8kb6
Crystal Structure of Canine TNF-alpha
Structural highlights
FunctionTNFA_CANLF Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation (By similarity). Induces insulin resistance in adipocytes via inhibition of insulin-induced IRS1 tyrosine phosphorylation and insulin-induced glucose uptake. Induces GKAP42 protein degradation in adipocytes which is partially responsible for TNF-induced insulin resistance (By similarity). Plays a role in angiogenesis by inducing VEGF production synergistically with IL1B and IL6 (By similarity). Promotes osteoclastogenesis and therefore mediates bone resorption (By similarity).[UniProtKB:P01375][UniProtKB:P06804] The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.[UniProtKB:P01375] Publication Abstract from PubMedThe canine anti-tumor necrosis factor-alpha (TNF-alpha) monoclonal antibody is a potential therapeutic option for treating canine arthritis. The current treatments for arthritis in dogs have limitations due to side effects, emphasizing the need for safer and more effective therapies. The crystal structure of canine TNF-alpha (cTNF-alpha) was successfully determined at a resolution of 1.85 A, and the protein was shown to assemble as a trimer, with high similarity to the functional quaternary structure of human TNF-alpha (hTNF-alpha). Adalimumab (Humira), a known TNF-alpha inhibitor, effectively targets and neutralizes TNF-alpha to reduce inflammation and has been used to manage autoimmune conditions such as rheumatoid arthritis. By comparing the structure of cTNF-alpha with the complex structure of hTNF-alpha and adalimumab-Fab, the epitope of adalimumab on cTNF-alpha was identified. The significant structural similarities of epitopes in cTNF-alpha and hTNF-alpha indicate the potential of using adalimumab to target cTNF-alpha. Therefore, a canine/human chimeric antibody, Humivet-R1, was created by grafting the variable domain of adalimumab onto a canine antibody framework derived from ranevetmab. Humivet-R1 exhibits potent neutralizing ability (IC(50) = 0.05 nM) and high binding affinity (EC(50) = 0.416 nM) to cTNF-alpha, comparable to that of adalimumab for both hTNF-alpha and cTNF-alpha. These results strongly suggest that Humivet-R1 has the potential to provide effective treatment for canine arthritis with reduced side effects. Here, we propose a structure-guided antibody design for the use of a chimeric antibody to treat canine inflammatory disease. Our successful development strategy can speed up therapeutic antibody discovery for animals and has the potential to revolutionize veterinary medicine. Structure-based development of a canine TNF-alpha-specific antibody using adalimumab as a template.,Lee CC, Kuo WC, Chang YW, Hsu SF, Wu CH, Chen YW, Chang JJ, Wang AH Protein Sci. 2024 Feb;33(2):e4873. doi: 10.1002/pro.4873. PMID:38111376[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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