1. Background of Technology
1) Development of hepatitis treatment ‘Creaferon’ based on CTP technology
Out of all cancer cases, the annual occurrence rate for liver cancer worldwide is 4% with 560,000 patients. Among them, 390,000 reside in Asia. In our country, the number of liver cancer patients ranges from 12,000 ~ 15,000 annual cases. This is a figure similar with lung cancer and only 2nd behind stomach cancer. Even in terms of death rate, liver cancer is 3rd behind lung cancer and stomach cancer. Consequently, liver cancer is a critical disease which cannot be taken lightly in our country.
The cases of hepatitis in Korea are caused by Hepatitis B (HBV), comprising 70% of all hepatitis cases and Hepatitis C (HCV), comprising 13%. The causes of the other 18% are known to be due to alcohol, drugs, and other related causes.
As liver cancer progresses from hepatitis to liver cirrhosis to liver cancer, liver cancer treatments become very important. Particularly, efforts to develop treatments for viral hepatitis are active all across the world. The current leading treatments for viral hepatitis are Interferon- α, Lamivudine, and Ribavirin. For the past decade, Interferon has been used as a treatment for chronic hepatitis B and hepatitis C, yet the treatment has limitations, including pain and severe side effects.
While the recently developed Hepatitis B treatment, Lamivudine, is effective, recurrence occurs once the treatment is discontinued. Another problem with Lamivudine has been the appearance of tolerant viruses. As a result, it has been reported that the joint use of Interferon and Lamivudine is an effective method to treat viral Hepatitis B. In addition, Hepatitis C treatment, Ribavirin, which is known to be ineffective when administered independently, has shown an efficacy improvement by two-fold when taken together with Interferon. Such a combination has become the standard method of treating chronic hepatitis C.
As described above, it is a priority to minimize the side effects of Interferon while increasing its efficacy as the effects of Interferon are very important for treating chronic hepatitis B and C. The CPT developed at Creagene shows liver-specific mobility and allows most of the Interferon to move specifically into the liver when Interferon is combined with CPT. Such mobility allows a concentrated effect even in small doses while decreasing side effects and increasing efficacy.
Because NLS (nuclear localization signal) of the PTD has been modified so as not to transport substances into the nucleus, CTP can minimize gene damages caused by attached bio-polymers by keeping them in the cytoplasm not in the nucleus. CTP shows much less cytotoxicity than other cell penetration peptide such as PTD or poly-Arg. Especially, CTP shows the specific tropism to the liver and lymph node in mouse models (Fig.1).
2. Description on Technology Applied
(A) Summary of CTP
Refers to the Cytoplasmic Transduction Peptide newly developed by Creagene through our unique technologies
Analysis and remodeling of HIV-1 TAT protein PTD (peptide transduction domain), widely known as an effective way of delivering genes, antisense nucleic acid and proteins into cells, to develop a method of mobility into only cells
In the case of conjoining with macromolecular substances, such as nucleic acids or proteins, delivers macromolecular substances into cells at 2~5 times better cell wall transmission efficiency rates compared to PTD.
By transforming the nuclear localization signal of PTD to allow substances to not be delivered inside of the nucleus but remain in only the cytoplasm, minimizes genetic damage caused by the conjoined substance
Creaferon was developed via Creagene technology with existing hepatitis treatment Interferon by conjoining the CTP.
3. Differential Point, Superiority or Characteristics of Technology Applied
CTP is significantly lower in cellular toxicity compared to delivery agents, such as PTD and poly-Arg. At the same time, it effectively enters the cell membrane by forming into compounds through powerful ion interactions even with nucleic acid, known for extremely weak cellular transmission due to a large distribution of positive ions. Particularly, in vivo experiments on mice has shown extremely strong liver and lymph node localization (mobility)