Core Technology for Gene medicine

One of the Takara Bio’s core technologies for gene medicine is an efficient retroviral transduction method― the RetroNectin^® method―that was developed in collaboration with Indiana University in the U.S. Takara Bio holds the exclusive rights for worldwide use of this powerful technology, which is used in ex vivo gene therapy to enable efficient transduction of genes into hematopoietic stem cells and other blood cells. Before the advent of the RetroNectin^® method, this process was considered difficult. Hematopoietic stem cells give rise to various blood cells such as red blood cells, white blood cells, and lymphocytes.
A second core technology is a lymphocyte expansion- culture system using RetroNectin^® reagent. The lymphocyte expansion culture system can be used both in gene and cell therapies. In the RetroNectin^® expansionculture system, human lymphocytes are expanded in culture in the presence of RetroNectin^® reagent in combination with interleukin-2 (IL-2) and anti-CD3 monoclonal antibodies (anti-CD3 antibody). This makes it possible to obtain cell groups containing a high number of naïve T-like cells that are viable and which excel in antigen recognition.

Licensing the RetroNectin^® Method

Our RetroNectin^® method is used by various public medical institutions conducting clinical trials in gene therapy as well as in several privately funded clinical trials, and is rapidly becoming the standard for ex vivo gene therapy. As of the end of July 2007, the RetroNectin^® method was being used by 38 public medical institutions, mainly in the U.S., and is licensed out to 4 overseas private corporations.

Clinical Development of Gene Therapies

As part of our goal to commercialize gene medicine, we are also pursing the following clinical developments of gene therapies.

1.HSV-TK Gene Therapy

MolMed S.p.A. of Italy, to which we have licensed out the RetroNectin^® method, is conducting clinical trials in Europe using HSV-TK gene therapies for leukemia. Takara Bio has obtained exclusive rights from MolMed to use these treatment technologies in most of Asia.
Together with the National Cancer Center in Japan, we have established a Good Manufacturing Practice (GMP)-compliant Cell Processing Room at the National Cancer Center in order to promote clinical trials of HSV-TK gene therapies for leukemia in Japan. Presently, we are working to receive approval of our Confirmation Application, so we can begin clinical trials of this gene therapy.

2.TCR Gene Therapy

Takara Bio is collaborating with Mie University School of Medicine in the clinical development of T-cell receptor (TCR) gene therapy targeting esophageal cancer. This treatment involves the transduction of TCR genes that are capable of identifying cancer antigens into lymphocytes, which are then reinfused into the patient. These gene-transduced lymphocytes specifically identify cancer cells and attack them, eliminating the cancer cells. The TCR gene therapy approach has been found so promising that TCR clinical trials targeting melanoma using our RetroNectin^® method are currently being conducted at the National Cancer Institute in the U.S. Significantly, TCR therapies combine both cell therapy and gene therapy. In order to begin a clinical study of TCR gene therapy, we have set up a cell processing room at Mie University, and will pursue research and development jointly with the University.

3.MazF Gene Therapy

The Company is engaged in research and development of gene therapy to treat AIDS, using the MazF ribonuclease. T cells infected with the AIDS virus (HIV) start to reproduce the HIV viruses after Tat proteins derived from HIV are initially expressed. By genetically transducing expression vectors that are constructed to promote the expression of MazF by Tat proteins, this therapy aims to eliminate HIV by preventing the reproduction of the virus. We are currently engaged in joint research with the Chinese Center for Disease Control and Prevention and the Tsukuba Primate Research Center, National Institute of Biomedical Innovation, concerning animal testing of the MazF gene therapy on monkeys.

Cell Therapy

In the field of cell therapy, the Company is involved in clinical development of a cancer immunotherapy using the RetroNectin^® expansion-culture system, as well as providing support for other cancer immunotherapies.

Cancer Immunotherapy using RetroNectin^® Expansion- Culture System

Takara Bio is progressing with clinical development of adoptive immunotherapy in partnership with the Cancer Institute and Hospital (CIH), Chinese Academy of Medical Science. In December 2005 Takara Biomedical Technology (Beijing) Co., Ltd., one of the Company’s subsidiaries, and the CIH applied to the Beijing Drug Administration for permission to begin clinical trials of a cancer immunotherapy using the RetroNectin^® expansion-culture system to treat renal cancer. This application is currently being reviewed.
In Japan, we are pushing forward jointly with Mie University School of Medicine with clinical development of cancer immunity reconstruction therapy using the RetroNectin^® expansion-culture system for refractory cancers. Cancer immunity reconstruction therapy is a cancer treatment method that uses a combination of highly cytotoxic anti-cancer drugs and autologous lymphocytes expanded using the RetroNectin^® expansionculture system. In this therapy, the patient’s antigen-presenting cells are stimulated to eat cancer cells destroyed by the anticancer drugs and then display cancer antigens on their surface. Then, naïve T-like cells, expanded using the Retronectin^® expansion-culture system, are transplanted back into the patient, whose antigen presenting cells are now displaying a large number of cancer-specific antigens. This efficiently induces cancer-specific cytotoxic T-cells from the transplanted naïve T-like cells, which are expected to have a tumor-fighting effect. We are planning to begin a clinical study of cancer immunity reconstruction therapy at Mie University School of Medicine shortly.