Anti-drug Antibodies Positive Patients Research Articles

Furthering the clinical development of navicixizumab in advanced epithelial ovarian cancer patients with a population pharmacokinetic model and exploratory exposure-safety-efficacy response analyses (225)

Objectives: Cumulative data from navicixizumab clinical trials were analyzed to establish a population pharmacokinetic model, which was further used to characterize the relationships of navicixizumab exposure with safety and efficacy parameters. Methods: A population pharmacokinetic model was developed using data from clinical trials with navicixizumab in advanced cancer patients (B83-001), in combination with paclitaxel in advanced ovarian cancer patients (B83-002) and combination with standard of care in colorectal cancer patients (B83-003). Exposure-safety analyses focused on the relationship between navicixizumab exposures and systemic hypertension as measured with mean arterial pressure data and incidence of pulmonary hypertension assessed using peak tricuspid velocity data. For the purposes of this analysis, pulmonary hypertension was defined as peak tricuspid velocities >3.4 m/s. Exposure-efficacy analyses focused on objective response rates collected using RECIST version 1.1 and sum of the longest diameters of the target lesion. Results: The overall pharmacokinetic profile of navicixizumab was best described by a 2-compartment model with dose-proportional pharmacokinetics observed at doses ≥ 2.5 mg/kg. The effects of patient weight and patient antidrug antibody (ADA) status were identified as significant covariates in the model, where ADA positivity was associated with reduced clearance values. Changes in mean arterial pressure were concentration-dependent, where both Stage III/IV and ADA positive patients had lesser changes in mean arterial pressures. While peak tricuspid velocities were not related to navicixizumab concentrations, dose, disease stage, or disease indication, pulmonary hypertension was observed as being related to cumulative navicixizumab exposures as measured by AUC and total dose. Navicixizumab exposures were not significantly related to objective response rates. Ovarian stage III/IV cancer patients demonstrated a significant relationship between higher exposure and significantly greater reductions in target tumor size. Conclusions: A robust pharmacokinetic model was developed, demonstrating linear navicixizumab pharmacokinetics at doses ≥ 2.5 mg/kg. While the impact of ADA on navicixizumab clearance was statistically significant, the impact at therapeutically relevant doses was not clinically meaningful. Changes in mean arterial pressures with navicixizumab concentrations support a favorable adverse event profile in the ovarian patient population, while cumulative dose and exposures are associated with peak tricuspid velocities ≥ 3.4 m/s. When both ORR and changes in target tumor size were considered, cumulative navicixizumab exposures were associated with increased efficacy in ovarian cancer patients. Cumulative data reported herein support continued clinical development of navicixizumab, especially in ovarian cancer patients. Objectives: Cumulative data from navicixizumab clinical trials were analyzed to establish a population pharmacokinetic model, which was further used to characterize the relationships of navicixizumab exposure with safety and efficacy parameters. Methods: A population pharmacokinetic model was developed using data from clinical trials with navicixizumab in advanced cancer patients (B83-001), in combination with paclitaxel in advanced ovarian cancer patients (B83-002) and combination with standard of care in colorectal cancer patients (B83-003). Exposure-safety analyses focused on the relationship between navicixizumab exposures and systemic hypertension as measured with mean arterial pressure data and incidence of pulmonary hypertension assessed using peak tricuspid velocity data. For the purposes of this analysis, pulmonary hypertension was defined as peak tricuspid velocities >3.4 m/s. Exposure-efficacy analyses focused on objective response rates collected using RECIST version 1.1 and sum of the longest diameters of the target lesion. Results: The overall pharmacokinetic profile of navicixizumab was best described by a 2-compartment model with dose-proportional pharmacokinetics observed at doses ≥ 2.5 mg/kg. The effects of patient weight and patient antidrug antibody (ADA) status were identified as significant covariates in the model, where ADA positivity was associated with reduced clearance values. Changes in mean arterial pressure were concentration-dependent, where both Stage III/IV and ADA positive patients had lesser changes in mean arterial pressures. While peak tricuspid velocities were not related to navicixizumab concentrations, dose, disease stage, or disease indication, pulmonary hypertension was observed as being related to cumulative navicixizumab exposures as measured by AUC and total dose. Navicixizumab exposures were not significantly related to objective response rates. Ovarian stage III/IV cancer patients demonstrated a significant relationship between higher exposure and significantly greater reductions in target tumor size. Conclusions: A robust pharmacokinetic model was developed, demonstrating linear navicixizumab pharmacokinetics at doses ≥ 2.5 mg/kg. While the impact of ADA on navicixizumab clearance was statistically significant, the impact at therapeutically relevant doses was not clinically meaningful. Changes in mean arterial pressures with navicixizumab concentrations support a favorable adverse event profile in the ovarian patient population, while cumulative dose and exposures are associated with peak tricuspid velocities ≥ 3.4 m/s. When both ORR and changes in target tumor size were considered, cumulative navicixizumab exposures were associated with increased efficacy in ovarian cancer patients. Cumulative data reported herein support continued clinical development of navicixizumab, especially in ovarian cancer patients.

P243 Anti-rituximab antibodies demonstrate neutralising capacity, associate with lower circulating drug levels and early relapse in patients undergoing treatment for systemic lupus erythematosus

Abstract Background/Aims A major limitation of biologic therapy is formation of anti-drug antibodies (ADA). We previously demonstrated that ADA to rituximab are more prevalent in patients undergoing treatment for systemic lupus erythematosus (SLE) than rheumatoid arthritis and vasculitis, and predict subsequent infusion reactions. However, little is known regarding the long-term dynamics of ADA to rituximab. In this study we evaluated the longitudinal impact of ADA positivity in terms of drug kinetics, treatment response and neutralising capacity in SLE. Methods Patients with SLE undergoing treatment with rituximab were recruited to this study (n = 35). Serum samples were collected at the following intervals post-treatment; 1-3 months, 6 months, 12 months, 36 months (n = 114). Clinical and laboratory data was collected pre-treatment and at each time point. ADA were detected using an electrochemiluminescent immunoassay. Serum rituximab levels were measured via ELISA. A complement dependent cytotoxic assay was used to determine neutralising capability of ADA in a subgroup of positive samples (n = 38). Results ADA were found to be persistently positive over the 36-month follow-up period in 64.3% of patients. There was no significant difference in baseline disease activity (BILAG / SLEDAI-2K) between those who were subsequently ADA positive vs negative. ADA positive patients were younger at diagnosis compared with ADA negative (mean 22.50 ± 9.10 vs 37.29 ± 11.31 years, p = 0.002). Multivariate logistic regression found older age at diagnosis was associated with reduced incidence of persistent ADA with a 22% decrease in risk for each addition year after diagnosis (p = 0.03). ADA positive patients had a significantly lower C3 level at baseline (mean 0.61 ± 0.23 vs 0.87 ± 0.30, p = 0.026), which remained lower at each subsequent time point post-treatment up to 12 months. ADA titres peaked earlier and remained higher in those who had been treated with rituximab previously compared with those who were rituximab naive (median 132 AU/ml vs 7 AU/ml at 1-3 months). At 6 months post-treatment, patients with detectable ADA had a significantly lower circulating drug level than ADA negative (p = 0.0018). In terms of clinical response, ADA positive patients had an initial significant improvement in disease activity (SLEDAI-2K) by 3 months (p < 0.001). However, response was not maintained at 12 months. In comparison, ADA-negative patients showed a significant improvement in SLEDAI-2K at 6 months and this was maintained across the 36-month follow-up period. BILAG defined relapse within 12 months of treatment was only seen in ADA positive patients. Finally, all ADA positive samples were found to neutralise rituximab in vitro. Conclusion ADA to rituximab were common and persisted over the 36 month period of this study. ADA associated with earlier drug elimination, increased relapse rates and demonstrated neutralising capacity suggesting that ADA could be a significant limitation to sustained response to treatment. Disclosure C. Wincup: Grants/research support; Lupus UK, Versus Arthritis, British Society for Rheumatology. N. Dunn: None. C. Ruetsch-Chelli: None. A. Manouchehrinia: None. N. Kharlamova: None. M. Naja: None. B. Seitz-Polski: None. D. Isenberg: None. A. Fogdell-Hahn: None. C. Ciurtin: None. E. Jury: None.

Interferon-beta specific T cells are associated with the development of neutralizing antibodies in interferon-beta treated multiple sclerosis patients

Beta-interferons are still among the most commonly used drugs to treat Multiple Sclerosis (MS). The use of beta-interferons is limited by the development of anti-drug antibodies (ADA), which may abrogate the treatment effect of the drug. Although the antibody response has been well studied, little is known about the T cell response to interferon-beta (IFN-β). We investigated T cell responses in four treatment naïve MS patients and twenty-three patients treated with IFN-β who had or had not developed ADA to IFN-β. T cell responses were determined by split-well and primary proliferation assays against different IFN-β protein preparations and a set of overlapping peptides covering the full sequence of IFN-β. T cell responses to IFN-β were observed in all donors. ADA positive patients showed higher T cell responses to IFN-β protein than ADA negative patients and untreated controls. We identified two immunodominant regions; T cell responses to IFN-β1-40 were observed in all patients independent of ADA status, while T cell responses to IFN-β125-159 were stronger in ADA positive than ADA negative patients. IFN-β specific T cell responses were HLA class II restricted and in ADA positive patients skewed towards a Th2 phenotype. In IFN-β treated patients we observed a correlation between IFN-β specific T cell responses, serum ADA titer and loss of biological activity of IFN-β treatment. Our studies demonstrate the occurrence of an antigen specific HLA class II restricted Th2 T cell response associated with the development of ADA in IFN-β treated patients.

Higher body mass index and anti-drug antibodies predict the discontinuation of anti-TNF agents in Korean patients with axial spondyloarthritis

ObjectiveThe development of anti-drug antibodies against tumor necrosis factor inhibitors is a likely explanation for the failure of TNF-inhibitors in patients with spondyloarthritis. Our study determined the existence and clinical implications of ADAbs in axial spondyloarthritis patients. MethodsAccording to the Assessment of SpondyloArthritis International Society classification criteria for axial spondyloarthritis, patients treated with adalimumab or infliximab were recruited consecutively. Serum samples were collected at enrollment to measure anti-drug antibodies and drug levels. ResultsOf 100 patients, the mean duration of current TNF inhibitor use was 22.3±17.9 months. Anti-drug antibodies were detected in 5 of 72 adalimumab users compared to 5 of 28 infliximab users (6.9% vs. 17.9%). Anti-drug antibodies-positive patients had a significantly higher body mass index than anti-drug antibodies-negative patients among both adalimumab (28.4±5.9kg/m2 vs. 24.3±2.9kg/m2, respectively, p=0.01) and infliximab users (25.9±2.8kg/m2 vs. 22.6±2.8kg/m2, respectively, p=0.02). During the median 15-month follow-up period, drug discontinuation occurred more frequently in the anti-drug antibodies-positive group than the anti-drug antibodies-negative group (30.0% vs. 6.5%, respectively, p=0.04). In logistic regression, anti-drug antibodies positivity (OR=5.85, 95% CI 1.19–28.61, p=0.029) and body mass index (OR=4.35, 95% CI 1.01–18.69, p=0.048) were associated with a greater risk of stopping TNF inhibitor treatment. ConclusionsOur result suggests that the presence of anti-drug antibodies against adalimumab and infliximab as well as a higher body mass index can predict subsequent drug discontinuation in axial spondyloarthritis patients.

Immunogenicity and Lupus-Like Autoantibody Production Can Be Linked to Each Other along With Type I Interferon Production in Patients with Rheumatoid Arthritis Treated With Infliximab: A Retrospective Study of a Single Center Cohort.

Besides anti-drug antibodies, anti-nuclear antibodies and anti-DNA antibodies are often induced in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors. We examined the association between immunogenicity, autoantibody production, and serum cytokine profiles in patients with rheumatoid arthritis treated with infliximab. Japanese patients with rheumatoid arthritis (n = 57) were retrospectively examined. Serum trough levels of infliximab, anti-drug antibody, anti-nuclear antibody, and anti-DNA (Farr), anti-single-stranded DNA and anti-double-stranded DNA antibodies were measured. Interleukin-6, interferon-γ, interferon-α, and B-cell activating factor levels were also measured in the same sera. Then, we validated the association between anti-drug antibody and these serum markers along with clinical response to infliximab. Anti-drug antibodies developed in twenty-one patients (36.8%), whose serum trough levels of infliximab were significantly lower than those in anti-drug antibody-negative patients (0.09 ± 0.03 vs. 2.48 ± 0.326 μg/mL, p < 0.0001). There were no significant differences in clinical backgrounds between the two groups. The anti-drug antibody-positive patients were more likely to develop anti-nuclear antibody titers of ≥ ×160 compared to the negative patients (14 to 57% vs. 17 to 33%). In addition, anti-DNA antibodies (Farr) (from 1.5 ± 0.4 to 35 ± 17 IU/mL, p = 0.0001), especially IgM-anti-double stranded DNA antibody (from 5.1 ± 0.7 to 41 ± 8.9 IU/mL, p < 0.0001), and IgG-anti-single stranded DNA antibody (from 13 ± 1.1 to 35 ± 13, p = 0.0145) were significantly increased in anti-drug antibody-positive but not in negative patients. Moreover, the anti-drug antibody-positive, but not the negative patients, showed significant increased levels of interferon-α (from 248.7 ± 102.3 to 466.8 ± 135.1 pg/mL, p = 0.0353) and B-cell activating factor (from 1073 ± 75.1 to 1387 ± 136.5 pg/mL, p = 0.0208) following infliximab treatment. The development of anti-drug antibody against infliximab and lupus-like autoantibody production in patients with rheumatoid arthritis treated with infliximab can be linked each other along with increased lupus-associated cytokine levels including type I interferons.

THU0158 Inhibition of Radiographic Progression and Its Association with Clinical Parameters in RA Patients Treated with CT-P13 and Innovator Infliximab in PLANETRA Study

BackgroundCT-P13 is a biosimilar of innovator infliximab (INX), approved by the European Medicines Agency in 2013. Clinical data up to 1 year from PLANETRA have been reported at EULAR 20131ObjectivesTo...

OP0157 Clinical Response of Disease Activity, Disability and Mobility Indices in Relation to Anti-Drug Antibody in the Planetas

BackgroundRecently, the European Medicines Agency approved a biosimilar to infliximab, CT-P13. Biosimilars are not only required to have biochemical and pharmacokinetics (PK) equivalence, but also must demonstrate similarity in their...

Drug levels, anti-drug antibodies, and clinical efficacy of the anti-TNFα biologics in rheumatic diseases

The objectives of this study are to evaluate the effect of anti-drug antibodies on the clinical efficacy and withdrawal rate of the anti-TNFα biologics in patients with rheumatic diseases. Consecutive patients with rheumatic diseases recently commenced on anti-TNFα biologics were recruited. Serum samples were collected for assay of drug level and antibody titer against the corresponding biologics. Comparison of the clinical efficacy and drug retention rate was performed between patients with and without anti-drug antibodies. Fifty-eight Chinese patients were studied (64 % women; age 47.8 ± 12.9 years; disease duration 6.7 ± 6.4 years). The proportion of patients using infliximab (IFX), adalimumab (ADA), and etanercept (ETN) was 41, 28, and 31 %, respectively. Antibodies against IFX, ADA, and ETN were demonstrated in 12(50 %), 5(31 %) and 0(0 %) patients, respectively. Patients who developed anti-drug antibodies had significantly lower levels of the corresponding drugs (IFX level: 0.004 ± 0.01 vs 3.81 ± 3.49 μg/ml; p = 0.002; ADA level: 0.0 vs 7.6 ± 8.3 μg/ml; p = 0.008). Anti-drug antibody-positive patients had a significantly higher cumulative drug withdrawal rate due to inefficacy (64.7 and 71.8 % vs 10.3 and 10.3 % at month 12 and month 24, respectively; p < 0.001). In rheumatoid arthritis and psoriatic arthritis, non-responders was significantly more frequent in antibody-positive patients (54 vs 13 %; p = 0.01). In spondyloarthritis, the improvement in ankylosing spondylitis disease activity score was significant in patients without antibodies (3.89 ± 0.82 to 2.22 ± 0.86; p = 0.01) but not in those with anti-drug antibodies (3.40 ± 1.67 to 3.23 ± 1.40; p = 0.73). We concluded that the presence of neutralizing antibodies is associated with lower serum levels of the anti-TNFα biologics, leading to lower efficacy and higher withdrawal rate.

THU0171 Influence of Immunogenicity of Anti-TNF Therapy in RA Patients with a Long-Term Treatment with Infliximab or Adalimumab

BackgroundThe anti-TNF therapy has been a great progress in RA patients treatment. However, a proportion of patients develop primary inefficacy or loss of response, resulting in switching or treatment discontinuation....

FRI0426 Immunogenicity, adalimumab levels and clinical response in ankylosing spondylitis patients during 24 weeks of follow-up.

BackgroundImmunogenicity influences adalimumab levels and therefore clinical response in patients with rheumatic diseases.ObjectivesTo study the relation between clinical response, adalimumab levels and anti-drug antibodies (ADA) in ankylosing spondylitis (AS) patients.MethodsObservational...