Development of the protease-activated pro-antibody drug to enhance the specificity of disease target therapy

• Main Authors: Yun-Chi Lu, 呂韻綺
• Other Authors: Tian-Lu Cheng
• Format: Others
• Language: zh-TW
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/hg23wr

碩士 === 高雄醫學大學 === 生物醫學暨環境生物學研究所 === 100 === Therapeutic antibody drug is widely used to cure many diseases, and the global market have been climbed to 35.5 billion US dollars. However, the antibody treatment presented can’t distinguish the target antigen in disease region from normal region which causes systemic targeting and induces the side effects. Consequently the enhancement of antibody-specificity to disease region is critical important. Our strategy is use of matrix metalloproteinase 2 (MMP2) substrate peptide as the linker to combine the inhibit domain (Di-hinge) and antibody binding site to generate the MMP2-activated pro-antibody. The Di-hinge domain will cover the antibody-binding site inhibiting binding capacity of antibody. The matrix metalloproteinase 2 (MMP2) substrate peptide can only be hydrolyzed by MMP2 which over-expressed in the disease region, then the antibody can specifically target to the disease region to improve the selectivity of disease target therapy. In previous results ,we have already confirmed that the Di-hinge domain could reduce the binding capacity of anti-TNF-?? Ab. Upon the MMP2 treatment, the binding capacity of Di-hinge MMP2 anti-TNF-?? Ab. will be improved from 2% to 100%, suggesting that the Di-hinge inhibit domain could reduce the binding capacity, and it could be re-active via MMP2 treatment. In addition, we have also indicated the Di-hinge inhibit domain can reduce the binding capacity of anti-HER2 or anti-EGFR antibody, suggesting that the scheme of MMP2-activated pro-antibody is practicable for any antibody. According to these results, we consider the MMP2-activated pro-antibody can enhance the specificity of antibody and achieve selective target therapy in clinic.