A Dual Target-directed Agent against Interleukin-6 Receptor and Tumor Necrosis Factor α ameliorates experimental arthritis

Kim, Young-Kyun; Yi, Hyoju; Jung, Hyerin; Rim, Yeri Alice; Park, Narae; Kim, Juryun; Jung, Seung Min; Park, Sung-Hwan; Park, Young Woo

doi:10.1038/srep20150

Cited by 28 publications

(24 citation statements)

References 46 publications

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“…neutralizing Abs that were patented [393,394]. The first approach could ameliorate the clinical progress in CIA more than the single treatments did [395]. Additionally, RA patients were treated with the combination of IL1 and TNF neutralizing drugs although this therapy did not have added value [396], although this strategy seemed promising in preclinical sepsis models and in acute myeloid leukemia [76,397].…”

Section: Multispecific Approachesmentioning

confidence: 99%

A New Venue of TNF Targeting

Steeland

Libert

Vandenbroucke

2018

Preprint

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The first FDA-approved drugs were small, chemically-manufactured and highly active molecules with possible off-target effects. After this first successful wave of small drugs, biotechnology allowed the development of protein-based medicines such as antibodies. Conventional antibodies bind a specific protein and are becoming increasingly important in the therapeutic landscape. A very prominent class of biologicals are the anti-TNF drugs that are applied in several inflammatory diseases that are characterized by dysregulated TNF levels. Marketing of TNF inhibitors revolutionized the treatment of diseases such as Crohn’s disease. However, these inhibitors also have undesired effects, some of them directly associated with the inherent nature of this drug class such as immunogenicity, whereas others are linked with their mechanism of action. Recently, researchers tried to design innovative drugs with reduced side effects aiming to make them more effective and safer. Molecules with more specificity e.g. that target one specific TNF format or receptor, or that neutralize the TNF signaling pathway in specific cells, are generated. Alternatively, TNF-directed biologicals without the typical antibody structure are manufactured. Here, we review the complications related to the use of conventional TNF inhibitors, together with the anti-TNF alternatives and the different (neurodegenerative) diseases that might benefit from selective approaches.

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Section: Multispecific Approachesmentioning

confidence: 99%

A New Venue of TNF Targeting

Steeland

Libert

Vandenbroucke

2018

Preprint

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“…44 Similarly, a variety of dual target drugs have been developed to block IL-17 in combination with TNF, and their efficacies have been evaluated in arthritic diseases. A dual target inhibitor of IL-6R and TNFR2 was shown to inhibit synovial fibroblast proliferation and migration, osteoclastogenesis, and disease severity more effectively than single-target drugs.…”

Section: Discussionmentioning

confidence: 99%

A bispecific soluble receptor fusion protein that targets TNF‐α and IL‐21 for synergistic therapy in inflammatory arthritis

et al. 2019

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This study was aimed at investigating the therapeutic effects of BITRAP, a bispecific fusion protein targeting TNF-α and IL-21, on the development of autoimmune arthritis in humans and mice. To verify the effects of BITRAP in human, peripheral blood mononuclear cells were cultured with BITRAP under IL-17-producing T (Th17) cell-polarizing conditions or osteoclast differentiation conditions. BITRAP treatment inhibited the production of IL-17 and vascular endothelial growth factor but increased the production of IL-10 in CD4 + T cells, as well as directly suppressed osteoclastogenesis. Collagen-induced arthritis (CIA) and IL-1R antagonist (IL-1Ra) knockout mice were treated with BITRAP. Following injection in CIA mice, BITRAP rapidly migrated into the inflamed joints and remained there for 72 hours.Application of BITRAP attenuated the severity of autoimmune arthritis in CIA and IL-1Ra knockout mice by reducing the numbers of inflammatory cytokine-expressing cells and Th17 cells and antibody secretion. Finally, BITRAP suppressed STAT3 phosphorylation, as well as production of IL-17 and TNF-α, in murine splenic CD4 + | 249 PARK et Al.

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“…Several crucial factors CXCL1, CXCL2, CXCL5, CXCL6 and IL-8 are involved in the recruitment of neutrophils in inflammation of RA [ 15 , 28 ]. Th17 cells are known to contribute to arthritis pathogenesis in some patients treated with anti-TNF drugs [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…Anti-IL-17 treatment is effective in reducing the onset of clinical arthritis symptoms [ 10 ]. Dual inhibition of IL-1α/β [ 11 ], IL-1β/IL-17 [ 12 ], TNF-α/IL-17 [ 13 , 14 ], TNF-α/IL-6R [ 15 ] or TNF-α/Angiopoietin2 [ 16 ] is more potent than single targeting for the treatment of RA and other inflammatory disorders.…”

Section: Introductionmentioning

confidence: 99%

A native-like bispecific antibody suppresses the inflammatory cytokine response by simultaneously neutralizing tumor necrosis factor-alpha and interleukin-17A

Ying

Wang

et al. 2017

Oncotarget

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Anti-tumor necrosis factor (TNF) therapies are successful in the treatment of inflammatory disorders. However, some patients with rheumatoid arthritis (RA) fail to response anti-TNF drugs due to the compensation of other inflammatory signals. In this study, to reduce compensatory responses of interleukin-17A (IL-17A) during TNF-α inhibition, we generated an IgG-like bispecific antibodiy (bsAb) against TNF-α and IL-17A through a combination method of electrostatic Fc pairing and light chain crossover. This bsAb exhibited relatively high stability comparable to natural IgG antibodies, and retained the unaltered affinities to both of two targets. BsAb significantly decreased not only the expression level of neutrophil or Th17 chemokines, but also the secretion of IL-6/IL-8 on fibroblast-like synoviocytes (FLS) from a patient with RA. Meanwhile, TNF-α-mediated cellular cytotoxicity of fibroblasts was neutralized by bsAb. Importantly, we demonstrate that the combined blockade of TNF-α and IL-17A is more efficient than inhibition of either factor alone. Our results suggest the IgG-like anti-TNF-α/IL-17A bispecific molecule overcome the limited therapeutic responses using anti-TNF drugs. It may be a promising therapeutic agent for the treatment of autoimmune diseases.

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A Dual Target-directed Agent against Interleukin-6 Receptor and Tumor Necrosis Factor α ameliorates experimental arthritis

Cited by 28 publications

References 46 publications

A New Venue of TNF Targeting

A New Venue of TNF Targeting

A bispecific soluble receptor fusion protein that targets TNF‐α and IL‐21 for synergistic therapy in inflammatory arthritis

A native-like bispecific antibody suppresses the inflammatory cytokine response by simultaneously neutralizing tumor necrosis factor-alpha and interleukin-17A

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