Development of a Protease-Activated Antibody That Reduces the Side-Effects of Rheumatoid Arthritis (RA) Therapy

摘要

Therapeutic antibodies are widely used to treat many diseases. However, antibody treatments cannot distinguish the target antigens expressed in disease regions from normal tissues and leading to severe side effects. For example, long-term systemic injection of anti-TNFa Ab (Remicade?) for Rheumatoid arthritis (RA) treatment leads to serious side effects such as severe infections (pneumonia or septic arthritis) or elevate the risk of malignancy (up to 30%). It is very important to increase the selectivity of anti-TNFa Ab to disease site of RA and to reduce systemic side effects. To this aim, we have successfully developed a novel Ab locker which could efficiently block the antigen binding site of Ab and inhibit its binding activity. We used protease substrate peptide as a linker to connect the Ab locker and antigen binding site to generate the protease-activated pro-anti-TNFa Ab (pro-Remicade). The Ab locker can be cleaved by MMP highly-expressed region of RA, and then the Ab can specifically target the antigen at the disease region and improve the disease region selectivity of target therapy. In previous results, we have successfully demonstrated: (1) The antigen binding activity of anti-TNFa Ab (Remicade) can be inhibited by Ab locker, and (2) The inhibited antigen binding activity of pro-anti-TNFa Ab (pro-Remicade) can be revived by MMP. (3) The downstream signaling of TNFa was inhibited by pro-Remicade Ab after cleaved with MMP. Further, (4) In vivo therapy demonstrated that the pro-Remicade Ab can significantly relieve the inflammation phenotype in human TNFa transgenic mice. (5)Furthermore, Pro-Remicade reduced the side effect to improve the resistance to bacterial infection of mice. Successful development of the pro-Remicade can increase the selectivity of Ab drugs to disease region, increase the therapeutic efficacy, reduce the side effects (maintain immunity of patients) during treatment of RA and improve the quality of life of patients. In addition, this novel strategy will lead to revolutionary effects in the development of antibody drugs and generate "new generation of Ab drugs" and achieve selective target therapy.