| 内容提要: |
Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease with a broad range of clinical manifestations. SLE can present with many different symptoms, such as photosensitive skin rashes, arthritis/arthralgia nephritis, cardiac and pulmonary disease, CNS disorders and so on. Although SLE is a chronic illness that most often results in debilitated health, it can be life threatening if major organs are affected. It is becoming increasingly clear that accelerated atherosclerosis associated with SLE may contribute to premature mortality. So it is very necessary to discover drugs to treat the autoimmune diseases like SLE.
In the pathogenesis studies of autoimmune diseases, a tumor necrosis factor (TNF) family member, named B lymphocyte stimulator (BLyS), was initially identified as a factor responsible for B cell survival and maturation and subsequently found to be associated with autoimmune disease. Transgenic mice overexpression of BLyS produces autoantibodies and develops diseases akin to human autoimmune manifestations. So blocking BLyS binding to its receptors become a vital therapeutic target. There are currently three identified BLyS receptors: B cell maturation antigen (BCMA), transmembrane activator and calcium-modulating and cyclophilin ligand interactor (TACI), and BLyS receptor 3 (BR3) . Through binding to specific receptors, BLyS transmits signals and serves as an essential survival factor to regulate B cell proliferation, maturation, and immune response.
Since late 1999 and early 2000, an exploration quest of a potent BLyS antagonist has been emerged. Belimumab, a full human monoclonal antibody that specifically neutralizes BLyS has been approved by US FDA to treat SLE. Atacicept (TACI-Ig) is a soluble, recombinant fusion protein of the human IgG1 Fc and the extracellular domain of the TACI receptor that binds BLyS and APRIL and inhibits their action on B cells. A new phase II/III trial of atacicept in generalized SLE is currently open and recruiting patients in 2009. New biologic therapies targeted against BLyS are presently in development. These include BR3-Fc, AMG-623, and anti-BR3 Ab. Of these, only BR3-Fc and AMG-623 have begun clinical trials, and while both appear to be well tolerated by patients, their efficacy in treating SLE and improving disease activity remains unknown. Peptides showed more superiority in stronger penetrating power and inexpensive production using transformed bacterial cells. Now we construct Peptides (TA) based on the structural characteristics and interacting mode of TACI–BLyS complex, and fused with human IgG1 Fc to form TA-Fc peptibody. The activities of TA as well as TA-Fc will be analyzed in vitro and in vivo. |