The human anti-IL-1β monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis
© Alten et al.; licensee BioMed Central Ltd. 2008
Received: 2 January 2008
Accepted: 5 June 2008
Published: 05 June 2008
IL-1β is a proinflammatory cytokine driving joint inflammation as well as systemic signs of inflammation, such as fever and acute phase protein production.
ACZ885, a fully human monoclonal antibody that neutralizes the bioactivity of human IL-1β, was generated to study the potent and long-lasting neutralization of IL-1β in mechanistic animal models as well as in a proof-of-concept study in patients with rheumatoid arthritis (RA).
The mouse IL-1 receptor cross-reacts with human IL-1β, and it was demonstrated that ACZ885 can completely suppress IL-1β-mediated joint inflammation and cartilage destruction in mice. This observation prompted us to study the safety, tolerability and pharmacodynamic activity of ACZ885 in RA patients in a small proof-of-concept study – the first to be conducted in humans. Patients with active RA despite treatment with stable doses of methotrexate were enrolled in this dose escalation study. The first 32 patients were split into four cohorts of eight patients each (six were randomly assigned to active treatment and two to placebo). ACZ885 doses were 0.3, 1, 3 and 10 mg/kg, administered intravenously on days 1 and 15. To explore efficacy within 6 weeks of treatment, an additional 21 patients were randomly assigned to the 10 mg/kg cohort, resulting in a total of 20 patients dosed with 10 mg/kg and 15 patients treated with placebo. There was clinical improvement (American College of Rheumatology 20% improvement criteria) at week 6 in the 10 mg/kg treatment group; however, this did not reach statistical significance (P = 0.085). A statistically significant reduction in disease activity score was observed after 4 weeks in the 10 mg/kg group. Onset of action was rapid, because most responders exhibited improvement in their symptoms within the first 3 weeks. C-reactive protein levels decreased in patients treated with ACZ885 within 1 week. ACZ885 was well tolerated. Three patients receiving ACZ885 developed infectious episodes that required treatment. No anti-ACZ885 antibodies were detected during the study.
ACZ885 administration to methotrexate-refractory patients resulted in clinical improvement in a subset of patients. Additional studies to characterize efficacy in RA and to determine the optimal dose regimen appear warranted.
ClinicalTrials.gov identifier NCT00619905.
Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints that is associated with destruction of cartilage and bone. In addition to its local destructive nature, it also can have a pronounced systemic inflammatory component, presenting as fever, headache and fatigue, and may even affect other organs such as the skin, liver, spleen and lymph nodes. The contribution made by proinflammatory cytokines such as tumour necrosis factor (TNF)-α and IL-1 has been validated in preclinical animal models and in humans [1, 2].
Current therapy targeting IL-1 in RA is based on a recombinant form of the IL-1 receptor antagonist (IL-1Ra; anakinra), which binds to the IL-1 receptor without eliciting a signal and therefore competes with the binding of the two natural ligands, namely IL-1α and IL-1β. As compared with TNF-α inhibitors, it appears that treatment with the recombinant IL-1Ra is less efficacious in RA . However, it is unclear whether this is due to biological superiority of TNF-α over IL-1 in RA pathogenesis  or whether the approach to block the IL-1 receptor with anakinra is only partly effective in neutralizing IL-1 activity in vivo because of short half-life or inability to achieve sufficient exposure at the target site with the current dosing regimen .
The main elicitor of inflammatory responses in preclinical animal models appears to be IL-1β and not IL-1α. In murine collagen-induced arthritis  and antigen-induced arthritis [7, 8], inflammation and cartilage degradation were inhibited by blocking IL-1β but not IL-1α. In RA patients, IL-1β is over-expressed in inflamed synovial tissue, in particular in the lining layer and in sublining cells , and it is elevated in draining lymph from affected joints . Furthermore, IL-1β is localized to the synovial pannus in close proximity to bone and cartilage , and cartilage from arthritis patients exhibits upregulation of IL-1β mRNA as compared with normal cartilage. Increased levels of IL-1β in synovial fluid  have been described and were found to correlate with histological features of RA [13, 14]. Treatment with anakinra demonstrated improvement in histological characteristics of RA joint pathology , and evidence was provided that it delays the progression of radiographic joint damage . Thus, there is reason to believe that IL-1β is a crucial cytokine that drives inflammation and joint destruction in RA.
We report here results of preclinical studies and a proof-of-concept study in patients with RA, using a fully monoclonal antibody (ACZ885) directed against human IL-1β. ACZ885 is expected to have the half-life of a typical IgG1 antibody, thus ensuring full neutralization of IL-1β over a longer period of time as compared with recombinant IL-1Ra; the therefore study explored pharmacodynamic effects in RA patients (secondary to an evaluation of safety).
Materials and methods
In vivoactivity of ACZ885 in a human IL-1β-dependent mouse model of joint inflammation
Cells of the murine fibroblast line 3T3NIH were transfected with retroviral vector DFG-hIL-1β-neo, which contains the cDNAs for human (h)IL-1β and neomycin phosphotransferase (neoR), as described previously . The 3T3NIH fibroblast cell line was derived from a DBA background. One clone derived from the transduction, namely IB2 (3T3-hIL-1β), was selected, which produced high levels of hIL-1β (220 ng hIL-1β/24 hours per 106 cells) in vitro. hIL-1β-induced arthritis was induced by intra-articular injection of 104 IB2 cells into the right knee joints of DBA-1 mice. Mice were injected with ACZ885 or isotype control antibody CHI621, which is specific for human CD25 and does not cross-react with mouse cells or tissue. All mice were housed in filter top cages, and water and food were supplied ad libitum. The mice were studied at age 10 to 14 weeks. All animal experiments were approved by the Nijmegen University Animal Ethics Committee.
Administration of antibodies was intraperitoneal 2 hours before intra-articular injection of the IB2 clone. Joint inflammation was quantified using the 99mTc uptake method . By external gamma counting, this method measures the accumulation of a small radioisotope at the site of inflammation caused by locally increased blood flow and tissue swelling. The severity of inflammation is expressed as the ratio of 99mTc uptake in the right (inflamed) to that in the left (control) knee joint.
Proteoglycan synthesis was assayed as follows. Patellae with minimal surrounding tissue were placed in RPMI 1640 medium with glutamax, gentamycin (50 μg/ml) and 35S-sulphate (0.74 MBq/ml). After 3 hours of incubation at 37°C in a carbon dioxide incubator, patellae were washed in saline three times, fixed in 4% formaldehyde and subsequently decalcified in 5% formic acid for 4 hours. Patellae were punched out of the adjacent tissue, dissolved in 0.5 ml Luma Solve at 65°C (Omnilabo, Breda, The Netherlands), and after addition of 10 ml Lipoluma (Omnilabo) the 35S content was measured using liquid scintilation counting. For histological analysis, whole knee joints were removed and fixed in 4% formaldehyde for 7 days before decalcification in 5% formic acid and processing for paraffin embedding. Tissue sections (7 μm) were stained with haematoxylin/eosin or safranin O/fast green. Histopathological changes in the knee joints were scored in the patella/femur region on five semi-serial sections, spaced 140 μm apart. Scoring was performed on decoded slides by two separate observers, using the following parameters. In the haematoxylin/eosin stained slides the amount of cells infiltrating the synovial lining and the joint cavity was scored from 0 to 3. Proteoglycan depletion was scored in the safranin O stained slides on a scale from 0 to 3 (ranging from stained cartilage to fully destained cartilage). Cartilage damage was scored from 0 to 3 (ranging from unaffected cartilage to maximum chondrocyte death and cartilage destruction).
Design of clinical study
This was a randomized, double-blind, placebo-controlled, dose escalation study conducted to explore the safety, tolerability, pharmacokinetics and pharmacodynamics of ACZ885 in patients with active RA, despite ongoing treatment with a stable dose of methotrexate (MTX) of 15 mg/week or more for at least 3 months (CACZ885A2101). It is the first of its kind to be conducted in humans. Patients receiving stable doses of 10 mg/week methotrexate could be included if the patients could not tolerate higher doses.
Included patients were required to have a diagnosis of RA (American College of Rheumatology [ACR] 1987 revised classification for criteria for RA) with a disease duration of at least 6 months before randomization; active disease at screening; baseline evaluation (same evaluator) indicating more than six tender and six swollen joints out of 28 examined (including any effused joint); and either Westergren erythrocyte sedimentation rate of 28 mm/hour or greater, or C-reactive protein (CRP) of at least 6 mg/l. The inclusion criteria also required patients were have failed at least one disease-modifying antirheumatic drug in the past, but not deemed 'refractory to all therapies'. Their current treatment regimen included at least 15 mg methotrexate/week and with the current dose stable for approximately 3 months. Patients were required to have an otherwise stable RA therapeutic regimen, consisting of either a stable dose of nonsteroidal anti-inflammatory drugs and/or a stable dose of oral corticosteroids (prednisone or equivalent < 10 mg/day) for at least 4 weeks before randomization.
This multicentre study was conducted in accordance with GCP (Good Clinical Practice) guidelines and the Helsinki Declaration in three countries in Europe. The study protocol and patient informed consent form was approved by local ethics committees and health authorities. The primary objective was to evaluate the safety and tolerability of ACZ885 administered as an intravenous infusion. Secondary objectives included assessment of the preliminary biologic activity/pharmacodynamics of ACZ885 using ACR criteria for clinical response and Disease Activity Score using 28 joint counts (DAS28), evaluation of the pharmacokinetics of ACZ885 and examination of the potential immunogenicity of ACZ885.
ACR response criteria were evaluated at baseline and on days 8, 15, 22, 29 and 43 by the investigator, and at baseline and day 43 by a blinded observer at each site who was not otherwise involved in the study. Overall, there was no evidence of a systematic bias between the blinded observer and the investigator assessments. Patients were further followed for safety and pharmacokinetic assessments, and a formal end of study was reached at day 113. Investigators were free to change treatment after day 43 as they deemed necessary.
Statistical analyses were performed on the ACR 20%, 50% and 70% response criteria (ACR20, ACR50 and ACR70) rates. Separate statistical analyses were performed on the response rate at day 43 (assessed by a blinded observer) and the response rate up to and including day 43. Fisher's exact test was used to compare treatment groups. From these analyses, one sided P values are presented. The primary comparison was the comparison between the 10 mg/kg treatment group and placebo at day 43. For the DAS28 measurements, a repeated measures mixed effect analysis was performed. Baseline DAS28 was included in the model as a covariate. An unstructured correlation structure was assumed to adjust for correlation within patients. From this model the adjusted mean difference for each treatment group versus placebo at each time point was calculated, along within its 95% confidence interval. No multiplicity adjustments were made to the confidence intervals. A similar analysis was performed on the CRP measurements; however, because of the skewness of the CRP measurements, the analysis was performed on the loge scale and results were back-transformed onto the original scale.
The inclusion of six patients per dose group in each escalation step provided an 80% probability that at least one patient would report an adverse event that has an underlying incidence rate of 24%. With 20 patients receiving the highest ACZ885 dose (six patients in the last escalation step plus 14 patients in the expansion phase) and 15 patients receiving placebo (two patients in each of the four escalation steps plus seven patients in the expansion phase), there was at least 80% power to detect a statistically significant difference in ACR20 response rate comparing ACZ885 with placebo, assuming an underlying odds ratio of 6, a 5% significance level and a one-side test approach. Given an anticipated placebo ACR20 response rate of 20%, an odds ratio of 6 would translate into an ACR20 response rate of 60% for the ACZ885 treatment group.
ACZ885 is a human antibody that binds to human IL-1β with high affinity and neutralizes human IL-1β in vitro and in vivo
ACZ885 was derived by subjecting genetically engineered mice carrying part of the human immunoglobulin repertoire to immunization with human IL-1β. The antibody was initially identified from a hybridoma derived from these mice because of its ability to bind human IL-1β with high affinity (about 40 pmol/l). No cross-reactivity toward rodent IL-1β or human IL-1α was observed for ACZ885. The antibody was found to neutralize the bioactivity of human IL-1β on primary human fibroblasts in vitro with an 50% inhibitory concentration of 44.6 pmol/l (7.1 ± 0.56 ng/ml; n = 6).
Proof-of-concept clinical trial in patients with RA
Baseline demographics of participating patients
0.3 mg/kg (n = 6)
1.0 mg/kg (n = 6)
3.0 mg/kg (n = 6)
mg/kg (n = 20)
Placebo (n = 15)
Age (years; mean ± SD)
61 ± 7
53 ± 14
57 ± 7
50 ± 11
55 ± 10
hsCRP (mg/l; median [range])
DAS28 (mean ± SD)
6.5 ± 0.8
6.6 ± 1.2
6.7 ± 1.5
6.2 ± 0.7
6.7 ± 0.6
Number of tender joints (mean ± SD)
17 ± 9.2
15 ± 6.2
22 ± 8.5
17 ± 7.3
20 ± 6.3
Number of swollen joints (mean ± SD)
13 ± 6.3
12 ± 4.3
12 ± 7.4
11 ± 4.8
12 ± 5.2
Methotrexate dose (n/mg median [range])a
Clinical improvement as assessed by ACR criteria
Assessor (time point)
Placebo (n = 15)
P value (10 mg/kg versus placebo)
0.3 mg/kg (n = 6)
1.0 mg/kg (n = 6)
3.0 mg/kg (n = 6)
10 mg/kg (n = 19/20a)
Blinded observer (day 43)
Investigator (any time within 6 weeks of treatment start)
Relationship between CRP reduction and ACR response following ACZ885 treatment
CRP reduction at day 43 versus baseline
ACR response at day 43
20% to <50%
50% or more
10 mg/kg ACZ885
20 to <50%
50% or more
20 – <50%
50% or more
The serum concentrations of ACZ885 were determined in each dose group. The maximal concentration rose in a dose-proportional manner and reached a mean peak exposure of 329 μg/ml in the 10 mg/kg group after the second infusion, which decreased to less than 10 μg/ml by day 113. The elimination half-life was similar across all dose levels and averaged 21.5 ± 4.9 days (mean ± standard deviation). Details of exposure and its relationship to pharmacodynamic activities of ACZ885 will be reported elsewhere.
Safety and tolerability
During the study five serious adverse events leading to hospitalization were identified. Among them, two events in the 10 mg/kg dose group (fracture of the left trochanter major after a bicycle fall and one case of tracheobronchitis) and one in the 0.3 mg/kg group (potential recurrence of angina pectoris) were considered not to be related to the study medication. Two episodes identified in the 1 mg/kg dose group (one case of erysipelas and one case of pulmonary infection) were considered to be related to study medication. All patients with infectious events were treated with antibiotics and recovered fully within the expected time frame. None of the patients prematurely discontinued treatment because of adverse events. There were no infusion-related adverse events; in particular, no anaphylactic or anaphylactoid reactions were reported. Serum samples were tested for the presence of anti-ACZ885 antibodies at baseline, on days 43 and 71, and at the end of the study (day 113). No formation of anti-ACZ885 antibodies was detected at any time point during the study.
The overall adverse event profile was almost the same for active and placebo treatment. Headache was reported less frequently with ACZ885 treatment (28.9% versus 46.7% for placebo), and urinary tract infection was reported frequently often with ACZ885 (21% versus 6.7% for placebo). Overall, intravenous administration of ACZ885 up to 10 mg/kg given twice with 14 days between dosing was found to be well tolerated without evidence of immunogenicity.
ACZ885, a novel human monoclonal antibody directed against human IL-1β, was found to be highly active in inhibiting IL-1β mediated arthritis in a preclinical animal model. The low ED50 observed in this model of aggressive inflammation is remarkable, because the injected recombinant cells constitutively secrete human IL-1β without any physiological feedback control. These results prompted us to study ACZ885 in a dose-escalating, proof-of-concept study in patients with RA – the first of its kind in humans. The study's primary objective was to investigate safety and tolerability; therefore, it was not powered to investigate efficacy or to draw firm conclusions regarding superiority or inferiority to treatment with anakinra or TNF blockers in RA. The small sample size of 38 patients treated with various doses of ACZ885 and 15 patients on placebo does not allow any definitive conclusion about safety to be drawn. Whether an increase in infectious episodes under ACZ885 represents an early sign of the consequences of blocking IL-1 – similar to observations with anakinra  – needs confirmation, and careful monitoring in upcoming larger studies is required. Immunogenicity and infusion-associated events were not observed with two intravenous administrations.
The study provides evidence of a treatment effect by demonstrating that 50% of patients achieved an ACR20 response up to day 43 in the highest tested dose of 10 mg/kg intravenous, along with a robust reduction in serum CRP. No firm conclusion regarding any dose-response relation can be drawn, because of the small sample size (n = 6) of the cohorts treated with 0.3, 1, and 3 mg/kg ACZ885. The onset of action in those who responded was found to be rapid. The majority of these responders satisfied the EULAR criteria for moderate or good response or ACR20 response criteria within 3 weeks. Similar to experience with other biologics for the treatment of RA patients, there was a subset of patients who did not respond to treatment. On the other hand, some patients achieved an ACR50 or even ACR70 response within a short period of treatment. This observation reflects the common understanding that RA represents a heterogeneous disease and that, even by applying strict inclusion criteria, the studied disease in clinical trials is not homogenous. Therefore, a better understanding of the pathophysiology on an individual basis is required if we are to better predict the response to a certain treatment and hence avoid treatment failures. Consequently, there is a need to establish biomarkers that have high predictive value; recent progress has been made for TNF blockers [22, 23].
In the current study, CRP reduction was found to be necessary for achievment of clinical response, as expected, but it was not sufficient to explain or even predict clinical response, because CRP reduction was also observed in the absence of clinical response. Therefore, CRP reduction during treatment does not serve as a predictive biomarker for clinical responses at the individual level. Furthermore, levels of serum IL-6, TNF-α and IL-1Ra levels (as measured by enzyme-linked immunosorbent assay) were within the normal range in these patients and exhibited no conclusive changes during the course of the study (data not shown). At baseline, total IL-1β levels in serum were at or below the detection limit of the assay (about 1 pg/ml) and showed no difference between responders and nonresponders, indicating that baseline serum levels of these cytokines are of poor predictive value to identify treatment responders.
Almost all rheumatologists prefer to administer a TNF blocker rather than anakinra as a first biologic agent to treat RA patients, concordant with a recent consensus statement, and national and international registries . Treatment with recombinant IL-1Ra (anakinra) has been shown to be effective in RA , but its efficacy appears to be lower than that of TNF-α inhibitors  and its administration is frequently associated with injection-related adverse events. Whether anakinra's lower efficacy is due to an inferior biologic role of IL-1 as compared with TNF-α in the pathogenesis of RA or is simply due to the fact that anakinra cannot fully neutralize IL-1 is currently unclear. ACZ885 can completely neutralize IL-1β over a long period of time; it therefore offers an opportunity to study the relative biological role of IL-1β in the pathogenesis of RA. Further and larger studies will determine the efficacy of ACZ885 in treating signs and symptoms in patients with RA, and they may allow comparison with the efficacies of other biologic agents.
ACZ885 was found to inhibit IL-1β mediated joint inflammation in preclinical models. It was well tolerated in this first proof-of-concept study in RA patients and was associated with a significant treatment effect in about 50% of patients. Further studies are warranted to confirm these initial results, to establish a safety profile, to identify those patients who will profit most from blocking IL-1β, and to better understand the biological role played by IL-1β in the pathogenesis of RA.
= American College of Rheumatology
= C-reactive protein
= Disease Activity Score using 28 joint counts
= dose effective to achieve a mean of 50% improvement
= European League Against Rheumatism
= IL-1 receptor antagonist
= rheumatoid arthritis
= tumour necrosis factor.
The contributions of C Gabay (Geneva), P Villiger (Bern), D Uebelhart (Zuerich), H Dammann (Hamburg), S Schewe (Muenchen), Wseidel (Leipzig), A Perniok (Cologne) and FC Breedveld (Leiden) as further investigators in the clinical trial are highly appreciated.
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