Interleukin-6 (IL-6) is a classical cytokine associated with inflammation. Recent studies have shown that IL-6 is a pleiotropic cytokine with the ability to regulate inflammatory responses, immune reactions, hematopoiesis, and promote osteoclasts. It plays a remarkable role in diagnosing and treating various systemic diseases.
IL-6 Introduction
Interleukin 6 (IL-6) is a 26-kDa secreted protein, mature IL-6 consists of 184 amino acids and two N-glycosylation sites as well as four cysteine residues.
IL-6 can be produced by various cell types, such as monocytes, fibroblasts, and endothelial cells. When stimulated, many other cell types, including macrophages, T cells, B cells, mast cells, glial cells, eosinophils, keratinocytes, and granulocytes, also secrete IL-6.
IL-6 Signal Pathways
IL-6 can signal via two different pathways: classical signaling via the membrane bound IL-6R and IL-6 trans-signaling via a naturally occurring soluble IL-6R (sIL-6R).
Figure 1. IL-6 Signal Pathways [2]
In classic signaling, IL-6 binds to the membrane-bound IL-6R (mIL-6R), leading to the activation of a signal-transducing homodimer involving the glycoprotein 130 (gp130) receptor chain. Conversely, in IL-6 trans-signaling, soluble forms of IL-6R (sIL-6R), produced through either alternative splicing or limited proteolytic processing, form complexes with IL-6, thereby initiating the activation of membrane-bound gp130.
Subsequently, pathways such as JAK-STAT and RAS-RAF are activated to promote cellular proliferation, differentiation, oxidative stress and immune regulation. Classical IL-6 signaling is restricted to cells expressing IL-6R (macrophages, neutrophils, T cells, etc.). However, when IL-6 levels are elevated, the signal is widely expressed due to the ubiquitous nature of gp130.
Therapeutic Innovations through IL-6 Targeting
Targeting of the IL-6 pathway has led to innovative therapeutic approaches for a wide range of rheumatic disorders, including but not limited to rheumatoid arthritis, juvenile idiopathic arthritis, adult-onset Still's disease, giant cell arteritis, and Takayasu arteritis. Beyond rheumatic diseases, this approach has shown promise in addressing conditions like Castleman disease and cytokine release syndrome. Furthermore, it has opened doors to exploring potential applications in various other medical conditions, such as uveitis, neuromyelitis optica, and COVID-19 pneumonia.
FDA Approved IL-6 Inhibitors
The FDA has approved four IL-6 Inhibitors, including Tocilizumab (Actemra, 2010), Siltuximab (Sylvant, 2014), Sarilumab (Kevzara, 2017), and Satralizumab (Enspryng, 2020).
1. Tocilizumab: Co-developed by Chugai and Roche, it is the world's first humanized monoclonal antibody targeting IL-6R and was launched in the US in 2010. It has been approved for the treatment of rheumatoid arthritis, giant cell arteritis, systemic sclerosis-associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, cytokine release syndrome, and COVID-19.
Tocilizumab has played a vital role in combating novel coronavirus outbreaks, with research indicating a potential reduction in mortality by 8.5% for critically ill COVID-19 patients.
2. Siltuximab: This chimeric, anti-IL-6 monoclonal antibody was developed by Johnson & Johnson. It received FDA approval in 2014 for the treatment of patients with multicentric Castleman disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative.
3. Sarilumab: Developed by Sanofi and Regeneron, Sarilumab is a fully human monoclonal antibody against IL-6Rα. It was approved in 2017 for marketing in Canada and the USA for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) who had an inadequate response to disease-modifying antirheumatic drugs (DMARDs).
4. Satralizumab: Developed by Chugai Pharmaceuticals, Satralizumab is a pH-dependent humanized anti-IL-6R monoclonal antibody. In August 2020, it gained FDA approval for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults with specific antibodies, particularly patients who are anti-aquaporin-4 or AQP4 antibody-positive.
IL-6 or IL-6R Inhibitors in Pipeline
In addition to the above-marketed drugs, there are several IL-6 or IL-6R inhibitors in clinical development, including Novo Nordisk's ziltivekimab, Roche's RG6179, and Ushibi's olokizumab, etc.
1. Olokizumab
Olokizumab was initially developed by UCB as a humanized monoclonal antibody targeting IL-6. It was later transferred to R-Pharm in 2013 and is currently in the process of filing a marketing application.
A study conducted by Josef et al. and reported in the New England Journal of Medicine involved a 24-week, phase 3, multicenter trial of Olokizumab (NCT02760407). Patients with rheumatoid arthritis who had an inadequate response to methotrexate were randomly assigned in a 2:2:2:1 ratio to receive subcutaneous injections of Olokizumab at doses of either 64 mg every 2 or 4 weeks, adalimumab (40 mg every 2 weeks), or a placebo, while all patients continued methotrexate therapy. The study found that ACR20 responses occurred in 44.4% of patients treated with placebo at week 12, 70.3% of those receiving Olokizumab every 2 weeks, 71.4% of those receiving Olokizumab every 4 weeks, and 66.9% of those receiving adalimumab (Figure 2) [3].
Figure 2. ACR20 response after drug treatment [3]
2. Ziltivekimab
Ziltivekimab was initially developed by Corvidia Therapeutics as an IL-6 monoclonal antibody drug before Novo Nordisk took over the development of ziltivekimab in June 2020 with the acquisition of Corvidia Therapeutics for $2.1 billion.
Ziltivekimab is designed to reduce systemic inflammation by blocking the IL-6 pathway, thereby reducing the risk of major adverse cardiovascular events in patients with atherosclerotic cardiovascular disease (ASCVD) and chronic kidney disease (CKD), with an extended half-life, and available to be administered via once-monthly subcutaneous injections (Figure 3) [4].
Figure 3. ziltivekimab for the treatment of ASCVD and CKD
In 2021, Paul et al. reported the RESCUE clinical phase 2 trial of ziltivekimab in The Lancet, which found that ziltivekimab significantly reduced biomarkers of inflammation and thrombosis associated with atherosclerosis, including high sensitivity C-reactive protein (hsCRP) (Figure 4) [5].
Figure 4. ziltivekimab's RESCUE clinical phase 2 trial
Ziltivekimab is currently in the Phase 3 ZEUS trial, with results expected in 2024, and a series of Phase 3 trials are planned in the clinic, including HERMES, Functional Studies, and ARTEMIS, to validate its benefit in different cardiovascular disease populations.
Ziltivekimab is expected to be the first drug to target IL-6 in atherosclerotic cardiovascular disease, potentially improving patients' cardiovascular disease symptoms by reducing inflammation.
3. RG6179
RG6179 is an IL-6 monoclonal antibody developed by Roche that blocks classical and trans-signaling for diabetic macular edema, autoinflammatory diseases, macular edema, and uveitic macular edema (Figure 5) [6].
Figure 5. Structure and properties of RG6179
Results from the DOVETAIL Clinical Phase 1 study of RG6179 showed that patients in the RG6179 group had improved visual acuity and retinal thickness in all dosing cohorts. Treatment with RG6179 was well tolerated, with no serious treatment-related adverse events, elevated IOP, or treatment-related new cataracts (Figure 6).
Figure 6. Change in best-corrected visual acuity (BCVA) after RG6179 treatment
Roche recently initiated two international multicenter Phase 3 clinical studies, the Meerkat and SANDCAT studies, to evaluate the safety and efficacy, pharmacokinetics and pharmacodynamics of intravitreal administration of RG6179 for the treatment of patients with uveitis macular edema (UME).
4. Clazakizumab
Clazakizumab was originally developed by Alder Biopharmaceuticals as a humanized monoclonal antibody targeting IL-6. In 2009, BMS entered into a co-development agreement with Alder but returned its interest to Alder in 2014. Subsequently, in May 2016, Alder ceded its global interest in Clazakizumab to Vitaeris. In 2020, the US-based biologics company CSL Behring announced the acquisition of Vitaeris, with the aim of accelerating the development of treatment for chronic active antibody-mediated rejection (AMR).
References:
1. Mansur Aliyu, Fatema Tuz Zohora, Abubakar Umar Anka, Kashif Ali, Shayan Maleknia, Mohammad Saffarioun, Gholamreza Azizi,, Interleukin-6 cytokine: An overview of the immune regulation, immune dysregulation, and therapeutic approach, International Immunopharmacology, Volume 111, 2022, 109130, ISSN 1567-5769, https://doi.org/10.1016/j.intimp.2022.109130.
2. Xin Yao, Jiaqi Huang, Haihong Zhong, Nan Shen, Raffaella Faggioni, Michael Fung, Yihong Yao, Targeting interleukin-6 in inflammatory autoimmune diseases and cancers, Pharmacology & Therapeutics, Volume 141, Issue 2, 2014, Pages 125-139, ISSN 0163-7258, https://doi.org/10.1016/j.pharmthera.2013.09.004.
3. Josef S. Smolen et.al, Olokizumab versus Placebo or Adalimumab in Rheumatoid Arthritis, N Engl J Med 2022;387:715-26.
4. https://investor.novonordisk.com/q2-2023-presentation/?page=175
5. Paul M Ridker, Matt Devalaraja, Florian M M Baeres, Mads D M Engelmann, G Kees Hovingh, Milana Ivkovic, Larry Lo, Douglas Kling, Pablo Pergola, Dominic Raj, Peter Libby, Michael Davidson, IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial, Lancet 2021; 397: 2060–69
6. ARVO-2023-presentation-sharma-a-novel-intravitreal-anti-IL-6.pdf
7. https://assets.cwp.roche.com/f/176343/x/418a8c95c6/irp230727.pdf
8. Ashley A. Vo et.al, Clazakizumab for desensitization in highly sensitized patients awaiting transplantation, Am J Transplant. 2022;22:1133–1144.