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The human anti-IL-1 beta monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis.

Alten R, Gram H, Joosten LA, van den Berg WB, Sieper J, Wassenberg S, Burmester G, van Riel P, Diaz-Lorente M, Bruin GJ, Woodworth TG, Rordorf C, Batard Y, Wright AM, Jung T - Arthritis Res. Ther. (2008)

Bottom Line: A statistically significant reduction in disease activity score was observed after 4 weeks in the 10 mg/kg group.ACZ885 was well tolerated.ACZ885 administration to methotrexate-refractory patients resulted in clinical improvement in a subset of patients.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Internal Medicine II, Rheumatology, Schlosspark-Klinik Teaching Hospital Charité University Medicine Berlin, Heubnerweg, D-14059 Berlin, Germany.

ABSTRACT

Introduction: IL-1beta is a proinflammatory cytokine driving joint inflammation as well as systemic signs of inflammation, such as fever and acute phase protein production.

Methods: ACZ885, a fully human monoclonal antibody that neutralizes the bioactivity of human IL-1beta, was generated to study the potent and long-lasting neutralization of IL-1beta in mechanistic animal models as well as in a proof-of-concept study in patients with rheumatoid arthritis (RA).

Results: The mouse IL-1 receptor cross-reacts with human IL-1beta, and it was demonstrated that ACZ885 can completely suppress IL-1beta-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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov identifier NCT00619905.

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Related in: MedlinePlus

Blocking of IL-1 in mouse models of arthritis. (a) Inhibition of swelling. Mice were given different doses of ACZ885 or a control anti-CD25 antibody (CHI621, 12 mg/kg) intraperitoneally before injection of 10,000 3T3-huIL-1β cells into the right hind knee joint. Swelling was measured 3 days after cell injection (as described in Materials and methods) and is expressed as the ratio between the right (treated) and left (untreated) joint. The results presented represent the mean ± standard error or the mean (SEM; n = 5). **P < 0.01 by analysis of variance followed by Dunnett's test for multiple comparisons post hoc. NS, not significant. (b) Proteoglycan (PG) synthesis by chondrocytes in explanted patellae was measured by incorporation of 35S labelled sulphate in isolated cartilage from treated (right) and untreated (left) knee joints. The results are given as the ratio of 35S incorporation between right and left knee cartilage and represent the mean ± SEM (n = 5). Statistical analysis of the treated groups versus the control group (CHI621) was performed by analysis of variance followed by Dunnett's test for multiple comparisons post hoc. *P < 0.05; **P < 0.01. ED50, dose needed to achieve a mean of 50% effect. (c) Histology was analyzed at day 3 after local injection of 3T3-hIL-1β producing cells. Section of a mouse knee joint treated with isotype control antibody or AC885 are shown. Hematoxylin and eosin staining, original magnification (200×). Quantitative evaluation of the slides was done as described in Materials and methods and is presented in the graph. n = 5 joints per group; all comparisons between active and control were significant (P < 0.05, Mann-Whitney U-test).
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Figure 2: Blocking of IL-1 in mouse models of arthritis. (a) Inhibition of swelling. Mice were given different doses of ACZ885 or a control anti-CD25 antibody (CHI621, 12 mg/kg) intraperitoneally before injection of 10,000 3T3-huIL-1β cells into the right hind knee joint. Swelling was measured 3 days after cell injection (as described in Materials and methods) and is expressed as the ratio between the right (treated) and left (untreated) joint. The results presented represent the mean ± standard error or the mean (SEM; n = 5). **P < 0.01 by analysis of variance followed by Dunnett's test for multiple comparisons post hoc. NS, not significant. (b) Proteoglycan (PG) synthesis by chondrocytes in explanted patellae was measured by incorporation of 35S labelled sulphate in isolated cartilage from treated (right) and untreated (left) knee joints. The results are given as the ratio of 35S incorporation between right and left knee cartilage and represent the mean ± SEM (n = 5). Statistical analysis of the treated groups versus the control group (CHI621) was performed by analysis of variance followed by Dunnett's test for multiple comparisons post hoc. *P < 0.05; **P < 0.01. ED50, dose needed to achieve a mean of 50% effect. (c) Histology was analyzed at day 3 after local injection of 3T3-hIL-1β producing cells. Section of a mouse knee joint treated with isotype control antibody or AC885 are shown. Hematoxylin and eosin staining, original magnification (200×). Quantitative evaluation of the slides was done as described in Materials and methods and is presented in the graph. n = 5 joints per group; all comparisons between active and control were significant (P < 0.05, Mann-Whitney U-test).

Mentions: IL-1β requires highly potent antagonists in large excess to neutralize its biological activity in vivo. Anti-cytokine antibodies with low neutralizing capacity can potentially lead to enhanced bioactivity of the targeted cytokine by prolonging its half-life in vivo [19]. In light of this potential complication, we considered demonstration that ACZ885 is devoid of any biologically relevant carrier effect in an in vivo model to be an important prerequisite for conducting clinical trials. Therefore, we created an artificial mouse model of joint inflammation that relies upon continuous secretion of human IL-1β by transfected mouse NIH3T3 cells injected into one knee joint. Whereas IL-1β driven inflammation becomes apparent after 24 hours and leads to total destruction of the joint within 7 to 10 days, controlateral joints or joints receiving control 3T3 cells do not exhibit signs of inflammation. Application of ACZ885 intraperitoneally 2 hours before injecting the IL-1β producing cells completely suppressed joint swelling, with a 50% effective dose (the dose effective to reduce inflammation by a mean of 50%; ED50) of 0.06 mg/kg (Figure 2a). Also, treatment with ACZ885 restored the ability of cartilage explants to synthesize proteoglycan, which is otherwise suppressed in IL-1β exposed cartilage (Figure 2b). In addition, histopathology taken at day 3 after injection of 3T3-hIL-1β cells revealed that administration of AC885 protected against severe joint destruction (Figure 2c). Apart from the strong reduction of the joint inflammation (numbers of cells in the synovial tissues), no bone erosion was noted in the AC885 treated animals compared with controls. Thus, ACZ885 has sufficient potency to neutralize fully the biological activity of human IL-1β, even when it is produced at high concentrations in vivo, and it does not significantly prolong IL-1 activity.


The human anti-IL-1 beta monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis.

Alten R, Gram H, Joosten LA, van den Berg WB, Sieper J, Wassenberg S, Burmester G, van Riel P, Diaz-Lorente M, Bruin GJ, Woodworth TG, Rordorf C, Batard Y, Wright AM, Jung T - Arthritis Res. Ther. (2008)

Blocking of IL-1 in mouse models of arthritis. (a) Inhibition of swelling. Mice were given different doses of ACZ885 or a control anti-CD25 antibody (CHI621, 12 mg/kg) intraperitoneally before injection of 10,000 3T3-huIL-1β cells into the right hind knee joint. Swelling was measured 3 days after cell injection (as described in Materials and methods) and is expressed as the ratio between the right (treated) and left (untreated) joint. The results presented represent the mean ± standard error or the mean (SEM; n = 5). **P < 0.01 by analysis of variance followed by Dunnett's test for multiple comparisons post hoc. NS, not significant. (b) Proteoglycan (PG) synthesis by chondrocytes in explanted patellae was measured by incorporation of 35S labelled sulphate in isolated cartilage from treated (right) and untreated (left) knee joints. The results are given as the ratio of 35S incorporation between right and left knee cartilage and represent the mean ± SEM (n = 5). Statistical analysis of the treated groups versus the control group (CHI621) was performed by analysis of variance followed by Dunnett's test for multiple comparisons post hoc. *P < 0.05; **P < 0.01. ED50, dose needed to achieve a mean of 50% effect. (c) Histology was analyzed at day 3 after local injection of 3T3-hIL-1β producing cells. Section of a mouse knee joint treated with isotype control antibody or AC885 are shown. Hematoxylin and eosin staining, original magnification (200×). Quantitative evaluation of the slides was done as described in Materials and methods and is presented in the graph. n = 5 joints per group; all comparisons between active and control were significant (P < 0.05, Mann-Whitney U-test).
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Related In: Results  -  Collection

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Figure 2: Blocking of IL-1 in mouse models of arthritis. (a) Inhibition of swelling. Mice were given different doses of ACZ885 or a control anti-CD25 antibody (CHI621, 12 mg/kg) intraperitoneally before injection of 10,000 3T3-huIL-1β cells into the right hind knee joint. Swelling was measured 3 days after cell injection (as described in Materials and methods) and is expressed as the ratio between the right (treated) and left (untreated) joint. The results presented represent the mean ± standard error or the mean (SEM; n = 5). **P < 0.01 by analysis of variance followed by Dunnett's test for multiple comparisons post hoc. NS, not significant. (b) Proteoglycan (PG) synthesis by chondrocytes in explanted patellae was measured by incorporation of 35S labelled sulphate in isolated cartilage from treated (right) and untreated (left) knee joints. The results are given as the ratio of 35S incorporation between right and left knee cartilage and represent the mean ± SEM (n = 5). Statistical analysis of the treated groups versus the control group (CHI621) was performed by analysis of variance followed by Dunnett's test for multiple comparisons post hoc. *P < 0.05; **P < 0.01. ED50, dose needed to achieve a mean of 50% effect. (c) Histology was analyzed at day 3 after local injection of 3T3-hIL-1β producing cells. Section of a mouse knee joint treated with isotype control antibody or AC885 are shown. Hematoxylin and eosin staining, original magnification (200×). Quantitative evaluation of the slides was done as described in Materials and methods and is presented in the graph. n = 5 joints per group; all comparisons between active and control were significant (P < 0.05, Mann-Whitney U-test).
Mentions: IL-1β requires highly potent antagonists in large excess to neutralize its biological activity in vivo. Anti-cytokine antibodies with low neutralizing capacity can potentially lead to enhanced bioactivity of the targeted cytokine by prolonging its half-life in vivo [19]. In light of this potential complication, we considered demonstration that ACZ885 is devoid of any biologically relevant carrier effect in an in vivo model to be an important prerequisite for conducting clinical trials. Therefore, we created an artificial mouse model of joint inflammation that relies upon continuous secretion of human IL-1β by transfected mouse NIH3T3 cells injected into one knee joint. Whereas IL-1β driven inflammation becomes apparent after 24 hours and leads to total destruction of the joint within 7 to 10 days, controlateral joints or joints receiving control 3T3 cells do not exhibit signs of inflammation. Application of ACZ885 intraperitoneally 2 hours before injecting the IL-1β producing cells completely suppressed joint swelling, with a 50% effective dose (the dose effective to reduce inflammation by a mean of 50%; ED50) of 0.06 mg/kg (Figure 2a). Also, treatment with ACZ885 restored the ability of cartilage explants to synthesize proteoglycan, which is otherwise suppressed in IL-1β exposed cartilage (Figure 2b). In addition, histopathology taken at day 3 after injection of 3T3-hIL-1β cells revealed that administration of AC885 protected against severe joint destruction (Figure 2c). Apart from the strong reduction of the joint inflammation (numbers of cells in the synovial tissues), no bone erosion was noted in the AC885 treated animals compared with controls. Thus, ACZ885 has sufficient potency to neutralize fully the biological activity of human IL-1β, even when it is produced at high concentrations in vivo, and it does not significantly prolong IL-1 activity.

Bottom Line: A statistically significant reduction in disease activity score was observed after 4 weeks in the 10 mg/kg group.ACZ885 was well tolerated.ACZ885 administration to methotrexate-refractory patients resulted in clinical improvement in a subset of patients.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Internal Medicine II, Rheumatology, Schlosspark-Klinik Teaching Hospital Charité University Medicine Berlin, Heubnerweg, D-14059 Berlin, Germany.

ABSTRACT

Introduction: IL-1beta is a proinflammatory cytokine driving joint inflammation as well as systemic signs of inflammation, such as fever and acute phase protein production.

Methods: ACZ885, a fully human monoclonal antibody that neutralizes the bioactivity of human IL-1beta, was generated to study the potent and long-lasting neutralization of IL-1beta in mechanistic animal models as well as in a proof-of-concept study in patients with rheumatoid arthritis (RA).

Results: The mouse IL-1 receptor cross-reacts with human IL-1beta, and it was demonstrated that ACZ885 can completely suppress IL-1beta-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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov identifier NCT00619905.

Show MeSH
Related in: MedlinePlus