

Finally, we hope that with the advancement of research and technology, studies on exosomes as drug carriers will achieve rapid progress and new breakthroughs, thereby benefiting patients at an earlier date.

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