Abstract
Interleukin-6 (IL-6), a pleiotropic cytokine that regulates immune responses and inflammatory reactions, plays a pivotal role in the development of rheumatoid arthritis (RA). Blockade of IL-6 signaling with the monoclonal antibody (mAb) represents an important advancement in RA treatment. Although two IL-6 receptor antibodies are already available in the clinic, there is no mAb specifically targeting the human IL-6 to block IL-6 signaling for RA treatment. In this study, we have developed a novel humanized anti-IL-6 mAb HZ-0408b with potent binding and neutralizing activity to human IL-6. We demonstrated that HZ-0408b has a high species specificity and low cross-reactivity. Moreover, HZ-0408b showed a more potent inhibitory effect on IL-6 signaling than Siltuximab, an FDA-approved anti-IL-6 chimeric mAb. HZ-0408b is comparable to Olokizumab, a humanized mAb against IL-6 that is already in phase III studies. We observed that HZ-0408b is well tolerated at doses that can achieve therapeutic serum levels in cynomolgus monkey. Most importantly, we proved that HZ-0408b treatment significantly ameliorated joint swelling after the onset of arthritis and dramatically reduced plasma C-reactive protein (CRP) levels in a monkey collagen-induced arthritis (CIA) model. Collectively, our findings using non-human primates indicate that humanized anti-IL-6 mAb HZ-0408b has excellent safety and efficacy profiles for RA therapy.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune disorder that is characterized by inflammation of synovial joint tissues and which affects up to 1% of the world’s population
We examined whether the humanized anti-IL-6 monoclonal antibody (mAb) can inhibit IL-6 stimulated secretion of serum amyloid A (SAA), which is mainly produced in the liver and dramatically increased during inflammation
Using Bio-layer Interferometry (BLI) assay for binding affinity test, we found that the KD of HZ0408b for IL-6 was 3.474e-8 M, while Olokizumab was 2.425e-8 M, which indicates that the binding affinity of HZ0408 to rhIL-6 is similar to Olokizumab
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disorder that is characterized by inflammation of synovial joint tissues and which affects up to 1% of the world’s population. Among the factors involved in RA, interleukin (IL)-6 plays an essential role in the chronic inflammation associated with RA. IL-6 is a pleiotropic cytokine with a wide range of biological activities in immune regulation, inflammation, hematopoiesis, and oncogenesis [1, 2]. Since the discovery of IL-6 in 1986 [3], remarkable progress has been made in the understanding of the IL-6 receptor system, signaling transduction mechanism, and its biological activities. IL-6 exerts its biological activities through two receptor components: an 80-kDa ligand-binding chain (IL6R) and a 130-kDa non-ligand-binding signal transducer glycoprotein 130 (gp130) [4]. IL-6 stimulation induces tyrosine phosphorylation and recruitment of transcriptional factor signal transducer and activator of transcription 3 (STAT3), which dimerizes and is translocated to the nucleus to initiate the transcription of specific genes [5]
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