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Interleukin-6 Biology Takes Center Stage
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The interleukin-6 pathway has been on the radar of the rheumatology community as an important marker and a target for therapy, perhaps most notably since the FDA approval of tocilizumab for rheumatoid arthritis in 2010. A number of agents with activity in the pathway are close to market or are in the pipeline.
Some experts contend these are poised to take the mantle as first-line therapy in rheumatoid arthritis (RA) and other rheumatic diseases. However, some recently published studies have yielded a mixed bag of results indicating that perhaps the boundaries of these agents still need to be more clearly defined.
Iain B. McInnes, PhD, Muirhead Professor of Medicine, ARUK Professor of Rheumatology and director of the Institute of Infection Immunity and Inflammation at the College of Medical, Veterinary and Life Sciences, University of Glasgow, spoke about interleukin-6 (IL-6).
“It is an effector and immune regulatory cytokine with broader effects in regulating immune interactions with endocrine metabolic and neurologic pathways,” he told Healio Rheumatology. “It serves to integrate immune function with these other essential body systems. It is being explored for use in some other inflammatory conditions, such as vasculitis. However, paradoxically, it has not been helpful in diseases, such as ankylosing spondylitis. More clinical trial work is required.”
The pathway has both pro-inflammatory and anti-inflammatory properties, which has made it a particularly compelling area of research and intervention. T-cells and macrophages secrete IL-6 as a way of mounting an immune response during infection or after types of tissue damage. Thus, according to McInnes, it is unclear which inflammatory diseases will benefit from intervention along the IL-6 pathway.
Ernest H. Choy, MD, FRCP, head of Rheumatology and Translational Research at the Institute of Infection and Immunity, director of Arthritis Research at the UK CREATE Centre and Welsh Arthritis Research Network (WARN) at the Cardiff University School of Medicine, offered a possible explanation.
“The unique biology of IL-6, which is different from [tumor necrosis factor] TNF, suggests the spectrum of rheumatic diseases that may benefit from IL-6 inhibition,” he said. “They may be different from [tumor necrosis factor] TNF inhibitors.”
There are a number of agents to discuss. Beyond tocilizumab (Actemra, Genentech), siltuximab (Sylvant, Janssen) targets IL-6 itself while sarilumab (Regeneron) targets the IL-6 receptor. Other agents include sirukumab (GlaxoSmithKline) and olokizumab (UCB Pharma), which are human monoclonal antibodies; elsilimomab (Creative Biolabs), a mouse monoclonal antibody; CPSI-2346, a macrophage-specific inhibitor of the p38 mitogen-activated protein kinase pathway; and ALX-0061 (Ablynx), an anti-IL-6R nanobody. Studies are also underway for investigational compounds gerilimzumab (formerly ARGX-109, Argenx N.V. or Bird Rock Bio), FM101 (Femta Pharmaceuticals) and FE301 (Ferring Pharmaceuticals), which targets the IL-6/soluble IL-6R complex and may herald a new way of looking at IL-6.
In this Cover Story, Healio Rheumatology addresses the clinical relevance of the pathway, new drugs that are in the pipeline, the similarities and differences between the drugs currently available and those that are emerging, the biology of the IL-6 pathway and the nature of signaling along this pathway.
The Stage
In a published study, Srinivasan Srirangan, MBBS, MSc(Rheuml), MRCP(UK) and Choy suggested IL-6 is abundant in the synovial fluid and serum of individuals with RA, and that these levels have shown associations with disease activity and joint damage. They noted IL-6 is associated with the promotion of synovitis and joint damage by a number of pathways, including neutrophil migration, osteoclast maturation and vascular endothelial growth factor (VEGF)-stimulated pannus proliferation, according to the researchers. The protein also may mediate certain systematic manifestations of RA, such as the acute-phase reaction. They described this reaction as including C-reactive protein, anemia due to the production of hecipidin, fatigue through the hypothalamic-pituitary-adrenal axis and osteoporosis resulting from an impact on osteoclasts.
“In addition, IL-6 may contribute to the induction and maintenance of the autoimmune process through B-cell maturation and TH-17 differentiation,” they wrote, and suggested that blocking IL-6 blockade is a desirable therapeutic option. “Following successful animal studies, a humanized anti-IL-6R monoclonal antibody, tocilizumab, entered into clinical trials and it has been shown to be an effective treatment in several large phase 3 clinical trials in RA with rapid and sustained improvement in disease activity, reducing radiographic joint damage and improving physical function.”
For Choy, the link between IL-6 and TH-17 is critical.
“Tocilizumab has been approved for the treatment of many chronic inflammatory conditions, including rheumatoid arthritis, systematic juvenile arthritis, polyarticular juvenile arthritis,” Choy told Healio Rheumatology. “Clinical trials in systematic sclerosis and giant cell arteritis showed promising results. IL-6 may contribute to the induction and maintenance of the autoimmune process through B-cell maturation and TH-17 differentiation. IL-6 promotes the development of autoimmunity by promoting the development of TH-17 cells and reducing the number of immunosuppressive regulatory T cells. The consequence of this is development of chronic inflammation. IL-6 also promotes B cells maturation into plasma cells which are responsible for producing autoantibodies, such as rheumatoid factor and anti-[cyclic citrullinated peptide] CCP antibodies.”
Closer Look at gp130
Stefan Rose-John, PhD, director of the Department of Biochemistry at the Christian-Albrechts-Universität zu Kiel Medical School, and colleagues conducted a study on FE301, which Rose-John described “as [an] artificial designer protein consisting of the dimerized extracellular portion of gp130” in an interview with Healio Rheumatology. “The name of the protein is sgp130Fc and it is developed under the name FE301,” he said. “sgp130Fc is the extracellular portion of gp130 of the signaling receptor for IL-6 fused to the constant portion of a human IgG1 antibody. The sgp130Fc protein binds IL-6 complexed to the soluble IL-6 receptor (sIL-6R) but not IL-6 alone.”
In the study, he and colleagues wrote that soluble cytokine receptors have the capacity to bind ligands with “comparable affinity as membrane bound receptors.” They suggested most soluble receptors are antagonists and compete with membrane-associated counterparts, but that few soluble receptors serve as agonists. There are soluble receptors of the IL-6 family of cytokines, including sIL-6R, sIL-11R and soluble ciliary neurotrophic factor receptor, that can transmit signals through interaction with the universal-signal transducing receptor for all cytokines in the IL-6 family, gp130. The IL-6/sIL-6R complex stimulates a number of cell types that are not responsive to IL-6 alone. The researchers named this process trans-signaling. Limited proteolysis and translation from an alternatively spliced mRNA are the two mechanisms by which the generation of soluble cytokine receptors occurs.
“We have demonstrated that a soluble form of the IL-6 family signaling receptor subunit gp130, which is generated by differential splicing, is the natural inhibitor of IL-6 trans-signaling responses,” they wrote. “We have shown that in many chronic inflammatory diseases, including chronic inflammatory bowel disease, peritonitis, rheumatoid arthritis, asthma, as well as colon cancer, IL-6 trans-signaling is critically involved in the maintenance of a disease state, by promoting transition from acute to chronic inflammation. Moreover, in all these models, the course of the disease can be disrupted by specifically interfering with IL-6 trans-signaling using the soluble gp130 protein.”
Because of this, IL-6 responses to IL-6 alone, which Rose-John referred to as classic signaling, are not impacted by the protein. However, the IL-6 trans-signaling responses via IL-6 + sIL-6R are blocked.
“We have shown in the past that the IL-6 trans-signaling responses are the pro-inflammatory activities of IL-6, whereas IL-6 classic responses are important for the defense of the body against bacterial infections and the beneficial acute phase response of the liver,” he said. “Neutralization of IL-6 with either anti-IL-6 or anti-IL-6R antibodies block both, classic- and trans-signaling of IL-6.”
The current results indicate the specific blockade of IL-6 trans-signaling does not lead to liver inflammation, which is seen when all IL-6 activity is lost, according to Rose-John. “Interestingly, the infiltration of macrophages into the adipose tissue is prevented by specific blockade of IL-6 trans-signaling implicating that the metabolic side effects of IL-6 total blockade can be prevented by the specific blockade of IL-6 trans-signaling,” he said.
Rose-John and colleagues have initiated a phase 2 clinical trial at the University Hospital in Kiel.
“We are treating patients with inflammatory bowel disease [IBD],” he said. “It has been shown that a complete blockade of IL-6 biologic activity with neutralizing antibodies can lead to perforations of the gut. We hypothesize from animal studies that IL-6 classic signaling is important for the regeneration of the intestine. This is blocked by neutralizing antibodies but not by the sgp130Fc protein. In animal experiments, we could show that RA, IBD, peritonitis, lupus and many other inflammatory diseases are blocked by specific blockade of IL-6 trans-signaling.”
Rose-John is encouraged by the extent to which the group’s research has moved the field forward.
“We are convinced that we have achieved a differentiation of the anti- and pro-inflammatory activities of the cytokine IL-6,” he said. “We have found a way to specifically block the ‘bad’ side of the cytokine without compromising the protective effects of this cytokine. We think this could also be achieved for other cytokines, such as TNF-a[lpha], IL-17 or IL-23. For this goal to be achieved more basic research will be necessary.”
Eye on Tocilizumab
While tocilizumab has been part of the armamentarium for a number of years, ongoing studies continue to shed light on how it may be used to maximum efficacy. In the MEASURE study, a study in which McInnes was involved, Thompson and colleagues aimed to characterize the role of IL-6R inhibition using tocilizumab on certain risk factors in RA. The randomized, multicenter, two-part, phase 3 trial included 132 patients assessed during a 24-week double-blind period and an 80-week open-label period. The researchers measured lipid and lipoprotein levels, HDL composition and markers of coagulation along with thrombosis and vascular function outcomes. Median total cholesterol was higher in the tocilizumab group compared with placebo at 12 weeks, 12.6% vs. 1.7%. Other 12-week results indicated LDL cholesterol (28.1% vs 2.2%) and triglyceride levels (10.6% vs. 1.9%) also were increased in the study drug group compared with placebo. Mean small LDL levels, mean oxidized LDL and HDL cholesterol concentrations were not significantly different between the two treatment groups. A decrease in HDL-associated serum amyloid A content was reported in the tocilizumab group, according to the results.
The study drug also yielded reductions of more than 30% in secretory phospholipase A2-IIA, lipoprotein(a), fibrinogen and D-dimers compared with placebo. Conversely, paraoxonase was elevated in the tocilizumab arm compared with the placebo arm. Other results indicated similar ApoB/ApoA1 ratios over time in both the study drug and placebo arms. Placebo yielded greater decreases in pulse wave velocity than tocilizumab at 12 weeks (adjusted mean difference 0.79 m/s), according to the results.
“These data provide the first detailed evidence for the modulation of lipoprotein particles and other surrogates of vascular risk with IL-6R inhibition,” the researchers concluded. “When compared with placebo, [tocilizumab] induced elevations in LDL-C but altered HDL particles towards an anti-inflammatory composition and favorably modified most, but not all, measured vascular risk surrogates. The net effect of such changes for cardiovascular risk requires determination.”
“MEASURE was designed to examine the effects of blocking IL-6 signaling in patients with RA on the levels of vascular risk biomarkers, and especially to look at the effects on lipid metabolism,” McInnes said. “It demonstrated that IL-6 biology is intricately linked to metabolic function and therefore that tocilizumab has the potential to alter the composition and function of lipid containing particles in the blood of patients. It also showed that IL-6 blockade leads to reductions in factors that can be associated with blood clotting and therefore with vascular risk. It did not, however, conclude definitively as to whether the effects of tocilizumab on vascular risk measures were favorable or otherwise for vascular function and cardiac or stroke outcomes in RA.”
McInnes added that tocilizumab continues to be used widely in the treatment of RA.
“It appears to be effective and generally well-tolerated and provides a useful mode of action for the management of this chronic condition,” he said.
Sarilumab, Clazakizumab
Strand and colleagues investigated sarilumab plus methotrexate in a cohort of 1,197 patients with RA who had an inadequate response to methotrexate alone. Patients in the study arm received 150 mg or 200 mg plus methotrexate subcutaneously for 52 weeks. A number of patient-reported outcome measures were used to evaluate outcomes, including patient global assessment of disease activity, pain, health assessment questionnaire disability index, Short Form-36 health survey and functional assessment of chronic illness therapy-fatigue. The findings showed both doses of the study drug plus methotrexate yielded improved patient-reported outcomes compared with placebo plus methotrexate. The researchers described the improvements as “clinically meaningful.”
“Sarilumab is another anti-IL-6R monoclonal antibody, so it is similar to tocilizumab,” Choy said. “Clinical trials results were positive so it may become available later this year.”
Mease and colleagues investigated clazakizumab in a cohort of 165 patients with psoriatic arthritis in a randomized, double-blind, placebo-controlled, dose-ranging study. Patients received 25 mg, 100 mg or 200 mg of the drug with or without methotrexate. ACR20 criteria at week 16 served as the primary outcome measure. Week 16 results indicated that clazakizumab 100 mg yielded improved ACR20 response rates compared with placebo (52.4% vs. 29.3). The 25-mg dose also bested placebo in terms of ACR20, as did the 200-mg dose, but not significantly. Clazakizumab also demonstrated numerically higher ACR50 and ACR70 response rates than placebo at weeks 16 and 24, according to the results. Other findings indicated musculoskeletal manifestations significantly improved with clazakizumab, while skin disease showed minimal improvements. There was no clear dose response, but the study drug was well-tolerated.
“Clazakizumab may be an effective treatment option for musculoskeletal aspects of [psoriatic arthritis] PsA, but because of the lack of a dose response in this study, further studies are required to confirm the appropriate dose,” the researchers concluded. “The safety profile is consistent with the pharmacology of IL-6 blockade and prior clinical experience with this antibody in rheumatoid arthritis.”
“Currently, we are seeing other follow on antibodies emerging that will also target IL-6 in patients,” McInnes said. “Agents are being developed, or are almost approved, that target either the cytokine itself — that is, IL-6 blockers — or target the receptor for the cytokine, analogous to tocilizumab. It is not yet clear what advantage these new agents will confer over the already available IL-6R blocker tocilizumab, though time will tell.”
Olokizumab, Sirukumab
Takeuchi and colleagues conducted a phase 3, dose-ranging, double-blind, placebo-controlled, randomized trial of olokizumab. There were six dosing regimens and 119 patients included in the analysis. Change from baseline in DAS28 C-reactive protein served as the primary endpoint, while ACR20/ACR50/ACR70 response rates at week 12 were the secondary endpoints. Patients treated with 60-mg, 120-mg and 240-mg 4-week cumulative doses of the study drug showed greater improvements in the primary endpoint at week 12 compared with patients receiving placebo. For the secondary endpoints, patients treated with all cumulative dose groups improved in ACR20 and ACR50 at week 12 compared with placebo. Adverse event rates were comparable in the treatment and placebo groups.
“[Olokizumab] demonstrated improvements in efficacy variables vs. placebo in Asian patients with moderately to severely active RA who had previously failed anti-TNF therapy,” the researchers concluded. “The safety profile was as expected for this class of drug.”
Rovin and colleagues investigated sirukumab in a cohort of 25 patients with class III or IV active lupus nephritis. There were 21 patients in the active study drug group and four who received placebo. Reduction in proteinuria served as the primary endpoint. Nineteen patients completed the study through 24 weeks. Results at that time point indicated a 0% change in proteinuria in the study drug patients and median reduction of proteinuria of -43.3% in the placebo group.
“This proof-of-concept study did not demonstrate the anticipated efficacy nor did it demonstrate an acceptable safety profile for sirukumabtreatment in this population of patients with active lupus nephritis receiving concomitant immunosuppressive treatment,” the researchers concluded.
“Large phase 3 clinical trials in systemic sclerosis, giant cell arteritis and psoriatic arthritis will elucidate the role of IL-c6 inhibition in the treatment of these diseases,” Choy said. “Other companies are developing anti-IL-6 antibodies, such as sirukumab and olokizumab.”
Investigational Agents
Van Roy and colleagues investigated ALX-0061, which they described as a “a bispecific nanobody with a high affinity and potency for IL-6 receptor (IL-6R), combined with an extended half-life by targeting human serum albumin.” They investigated the pharmacologic properties of the drug in cynomolgus monkeys. Results indicated a 200-fold increase of target affinity that occurred as a result of affinity maturation of the parental domain, according to the results. The drug had a high affinity for sIL-6R (0.19 pM), which translated to a neutralization of sIL-6R in vitro in a concentration-dependent manner. Parameters, such as C-reactive protein, fibrinogen and platelets, were inhibited in this manner. The half-life was 6.6 days following a single injection.
“ALX-0061 represents a minimized bispecific biotherapeutic of 26 kDa, nearly six-times smaller than monoclonal antibodies,” the researchers concluded. “High in vitro affinity and potency was demonstrated. Albumin binding as a half-life extension technology resulted in describable and expected pharmacokinetics. Strong IL-6R engagement was shown to translate to in vivo effect in non-human primates, demonstrated via biomarker deregulation as well as clinical effect. Presented results on preclinical pharmacological properties of ALX-0061 are supportive of clinical development in RA.”
Regarding other agents, ARGX-109 and FM101 remain in preclinical development.
The ambiguity surrounding IL-6 has made for challenges in the lab, according to McInnes.
“The role of IL-6 is not so clear, so it is difficult to assess which other inflammatory diseases it will provide benefit for,” he said. — by Rob Volansky
- References:
- Calabrese LH and Rose-John S. Nature Reviews Rheumatology. 2014;doi:10.1038/nrrheum.2014.127.
- McInnes IB, et al. Ann Rheum Dis. 2013; doi:10.1136/annrheumdis-2013-204345.
- Mease PJ, et al. Arthritis Rheumatol. 2016; doi:10.1002/art.39700.
- Rose-John S, et al. J Leukoc Biol. 2006; 80:227-236.
- Rovin BH, et al. Arthritis Rheumatol. 2016; doi:10.1002/art.39722.
- Srirangan S, et al. Ther Adv Musculoskelet Dis. 2010; doi:10.1177/1759720X10378372.
- Strand V, et al. Arthritis Res Ther. 2016; doi:10.1186/s13075-016-1096-9.
- Takeuchi T, et al. Mod Rheumatol. 2016; doi:10.3109/14397595.2015.1074648.
- Van Roy M, et al. Arthritis Res Ther. 2015; doi:10.1186/s13075-015-0651-0.
- For more information:
- Ernest H. Choy, MD, FRCP, can be reached at Cardiff University School of Medicine, Tenovus Building, Heath Park Campus, Cardiff, CF14 4XN, United Kingdom; email: choyeh@cardiff.ac.uk.
- Iain B. McInnes, PhD, can be reached at the College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland UK, G128QQ; email: iain.mcinnes@glasgow.ac.uk.
- Stefan Rose-John, PhD, can be reached at the Christian-Albrechts-Universität zu Kiel, Medical Faculty; Olshausenstrasse 40, D-24098 Kiel, Germany; email: rosejohn@biochem.uni-kiel.de.
Disclosures: Choy reports he receives research grants and is a member of advisory boards and speaker bureaus for Abbott Laboratories, Allergan, Amgen, AstraZeneca, Biogen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai Pharma, Daiichi Sankyo, Eli Lilly, Ferring Pharmaceutical, GlaxoSmithKline, Hospira, ISIS, Jazz Pharmaceuticals, Janssen, MedImmune, Merrimack Pharmaceutical, MSD, Napp, Novimmune, Novartis, Pfizer, Regeneron, Roche, R-Pharm, Sanofi-Aventis, Synovate, Tonix and UCB Pharma. McInnes reports he receives grant funding or honoraria from Roche, GlaxoSmithKline, Sanofi, AbbVie, Pfizer, Eli Lilly, UCB Pharma and Bristol-Myers Squibb, all of which are concerned with the delivery of medicines to people with RA. Rose-John reports he is an inventor on patents owned by CONARIS Research Institute, which develops the sgp130Fc protein together with Ferring Pharmaceuticals, and he has stock ownership in CONARIS; he was a consultant for Genentech Roche, Chugai, AbbVie and Janssen and a speaker for Genentech Roche, Chugai, Janssen and GlaxoSmithKline.