Core Technology for Gene medicine

One of 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 United States. Takara Bio holds exclusive rights for worldwide applications 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 and white blood cells.

A second core technology is a T lymphocyte expansion-culture system (culture for proliferating lymphocytes) that uses the RetroNectin^® reagent. The T lymphocyte expansion-culture system can be used both in cell and gene therapies. In the RetroNectin^® expansion-culture system, human lymphocytes are expanded in culture in the presence of the RetroNectin^® reagent in combination with interleukin-2 and anti-CD3 monoclonal antibody. Cell populations including a high proportion of naive T cells that have a significant in vivo persistence and strong antigen recognition are acquired.

Licensing the RetroNectin^® Method

Our RetroNectin^® method is used by various public medical institutions conducting clinical research in gene therapy as well as by several privately funded clinical trials, and is becoming the standard for ex vivo gene therapy. As of the end of July 31, 2010, the RetroNectin^® method was being used by public medical institutions, mainly in the United States, for over 50 clinical gene therapy studies. In addition, the RetroNectin^® method is licensed out to four overseas private corporations. We plan to actively outlicense the method worldwide.

Clinical Development of Gene Therapies

Not only are we licensing out the RetroNectin^® method, but we also plan to commercialize gene therapies and are proceeding with clinical trials on the following.

1.HSV-TK Gene Therapy

MolMed S.p.A, of Milan, Italy, which has in-licensed the RetroNectin^® method from Takara Bio, is now conducting a Phase III clinical trial of HSV-TK gene therapy for high-risk, acute hematological malignancies in Italy. Takara Bio has exclusive rights to this treatment technology in most Asian countries.

1) Clinical trials (donor lymphocyte infusion method)

Takara Bio commenced a clinical trial of HSV-TK gene therapy (donor lymphocyte infusion (DLI) method) for treatment of patients with relapsed leukemia at the National Cancer Center Hospital. This is the first ex vivo gene therapy clinical trial to be launched in Japan. In December 2009, the first subject received gene-transduced cells. This trial involves donor lymphocyte infusions for recurrent leukemia patients following hematopoietic stem cell transplants. Donor lymphocyte infusion has been shown to be highly effective for patients with many types of leukemia, but graft versus host disease (GVHD) can be a serious side effect. When donor lymphocytes are transduced with the HSV-TK gene, ganciclovir can be used so as to kill any donor lymphocytes that are a source of GVHD.

2) Clinical research (haplo add-back)

The National Cancer Center Hospital, in cooperation with Takara Bio, commenced clinical research on another type of HSV-TK gene therapy, known as haplo add-back therapy, in December 2009. HSV-TK gene therapy (haplo add-back) is a therapy for patients with high-risk hematological malignancies in which patients are infused with donor lymphocytes transduced with the HSV-TK gene after hematopoietic stem cell transplantation from partially compatible (haplo-identical) family donors. A substantially similar therapy is currently undergoing Phase III clinical trials by MolMed in Italy.

2.TCR Gene Therapy

Mie University Hospital, in collaboration with Takara Bio, commenced clinical research on T-cell receptor (TCR) gene therapy targeting esophageal cancer in August 2009. This therapy involves the transduction of TCR genes that are capable of recognizing cancer antigens into the patient’s own lymphocytes, which are then re-infused into the patient. These gene-transduced lymphocytes specifically recognize cancer cells and attack them, thereby eliminating the cancer cells. The TCR gene therapy approach has been found promising, and TCR clinical trials targeting melanoma and other cancers using our RetroNectin^® method are currently being conducted at the National Cancer Institute in the United States.

In September 2009, a joint application by Takara Bio, Mie University and Keio University regarding an R&D project on comprehensive cancer immunotherapy was selected under the Translational Research Promotion Project. This project is led by Japan’s New Energy and Industrial Technology Development Organization (NEDO). In addition to the aforementioned clinical research being conducted at the Mie University Hospital, this project support further development of TCR gene therapy technology using next-generation retrovirus vectors.

3.MazF Gene Therapy

The Company is engaged in R&D of gene therapy for HIV patients using the MazF endoribonuclease. In T-cells infected with HIV, HIV replication is triggered by HIV-derived trans-activator of transcription (Tat) proteins. Our strategy is to suppress HIV replication by using a MazF expression vector that expresses MazF conditionally in an HIV Tat protein-dependent manner.

In March 2010, Takara Bio entered into a collaborative research agreement with the University of Pennsylvania to conduct preparations for a future ribonuclease MazF gene therapy clinical trial for HIV in the United States. At present, the Company and the University of Pennsylvania are aiming to commence a clinical trial in fiscal 2012, and are jointly conducting pre-clinical translational studies such as animal tests and other regulatory steps required for completion of an Investigational New Drug (IND) application to the Food and Drug Administration (FDA).

Cell Therapy

The Company is involved in the clinical development of cancer immunotherapy using the RetroNectin^® expansion-culture system, which has been named “RetroNectin^® induced T cell therapy.” Takara Bio also provides technical support services for other cancer immunotherapies.

1. RetroNectin^® Induced T-cell Therapy

Clinical research undertaken by the Kyoto Prefectural University of Medicine, in cooperation with Takara Bio, on RetroNectin^® induced T cell therapy targeting gastrointestinal cancer and lung cancer concluded in May 2010. This research demonstrated the safety of this therapy. The Kyoto Prefectural University of Medicine now plans to continue clinical research with the aim of confirming the effectiveness of RetroNectin^® induced T cell therapy. In addition, the Mie University Hospital, in collaboration with Takara Bio, has been conducting clinical research on RetroNectin^® induced T cell therapy for intractable cancers. In China, the Tianjin Cancer Institute & Hospital, Tianjin Medical University and Sun Yat-Sen University Cancer Center are also conducting clinical research on RetroNectin^® induced T cell therapy, with the cooperation of Takara Bio.

2. Technical Support Services for Cancer Immunotherapy

Activated lymphocyte therapy, a type of cancer immunotherapy that has extremely few side effects, is gradually expanding as a fourth category of cancer therapy to complement surgical therapy, chemotherapy and radiation therapy. The Company is providing technical support, on a fee basis, for activated lymphocyte therapy to the Iseikai Hyakumanben Clinic in Kyoto. This technical support includes cell processing, such as the culture and activation of lymphocytes necessary for the therapy. In May 2010, the Company began providing technical support on a fee basis to the Iseikai Hyakumanben Clinic for RetroNectin^® induced T cell therapy. The Company plans to pursue the development and commercialization of cell-processing technology effective in cancer immunotherapy.