2-1 Nihonbashi-Odenmacho Chuo-ku, Tokyo, 1030011 Japan■About Trans Chromosomics Our company was founded in 2014 to put the research outcomes of basic chromosome researches over 40 years into practical use. The beginning of the application of the chromosomal engineering research to medicine was the development of human mono chromosome library and the chromosome transfer technology. In the 1990's, we succeeded in developing the first fully human antibody-producing mouse in the world through collaboration research with Kirin Brewery Co., Ltd. (present Kyowa Hakko Kirin Co., Ltd.). This result has opened up a new era of antibody drugs. In the next 20 years, the foundation of artificial chromosome engineering technology has been completed, and many state-of-the-art platforms are being constructed for drug discovery to combat intractable diseases. Through extensive use of these technologies, we will strive to reach out, even a day earlier, to patients who suffer from intractable diseases. ■Our Mission We contribute to people's living and health by applying innovative chromosome engineering technology developed by Tottori University (Japan) to medical treatment and drug discovering widely. ■Our Business: Research and development and commissioned research of pharmaceuticals by utilizing chromosome engineering technology - Development of humanized model mice & rats - Fully human antibody producing mice (TC-mAb mouse) - Humanized ADME model mice & rats (Tc-huADME Model) - Humanized genetic rare disease model mice & rats - Down Syndrome mouse/rat model (A model animal with human chromosome 21 introduced) - Contract studies - Discovery of fully human antibodies - Pharmacokinetic study using humanized ADME model mice & rats 　- Animal production of above trans-chromosomic mice & rats ____________________________________________________________________________ ■Our Key Technology: Artificial Chromosome Vector The artificial chromosome is a vector having a minimal function and structure as a chromosome by removing the gene region from a natural human or mouse chromosome. It is possible to introduce Mb size giant genes and multiple genes. The artificial chromosome is maintained stably in the cell and is transmitted from the parent to children in mouse and rat. The artificial chromosome vector is not inserted into the chromosome of the host but exists independently within the cell nucleus. Since it can carry various genes, it functions as a high-performance remote controller that issues commands to cells. Examples of practical applications include fully human antibody-producing animals, rare disease animal models, and cells / animals for functional evaluation. ■Fully Human Antibodies Producing Mouse: TC-mAb mouse We established a new generation of human Ab producing Tc mice (TC-mAb mice), which stably maintain a mouse-derived engineered chromosome containing the entire human Ig heavy and kappa chain loci in a mouse Ig knockout background. Comprehensive, high-throughput DNA sequencing revealed that the human Ig repertoire, including variable gene use, was well recapitulated in TC-mAb mice. Despite slightly altered B cell development and a delayed immune response, immunized TC-mAb mice exhibited more subsets of antigen-specific plasmablast and plasma cells compared with wild-type mice, leading to high efficiency hybridoma production. Thus, TC-mAb mice offer a valuable platform to obtain fully human therapeutic Abs and to elucidate the regulation of human Ig repertoire formation. [Contract studies] - Animal production of above trans-chromosomic mice & rats - Custom fully human antibody development using TC-mAb mouse. - We can refer you to our company’s partner. ■Humanized ADME Model Mouse & Rats: Tc-huADME Model In order to solve the problem of animal species differences found in research and development, human pharmacokinetic-related gene was introduced into experimental animals with artificial chromosome vector. Since it is introduced with gene regulatory region induced, it reproduces timing specific and tissue specific expressions in mouse / rat. These animals are useful for predicting human-specific pharmacokinetics, enzyme induction / inhibition tests, and analysis of drug-drug interactions. In addition to supplying animals as collaborative research, we also conduct contract tests from drug administration to sampling. - A model animal in which a pharmacokinetic-related gene cluster is humanized. - Physiological gene expression confirmed in all tissues. - Breeding by mating is possible. [TC-huADME model lines] - hCYP3A-Tc, mCyp3a KO(CYP3A5*3) mouse - hCYP3A-Tc, mCyp3a KO(CYP3A5*1) mouse - hCYP3A-Tc, rCyp3a KO rat - hCYP3A-Tc, mCyp3a KO, hPXR KI mouse - hUGT2-Tc, mUgt2 KO mouse / rat - hMDR1-Tc, mMdr1a/1b KO mouse [Contract pharmacokinetic (PK/TK) studies] In pharmacokinetic (PK/TK) study at our company's partner, temporal blood collection will be conducted after test substance is administered to the animal.Generally, plasma or serum will be separated and delivered in a frozen state. We can also collect urine and feces and dissect for tissue sampling. - Non-GLP study : Conducted by our company. - GLP study : We request our partner company (SHIN NIPPON BIOMEDICAL LABORATORIES, LTD. (SNBL)). ■HepG2 Cell for stable expression of 4CYPs+POR HepG2 cell: TC-HepG2 HepG2 cells, a cell line derived from human liver cancer, have been used as an alternative model of the liver for many years. However, since expression of drug metabolism-related genes (mainly CYP) is remarkably low, and it is considered difficult to use them as a substitute for human primary hepatocytes. We have overcome this problem with artificial chromosome vector connected to four CYPs (CYP2C9, CYP2C19, CYP2D6, CYP3A4) and POR and provide cells showing high CYP activity. [Applications of TC-HepG2 cell] - Inhibition test / drug interaction test - Research of hepatotoxicity - High content screening ■Down Syndrome mouse/rat model: Evaluation of anxiety-like behavior　 A model animal with human chromosome 21 introduced. The animal is useful for; - Phenotypic analysis of higher brain dysfunction etc. - Evaluation of drugs for ameliorating symptoms. - Drug discovery by identifying causative genes. - Drug repositioning search Please refer to the attached PDF for details.

86 Nishi-cho Yonago, Tottori, 6838503 Japan■About Trans Chromosomics Our company was founded in 2014 to put the research outcomes of basic chromosome researches over 40 years into practical use. The beginning of the application of the chromosomal engineering research to medicine was the development of human mono chromosome library and the chromosome transfer technology. In the 1990's, we succeeded in developing the first fully human antibody-producing mouse in the world through collaboration research with Kirin Brewery Co., Ltd. (present Kyowa Hakko Kirin Co., Ltd.). This result has opened up a new era of antibody drugs. In the next 20 years, the foundation of artificial chromosome engineering technology has been completed, and many state-of-the-art platforms are being constructed for drug discovery to combat intractable diseases. Through extensive use of these technologies, we will strive to reach out, even a day earlier, to patients who suffer from intractable diseases. ■Our Mission We contribute to people's living and health by applying innovative chromosome engineering technology developed by Tottori University (Japan) to medical treatment and drug discovering widely. ■Our Business: Research and development and commissioned research of pharmaceuticals by utilizing chromosome engineering technology - Development of humanized model mice & rats - Fully human antibody producing mice (TC-mAb mouse) - Humanized ADME model mice & rats (Tc-huADME Model) - Humanized genetic rare disease model mice & rats - Down Syndrome mouse/rat model (A model animal with human chromosome 21 introduced) - Contract studies - Discovery of fully human antibodies - Pharmacokinetic study using humanized ADME model mice & rats 　- Animal production of above trans-chromosomic mice & rats ____________________________________________________________________________ ■Our Key Technology: Artificial Chromosome Vector The artificial chromosome is a vector having a minimal function and structure as a chromosome by removing the gene region from a natural human or mouse chromosome. It is possible to introduce Mb size giant genes and multiple genes. The artificial chromosome is maintained stably in the cell and is transmitted from the parent to children in mouse and rat. The artificial chromosome vector is not inserted into the chromosome of the host but exists independently within the cell nucleus. Since it can carry various genes, it functions as a high-performance remote controller that issues commands to cells. Examples of practical applications include fully human antibody-producing animals, rare disease animal models, and cells / animals for functional evaluation. ■Fully Human Antibodies Producing Mouse: TC-mAb mouse We established a new generation of human Ab producing Tc mice (TC-mAb mice), which stably maintain a mouse-derived engineered chromosome containing the entire human Ig heavy and kappa chain loci in a mouse Ig knockout background. Comprehensive, high-throughput DNA sequencing revealed that the human Ig repertoire, including variable gene use, was well recapitulated in TC-mAb mice. Despite slightly altered B cell development and a delayed immune response, immunized TC-mAb mice exhibited more subsets of antigen-specific plasmablast and plasma cells compared with wild-type mice, leading to high efficiency hybridoma production. Thus, TC-mAb mice offer a valuable platform to obtain fully human therapeutic Abs and to elucidate the regulation of human Ig repertoire formation. [Contract studies] - Animal production of above trans-chromosomic mice & rats - Custom fully human antibody development using TC-mAb mouse. - We can refer you to our company’s partner. ■Humanized ADME Model Mouse & Rats: Tc-huADME Model In order to solve the problem of animal species differences found in research and development, human pharmacokinetic-related gene was introduced into experimental animals with artificial chromosome vector. Since it is introduced with gene regulatory region induced, it reproduces timing specific and tissue specific expressions in mouse / rat. These animals are useful for predicting human-specific pharmacokinetics, enzyme induction / inhibition tests, and analysis of drug-drug interactions. In addition to supplying animals as collaborative research, we also conduct contract tests from drug administration to sampling. - A model animal in which a pharmacokinetic-related gene cluster is humanized. - Physiological gene expression confirmed in all tissues. - Breeding by mating is possible. [TC-huADME model lines] - hCYP3A-Tc, mCyp3a KO(CYP3A5*3) mouse - hCYP3A-Tc, mCyp3a KO(CYP3A5*1) mouse - hCYP3A-Tc, rCyp3a KO rat - hCYP3A-Tc, mCyp3a KO, hPXR KI mouse - hUGT2-Tc, mUgt2 KO mouse / rat - hMDR1-Tc, mMdr1a/1b KO mouse [Contract pharmacokinetic (PK/TK) studies] In pharmacokinetic (PK/TK) study at our company's partner, temporal blood collection will be conducted after test substance is administered to the animal.Generally, plasma or serum will be separated and delivered in a frozen state. We can also collect urine and feces and dissect for tissue sampling. - Non-GLP study : Conducted by our company. - GLP study : We request our partner company (SHIN NIPPON BIOMEDICAL LABORATORIES, LTD. (SNBL)). ■HepG2 Cell for stable expression of 4CYPs+POR HepG2 cell: TC-HepG2 HepG2 cells, a cell line derived from human liver cancer, have been used as an alternative model of the liver for many years. However, since expression of drug metabolism-related genes (mainly CYP) is remarkably low, and it is considered difficult to use them as a substitute for human primary hepatocytes. We have overcome this problem with artificial chromosome vector connected to four CYPs (CYP2C9, CYP2C19, CYP2D6, CYP3A4) and POR and provide cells showing high CYP activity. [Applications of TC-HepG2 cell] - Inhibition test / drug interaction test - Research of hepatotoxicity - High content screening ■Down Syndrome mouse/rat model: Evaluation of anxiety-like behavior　 A model animal with human chromosome 21 introduced. The animal is useful for; - Phenotypic analysis of higher brain dysfunction etc. - Evaluation of drugs for ameliorating symptoms. - Drug discovery by identifying causative genes. - Drug repositioning search Please refer to the attached PDF for details.