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The treatment of autoimmune and inflammatory diseases often requires targeting multiple pathogenic pathways. KYS202004A is a novel bispecific fusion protein designed to antagonize TNF-α and IL-17A, pivotal in the pathophysiology of autoimmune and inflammatory diseases. Our initial efforts focused on screening for optimal structure by analyzing expression levels, purity, and binding capabilities. The binding affinity of KYS202004A to TNF-α and IL-17A was evaluated using SPR. In vitro, we assessed the inhibitory capacity of KYS202004A on cytokine-induced CXCL1 expression in HT29 cells. In vivo, its efficacy was tested using a Collagen-Induced Arthritis (CIA) model in transgenic human-IL-17A mice and an imiquimod-induced psoriasis model in cynomolgus monkeys. KYS202004A demonstrated significant inhibition of IL-17A and TNF-α signaling pathways, outperforming the efficacy of monotherapeutic agents ixekizumab and etanercept in reducing CXCL1 expression in vitro and ameliorating disease markers in vivo. In the CIA model, KYS202004A significantly reduced clinical symptoms, joint destruction, and serum IL-6 concentrations. The psoriasis model revealed that KYS202004A, particularly at a 2  mg/kg dose, was as effective as the combination of ixekizumab and etanercept. This discovery represents a significant advancement in treating autoimmune and inflammatory diseases, offering a dual-targeted therapeutic approach with enhanced efficacy over current monotherapies., (Copyright © 2024. Published by Elsevier B.V.)

In recent decades when biological agents have flourished, a part of patients suffering from inflammatory bowel disease (IBD) have received the treatment of tumor necrosis factor inhibitors or IL-1 antibodies. This study aims to investigate the anti-colitis effects of bispecific antibody (FL-BsAb1/17) targeting IL-1β and IL-17A comparing with TNF-α soluble receptor medicine etanercept. IBD model in mice was established by drinking 3% DSS (dextran sulfate sodium salt). On the first day of drinking DSS, treatments with etanercept (5 mg/kg) or different doses of FL-BsAb1/17 (1 mg/kg, 5 mg/kg, and 10 mg/kg) were started by intraperitoneal injection every other day. The results demonstrated that FL-BsAb1/17 treatment was more effective than etanercept at the same dose (5 mg/kg) in relieving the typical symptom of ulcerative colitis induced by DSS (such as the severity score and intestinal shortening), and down-regulating the expression of inflammatory factors (IL-17A, IL-6, IL-12, IL-22, IL-1β, IL-23, TNF-α) in the serum and colon. FL-BsAb1/17 could also reduce the degree of intestinal fibrosis. The same dose of FL-BsAb1/17 (5 mg/kg) performed better than etanercept in down-regulating MDA and up-regulating SOD (superoxide dismutase), CAT (catalase), and T-AOC (total antioxidant capacity) in serum. Both FL-BsAb1/17 and etanercept could reduce the transcription of Bax and increase the transcription of Bcl-2 and slow down apoptosis in colitis colon tissue. We conclude that the blocking of IL-1β and IL-17A can inhibit DSS-induced ulcerative colitis and FL-BsAb1/17 may have potential to become a new dual-target candidate for colitis treatment., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In recent decades, biological agents such as tumor necrosis factor-α (TNF-α) inhibitors, have revolutionized the treatment of psoriasis. However, inhibition of a single cytokine may not achieve satisfactory therapeutic results. It is against this background that this research was undertaken to investigate the anti-psoriatic effect of a novel fusion protein (DTF) dual targeting TNF-α and interleukin-17 A (IL-17 A). Imiquimod (IMQ) was topically applied to the skin of mice to develop psoriasis-like skin and treated with etanercept or different doses of DTF. Results showed that DTF treatment (1 mg/kg, 3 mg/kg, 5 mg/kg) significantly attenuated IMQ-induced typical psoriasis-like inflammation, severity score, and epidermis thickening in a dose-dependent manner, and was again more efficient than etanercept (3 mg/kg) in alleviating all these parameters at the same dose. Furthermore, DTF was more potent than etanercept in suppressing the expression of inflammatory factors (IL-17 A, IL-6, IL-1β, IL-23, IL-22 and IL-12) in the serum, spleen and psoriasis-like skin compared with etanercept at the same dose. In addition, DTF was more efficient than etanercept in reducing the expression of keratins, decreasing the mRNA expression of Ly-6 G and Ly-6C, and enhancing the expression of filaggrin and caspase 14 in IMQ-induced psoriasis-like skin. We conclude that DTF alleviates IMQ-induced psoriasis by attenuating inflammatory cascades, reducing keratinocytes proliferation and improving epidermal barrier function through suppressing TNF-α and IL-17 A signal pathways. These data suggest that DTF has potential to be a novel therapeutic candidate for psoriasis., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Recently, targeting inflammatory cytokines in the pathogenic process of rheumatoid arthritis is now performed as a feasible biological method in therapy. However, treatments against single cytokine are often difficult to achieve the ideal therapeutic effect. Multi-target drugs permit more effective suppression of inflammation. In this study, we constructed an IgG-like bispecific antibody targeting IL-1β and IL-17A and expressed it in mammalian cells. The therapeutic efficacy was studied in CIA (collagen-induced arthritis) mice, which were administrated with either FL-BsAb1/17 (IgG-like bispecific antibody targeting IL-1β and IL-17A) or monovalent IL-1β Mab or IL-17A Mab (anti-IL-1β/IL-17A monoclonal antibody). We noticed that FL-BsAb1/17 had better effect on alleviating clinical symptom by significantly lowering arthritis score and relieving histological lesion on aspect of less damnification in synovial hyperplasia and cartilage destruction than monovalent Mab alone. In addition, FL-BsAb1/17 was more potent in inhibiting IL-1β, IL-17A, IL-6, TNF-α and anti-CCP antibody in the serum and in down-regulating the expression of IL-1β, IL-17A, IL-6, TNF-α, MMP-3 and RANKL in the spleen, compared to monovalent Mab alone. Further, the anti-inflammatory effect of FL-BsAb1/17 was demonstrated by significantly depressing Th17 cells expansion through decreasing phosphorylated STAT3 in the spleen of the CIA mice. FLS (fibroblast-like synoviocytes) from RA patients were used to examine the therapeutic efficacy of FL-BsAb1/17 in human pathological tissue. FL-BsAb1/17 could significantly decrease the production of IL-6 induced by IL-1β and/or IL-17A in FLS. In conclusion, FL-BsAb1/17 has the possibility to be a promising therapeutic agent for RA., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Rheumatoid arthritis (RA) is a chronic, systemic and autoimmune disease with overexpression inflammation cytokines. The biological therapy targeting these inflammatory cytokines has been applied for the clinic. Drugs aimed at a single target are ineffective in some patients with RA. However, double-target and multi-target drugs have huge advantages in therapy. Interleukin-1β (IL-1β) and Interleukin-17A (IL-17A) are the keys to inflammatory factors in RA. The bispecific antibody(BsAb)against both human IL-1β and human IL-17A was formed and expressed in E. coli. The binding specificity and efficiency of the BsAb was tested by enzyme-linked immunosorbent assay, Western blotting and several cells experiments including THP-1, 3T3-L1 and L929 in vitro. Different doses of BsAb (5, 2, 0.8mg/kg) were compared in collagen-induced arthritis (CIA) mice, with Adalimumab and Dexamethasone as the positive control. The effects on mice were determined by the degree of arthritis severity, cytokines levels, the level of IgG against CII and rheumatoid factor level in serum, the transcription levels of relative cytokines in the spleen, and histological damage. Furthermore, the activation of NF-κB was analyzed by Western blotting. In conclusion, BsAb can bind with IL-1β and IL-17A to alleviate the severity of arthritis, to decrease the levels of inflammation cytokines in serum, to down-regulate the expression of IL-1β, IL-2, IL-6, IL-17A, TNF-α, IFN-γ, and MMP-3, to up-regulate the expression of IL-10, to relieve histological damage and to inhibit bone destruction. BsAb inhibited nuclear translocation of the p65 subunit and cytoplasm IκB-α degradation by blocking IL-1β and IL-17A, the upstream of NF-κB pathway. High doses of BsAb had a more beneficial effect on CIA mice than Adalimumab and Dexamethasone. Thus, these results indicate that BsAb can be regarded as an ideal candidate for RA therapy., (Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)