Pateclizumab Biosimilar uses the same protein sequences as the therapeutic antibody pateclizumab. Pateclizumab is an immunoglobulin G1 kappa (IgG1kappa) monoclonal antibody targeting lymphotoxin alpha (LT-alpha) for the treatment of rheumatoid arthritis. A phase I study has assessed the safety, pharmacokinetics, and biologic activity of pateclizumab, and found that pateclizumab was generally well-tolerated in RA patients. Pateclizumab also has been investigated in clinical trial to study its efficacy and safety in combination with a disease-modifying anti-rheumatic drug (DMARD) compared with adalimumab in combination with a DMARD in patients with active rheumatoid arthritis. LT-alpha is a member of tumor necrosis factor superfamily family (TNFSF) and products by predominately by activated cells of the innate and adaptive immune response. Lymphotoxin alpha formerly named tumor necrosis factor-beta (TNF-beta) as it is a homologous protein to TNFalpha. When LTbeta is discovered, TNF-beta was renamed LT-alpha. LT-alpha plays different roles in immune regulation as its different secreted forms. LTalpha binds to TNF receptor 1 (TNFR1) and TNFR2 to promote inflammation as a form of soluble homotrimeric molecule (LTalpha3), whereas cell-bound LTalpha1beta2 (LT-alpha complex with LTbeta as LTalpha1beta2 heterotrimers on the surface of activated B, Th1 and Th17 cells) bind LTbeta receptors (LTbetaR) to mediate signaling pathway. Rheumatoid arthritis (RA) is an autoimmune disorder associated with progressive joint damage, pain, fatigue, and disability. TNF alpha is reported to be the main factor promoting the development of RA, so targeting TNFalpha is regarded as the routine method of RA treatment. However, a large number of RA patients did not respond to TNFalpha therapy, which prompted us to seek new treatments. In addition to TNFalpha, other cytokines have also been reported to be involved in the pathogenesis of RA, and LT- alpha is one of them. It was found that two forms of LTalpha homotrimer (LTalpha3 and LTalpha1beta2) increased in synovial fluid of RA patients, while the LTalpha, LTbeta and LTbetaR transcripts increased in synovium respectively. Study has demonstrated that the depletion of CD4 T helper (Th) subsets Th1 and Th17 (with high levels of surface LTalpha1beta2) by mouse LTalpha specific monoclonal antibody showed therapeutic efficacy in the preclinical mouse model of RA, which suggests the treatment possibility targeting LTalpha. Thus, humanized pateclizumab was designed to target LTalpha, binding to both the soluble LTalpha3 homotrimeric form and the surface-expressed LTalpha1beta2 heterotrimer, for the treatement of RA. By blocking the binding of LTalpha3 and LTalpha1beta2 to its cognate receptors LTbetaR and TNFR, pateclizumab specificly deplete of activated cells and inhibit the immune cell trafficking and/or recruitment to inflammatory sites. Depletion is limited to cells that express LTalpha1beta2 on the surface, which improves the targeting of therapy.
