earticle

영어

TNFα is a important mediator of inflammatory diseases including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), Crohn’s disease, psoriatic arthritis, and ankylosing spondylitis. In recent years, the biologics that inhibit the activity of the TNFα have become a major target for drug developers and it has been recognized that successful treatment strategies for RA. We produced and characterized a murine monoclonal antibody (mAb) TSK114 against human TNFα, and further developed the humanized mAb YHB1411-2 by complementary-determining region (CDR) grafting procedure. The neutralizing activity of YHB1411-2 to inhibit human TNFα-induced cytotoxicity in vitro was tested using WEHI cell based assay system. The neutralizing activity of YHB1411-2 showed 2~3 fold higher than that infliximab and adalimumab.
The TNFα neutralizing activity of YHB1411-2 in vivo was evaluated using galactosamine-sensitized mouse model. YHB1411-2 demonstrated a dose-dependent inhibition of mortality and a more potency than infliximab on the same dosage. Epitope mapping was conducted by yeast display technology and site directed mutagenesis. YHB1411-2 has two predominant binding regions located on the apical bottom and top of the subunit surfaces of trimeric TNFα. The therapeutic efficacy of YHB1411-2 was assessed by using transgenic mouse polyarthritis model. In the results, YHB1411-2 dose-dependently prevented the progress of polyarthritis. Especially, the severity of arthritis in Tg mice treated with YHB1411-2 was significantly reduced in comparison with infliximab treated Tg mice at the same dosage in the histopathological evaluation. In summary, our study showed that YHB1411-2 has higher TNFα-inhibitory activity in
vitro and in vivo than other TNFα blockers.