바이오스펙테이터

by Yoonseok Suh

Large-scale production of various CDVs is possible due to their more homogenous characteristics than exosomes. Partnering with Lonza will be a turning point. Along with two recent contracts and partne

Shingyu Bae, CEO of MDimune, said “Our vision is to develop a technology to achieve an unprecedented accuracy for drug delivery in the body". He explained that “For this, we have been developing BioDrone® Technology for drug delivery using cell-derived vesicles(CDVs) similar to exosomes".

MDimune, founded in 2015, has been developing the BioDrone Platform Technology based on cell-derived vesicles(CDVs) and drug development pipelines using it. CEO Bae emphasized, "CDVs are similar to exosomes, but they have unique characteristics, they exhibit substantial advantages for large-scale production because of their homogenous properties. They are versatile of using various cell types".

Exosomes are nanosized vesicles with a size of 80 to 150 nm. They are naturally released from various types of cells. A minuscule quantity of exosomes has been its drawback for commercialization. However, MDimune uses an extrusion method which has the advantage of not only being able to obtain a large amount of CDVs from a small number of cells, but also being able to produce them using a variety of cells.

In this respect, MDimune is different from Evox Therapeutics and Codiak Bioscience known to develop new drugs utilizing exosomes. Evox and Codiak have been developing drugs by loading small molecule drugs and nucleic acid-based therapeutics such as DNA and RNA in exosomes and delivering them to target tissues. Codiak is conducting a phase 1 clinical trials of a lead pipeline and Evox is preparing for clinical trials.

Evox has formed an R&D partnership with Takeda with tens of millions to hundreds of millions of dollars. Eli Lilly, Boehringer Ingelheim, and Codiak have signed collaboration agreements with Jazz Pharmaceuticals and Sarepta Therapeutics. By signing contracts, they are showing expectations for exosome-based treatments.

MDimune has the technology to manufacture CDVs using stem cells based on various tissues. Stem cell-derived CDVs have the cell regeneration potential that stem cells have. MDimune is using these to conduct research and apply them to various diseases. In addition, MDimune is developing anti-cancer drugs that can increase the therapeutic effect by loading small molecule drugs, chemotherapeutics, and nucleic acids in CDVs.

BioSpectator is looking into MDimune's BioDrone drug delivery technology and pipeline under development.

◆ Point 1. “BioDrone” Drug Delivery Platform Technology using Cell-Derived Vesicles(CDVs)

The core technology of MDimune is “BioDrone,” a drug delivery platform that uses cell-derived vesicles(CDVs) from various cell sources through an extrusion method. CEO Bae said, “The CDV extruded from cells of a specific tissue has a tropism that moves to the same specific area.” "This will enable targeted drug delivery to specific lesions.

MDimune points out that △ large-scale is possible and △ versatility of using various cell types as the advantage of the extrusion method. CEO Bae explained that the extrusion method can yield 10 to 100 times more amounts than the stem cell culture method used to obtain exosomes since one cell is split into multiple vesicles as cells are extruded through small pores."

These split vesicles contain various proteins, including diverse biomarkers, for loading drugs. Also, since it is a method of extruding cells, cells of all tissues can be applied under the same conditions. With a convention method, there is difficulty in that culture conditions vary depending on the type of cell.

In particular, vesicles extruded from cells of a specific tissue have the property of moving to the same area. If a specific ligand or biomarker is engineered into this, the targetability can be enhanced to deliver the desired drug to the desired place. For this reason, MDimune named it 'BioDrone'.

MDimune has transferred the “original patent of cell-derived vesicles” developed by POSTECH University in Pohang in 2015. Using an extrusion method, POSTECH University's research team has loaded a chemotherapeutics doxorubicin in U937, a hemocyte cancer cell line, and Raw264.7, a macrophage, and extruded it with 10 ㎛, 5 ㎛, and 1 ㎛ filters to obtain a drug-loaded exosome-mimetic nanoparticle(NV) (doi: 10.1021/nn402232g).

Subsequently, vesicles extracted from Raw264.7 cells and vesicles loaded with doxorubicin were administered to a mouse model of tumor. As a result, when doxorubicin-loaded vesicles were administered, the tumor size decreased to a maximum of one quarter. Besides, it was confirmed that cell division and apoptosis were induced in cancer cells of the mouse model (doi: 10.1021/nn402232g). Doxorubicin is a representative chemotherapeutic agent that can inhibit DNA replication and RNA transcription.

In particular, when doxorubicin was loaded in CDV, it showed an effective and less toxic anticancer effect even at a small dose. Specifically, doxorubicin was administered to a tumor model at a dose of 15 µg or 60 µg alone, or it was loaded into Raw264.7-derived CDV (Raw264.7-CDV) at 3 µg. As a result, the tumor size decreased to a similar level in the group administered with 60 µg doxorubicin and the group administered with Raw264.7-CDV + 3 µg doxorubicin(doi: 10.1021/nn402232g). Also, when Raw264.7-CDV + 3 ㎍ doxorubicin was administered, there was no toxicity such as leukocyte reduction or weight loss. However, such toxicity appeared in the 60 ㎍ doxorubicin group.

CEO Bae said, "It means that even at low doses, it can not only show the same efficacy as a high-dose, but also can reduce toxicity problems by increasing its targeting ability against cancer cells." Based on these results, MDimune is currently researching to evaluate the efficacy by loading various anticancer drugs in NK cell-based CDV.

◆ Point 2. Partnering with Lonza “It will be a turning point”

CEO Bae said, "It was a great opportunity that we were selected as Lonza's partner in a startup incubation program last year." MDimune was selected as a partner of a co-pilot project in the Startup Creasphere Program with Lonza, a global CMO company. The Startup Creasphere Program is a global startup incubation program hosted by Plug and Play in October last year. In Batch 5, where MDimune participated, 11 companies were directly selected by Sanofi, Lonza, Roche, and so on to conduct joint projects over a 12-week period with their sponsors.

Lonza explained that BioDrone technology was the reason for selecting MDimune because it was effective to have a large-scale production for CDVs with 10-30 times higher production rate as compared to normal exosomes through extrusion from various cells.

CEO Bae said, “Lonza is highly interested in exosome production technology. We were selected as a partner since they paid attention to our technology. After the 12-week project, we are currently discussing further cooperation.” He continued, "Since partnering with Lonza, we are receiving more partnership inquiries from Global Biotech than before."

Could this be the reason why? MDimune signed two partnerships this month alone. First, MDimune signed a partnership for drug delivery targeting technology with ExonanoRNA in the United States and a research and development partnership for tumor-targeted drug delivery with Evercyte GmbH in Austria.

◆ CDV-based COPD therapeutic candidate, "Lung cell regenerative effect in a mouse model”

CEO Bae said, "Except for anticancer drugs, all our pipelines are being developed using the regenerative effect of stem cells themselves." He introduced the pipeline under development that "Lead Pipeline is a CDV-based drug targeting chronic obstructive pulmonary disease(COPD), a rare and intractable disease."

MDimune administered adipose-derived stem cells(ASCs), ASCs-CDV, and 1/3 concentrations of ASCs-CDV to an elastase-induced mouse model of emphysema. As a result, when ASCs, ASCs-CDV, and 1/3 ASCs-CDV were administered, all showed significant lung cell regenerative effects compared to elastase. Especially, when 1/3 ASCs-CDV was administered, it showed the most lung cell-regenerating effect. In addition, as a result of investigating whether ASCs and ASCs-CDV could stimulate growth factor signaling, it was confirmed that the amount of FGF2 protein in 1/3 ASCs-CDV was at a normal level, but significantly higher than the elastase-administered group(doi:10.1038/emm.2016.127).

According to a poster published by MDimune at the International Society of Extracellular Vesicle(ISEV) last year, it was investigated whether ASC-CDV, labeled with CFSE (carboxyfluorescein succinimidyl ester) attached with green fluorescence, was administered intranasally to mice to penetrate into the brain. As a result, it was confirmed that ASC-CDV was delivered across the blood-brain barrier(BBB) to six locations including the prefrontal cortex, hippocampus, substantia nigra, and olfactory bulb.