Abstract
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.
Highlights
The pathogenesis of autoimmune disorders is not fully understood
The correct association of the light chain and their cognate heavy chains was achieved by exchanging the variable heavy (VH) and the variable light (VL) domains within the anti-IL-17A antibody
Co-transfection of HEK293 suspension cells with expression vectors encoding the anti-tumor necrosis factor (TNF)-α/IL-17A bsAb resulted in the production of soluble proteins with the high purity in SDS-PAGE assays (Figure 1B)
Summary
The pathogenesis of autoimmune disorders is not fully understood. Immune dysfunction is involved in complicated genetic and environmental factors [1]. Monoclonal antibody (mAb) drugs succeed in treatment of autoimmune diseases [2]. These mAbs have benefited millions of patients with chronic diseases, such as rheumatoid arthritis (RA), psoriasis and Crohn’s disease, and so on. Tumor necrosis factor alpha (TNF-α) is a potent inductor of the inflammatory response in innate immune response [3]. Anti-TNF-α mAbs are undoubtedly to be clinically efficacious for autoimmune diseases, especially for RA. In turn, trigger the production of inflammatory cytokines and chemokines. These TNFinduced cytokines are involved in the initiation and progression of inflammatory diseases. Recent studies indicate that there exists a shared cytokine framework, including TNF-α, interleukin (IL)-1, IL-6, IL-17 and IL-
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