만성 B형간염 치료제 개발을 위하여 간염바이러스(HBV) 항원에 대한 마우스 항체를 확보하고, 이로부터 인간화 항체를 개발하였음. YHB11110-13 항체의 생산세포주 개발, 세포주 배양공정 및 항체정제 공정을 확립하였고, 표준물질과 전임상 시료를 자체시설로 제조하였음. YHB1110-13은 항체단백질로서의 기본적인 특성을 갖고 있으며, 간염 바이러스 항원에 대한 우수한 중화능력을 보였고, 인간조직 세포와의 교차반응성 시험을 통하여 안전성이 확인되었음. YHB1110-13의 다양한 물리화학적 특성을 규명하였고, 이를 바탕으로
만성 B형간염 치료제 개발을 위하여 간염바이러스(HBV) 항원에 대한 마우스 항체를 확보하고, 이로부터 인간화 항체를 개발하였음. YHB11110-13 항체의 생산세포주 개발, 세포주 배양공정 및 항체정제 공정을 확립하였고, 표준물질과 전임상 시료를 자체시설로 제조하였음. YHB1110-13은 항체단백질로서의 기본적인 특성을 갖고 있으며, 간염 바이러스 항원에 대한 우수한 중화능력을 보였고, 인간조직 세포와의 교차반응성 시험을 통하여 안전성이 확인되었음. YHB1110-13의 다양한 물리화학적 특성을 규명하였고, 이를 바탕으로 의약품 개발 과정에 필수적인 기준 및 시험법 절차를 확립하여 허가규정에 적합한 시료의 기준을 제시하 였음. YHB1110-13이 인식하는 항원의 epitope부위를 확인하였고, 중국 등 동남아권에 분포비율이 높은 바이러스 타입에 효과적임을 확인함. 이는 XTL사 등의 경쟁 개발제품과 차별되는 특성임. 형질전환 마우스 모델에서의 효력시험에서는 YHB1110-13이 투여용량에 비례하는 바이러스 중화능력을 보여주었고, 최대 12시간까지 효력이 유지됨을 확인하였음. 본 연구개발 과제를 통하여 논문 2건, 자적재산권 10건을 확보하였고, 전임상 단계에 진입하여 치료제로서의 개발 가능성을 높인만큼 국내외 기업과 기술이전 또는 공동개발을 위한 협상을 진행중임.
Abstract▼
I. The Purpose and Necessity of Research ▶ Hepatitis B` is a serious disease caused by a virus that attacks the liver and the hepatitis B virus (HBV) can cause lifelong infection, cirrhosis of the liver, liver cancer, liver failure and death. ▶ Despite the availability of an HBV vaccine, there
I. The Purpose and Necessity of Research ▶ Hepatitis B` is a serious disease caused by a virus that attacks the liver and the hepatitis B virus (HBV) can cause lifelong infection, cirrhosis of the liver, liver cancer, liver failure and death. ▶ Despite the availability of an HBV vaccine, there are still more than 350 million chronically infected people worldwide. ▶ We tried to develop more safe and effective therapeutic drug by using the monoclonal antibody against HBV. II. Scope and Content of Research. ▶ Development of humanized antibody neutralizing Hepatitis B virus. ▶ Development of CHO cell line that highly expresses the antibody. ▶ Establishment of a large scale manufacturing process of YHB1110-13. ▶ Production of the YHB1110-13 sample by the process. ▶ Evaluation of biological and physicochemical properties of YHB1110-13. ▶ Cross reactivity study in human tissues. ▶ Efficacy study in therapeutic animal model. III. Results ▶ A murine antibody (muA9) having high affinity against S antigen of Hepatitis B virus (HBsAg) was developed. ▶ Chimeric(chA9) and humanized(huA9) monoclonal antibodies are developed from murine antibody. ▶ To increase the affinity of huAg as much as that of chA9, we investigated the physicochemical properties of framework residues. ▶ Antigen-binding affinity(Ka) of selected antibody (YHB1110-13) was 5-fold higher than YHB1110 and equivalent to chimeric antibody. ▶ Expression vector for the YHB1110-13 gene was constructed and transformed into CHO cell. ▶ A large scale manufacturing process of YHB1110-13 has been established. The perfusion culturing in bioreactor and purification process have been optimized ▶ In the continuous perfusion culture, YHB1110-13 was produced at the level of 50 mg/L for more than 50 days. YHB1110-13 was purified with high purity (>99%). ▶ Physicochemical properties of YHB1110-13 such as isoelectric point(pl) molecular weight, content of free thiol group, secondary structure, and 3D structure were analyzed. In vitro potency of YHB1110-13 evaluated by competitive ELSA method was 1,300±100 IU/mg. ▶ To establish the 'Specifications and test method' for YHB1110-13, we performed relevancy of test methods such as sterility, endotoxin, electrophoresis, isoelectric focusing, gel filtration chromatography, HCP, HCD, and potency test. ▶ YHB1110-13 does not demonstrate tissue cross reactivity in any of the 35 human tissues examined ▶ We verified in vivo efficacy using the transgenic mouse model, in which YHB1110-13 showed therapeutic effect with dose dependent manner. By treatment of 120 IU, 90% elimination of the HBV was sustained for 12 hours. ▶ We have secured intellectual property rights related to antibody genes and the use thereof in the treatment of HBV infection. IV. Plans to Apply the Results ▶ All technologies and experiences in this study will apply to development of a new therapeutic antibody. ▶ We are negotiating the deal with some companies for further development study and industrialization.
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