SwePub - search: WFRF:(Dunn Nicky)

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1.	Dunn, Nicky (author) Immunogenicity of biological therapies : frequency, predictability and clinical relevance in chronic inflammatory diseases 2021 Doctoral thesis (other academic/artistic)abstract Over the past three decades, biologic therapies have revolutionised the treatment of chronic inflammatory diseases such as multiple sclerosis (MS), systemic lupus erythematosus (SLE), and anti-neutrophil cytoplasmic antibody (AAV)-associated vasculitis (AAV) and for many, are now a core component of management. However, unlike chemically synthesised smallmolecule drugs, biologicals are larger and are produced using complex processes in or from living organisms, resulting in a propensity to stimulate an unwanted immune response to itself or related proteins. Immunogenicity of biologicals can lead to the formation of antidrug antibodies (ADAs), which can potentially inhibit the biological activity of a treatment and impair its safety and efficacy. Since the early stages of development, immunogenicity of biological therapies has been recognised as a potential limitation to their use, and progression towards the use of more humanised biological therapies over the years has aimed to minimise this issue. However, despite these developments and their improvements to effector functions and tolerability, immunogenicity has not been mitigated and, in some cases, has worsened. Immunogenicity testing is a required safety component of clinical trials; however, these results often do not accurately reflect the real-world setting and can fail to elucidate the less overt, rare and long-term implications of ADAs. Moreover, in several countries, biological therapies are used as an off-label therapy for some disease indications. Variation in the development and relevance of ADA between treatments and diseases limits the ability to extrapolate data to off-label indications. Therefore, further real-world studies are required to ascertain the extent and significance of this issue. The objective of this thesis was to investigate the frequency, predictability and clinical implications of ADA to rituximab, an anti-CD20 chimeric monoclonal antibody (mAb) in patients with MS, SLE and AAV, as well as the long-term effects of neutralising antibodies (NAbs) to interferon beta (IFNβ), a recombinant therapeutic protein, in patients with MS. Paper I was a prospective cross-sectional study investigating the frequency and possible clinical implications of ADAs to rituximab in 339 treated patients with MS. ADA status and titre were determined using an in-house validated bridging electrochemiluminescence (ECL) immunoassay, and the results were compared with a commercial enzyme-linked immunosorbent assay (ELISA) kit. The ELISA was found to be less sensitive than the ECL, with a false-negative rate of 27%. Using the ECL, a high frequency of ADAs were observed with 37% of patients relapsing-remitting MS (RRMS) and 26% of patients with progressive forms of MS, ADA-positive. A strong association was observed with both ADA status and titre and incomplete B cell depletion, indicating an effect of ADAs on the pharmacodynamics of rituximab. No difference was observed in clinical outcomes or safety; however, a trend towards poorer drug survival was noted in patients who were ADA-positive. In paper II, the frequency and risk factors for ADAs to rituximab were explored in 66 patients with SLE and 22 patients with AAV following first rituximab exposure in a mixed retrospective/prospective observational study. ADAs to rituximab were also detected using the in-house validated bridging ECL immunoassay with disease-specific cut-points. Higher rates of ADAs to rituximab were detected in SLE (37.8%) compared with none in AAV patients following first exposure to rituximab. Patients with SLE who developed ADAs were younger and had more active disease clinically and serologically at baseline. Following rituximab re-treatment, ADA positivity was associated with higher B cell counts and immediate infusion reactions. Paper III was a single-centre retrospective study that aimed to build on the findings of paper II, evaluating the presence and dynamics of persistent ADAs over time, their association with circulating rituximab level, and clinical implications of ADAs to rituximab. In this study, 35 rituximab-treated SLE patients, with 114 sera samples taken at specific time points between 1 month and 3 years post rituximab treatment cycle(s), were included. SLE was associated with a high rate of persistent ADAs to rituximab (64.3%). ADA titres tended to be higher earlier after re-treatment with rituximab compared to first exposure. Both persistence and titre of ADAs were associated with lower drug levels. Moreover, we confirmed in vitro that these antibodies can have neutralising capacity. Persistently positive patients appeared to have poorer clinical outcomes after re-treatment however, larger studies are required to clearly elucidate this. Together with results from paper II, these results support the use of routine testing in SLE patients prior to re-treatment with rituximab. In paper IV, the long-term implications of high-titre NAbs to IFNβ were investigated in a observational cohort study including 3104 patients with MS patients with just under 20,000 years of follow up data from the Swedish MS registry. Patients with high-titre NAbs to IFNβ had higher disease activity at baseline, which when adjusting for this, was observed to persist both during IFNβ treatment and after treatment change. These results suggest the impact of high-titre NAbs on IFNβ treatment effectiveness may lead to persistently higher disease activity, which is not entirely mitigated by subsequent treatments. In patients who are more susceptible to developing high-titre NAbs, these results may support the use of a more efficacious treatment earlier to prevent these potential complications. In conclusion, the included papers contribute towards our understanding of the short- and long-term implications of the immunogenicity of rituximab and IFNβ, aiming to support bestpractice decisions surrounding routine testing and clinical management in the studied diseases. Where required, routine testing could ensure that patients exposed to these biological therapies are optimally treated by minimising disease and economic burden due to ineffective treatment, adverse events and disease progression owing to ADAs.
2.	Faustini, Francesca, et al. (author) First exposure to rituximab is associated to high rate of anti-drug antibodies in systemic lupus erythematosus but not in ANCA-associated vasculitis 2021 In: Arthritis Research & Therapy. - : BMC. - 1478-6362. ; 23:1 Journal article (peer-reviewed)abstract Background Anti-drug antibodies (ADAs) can impact on the efficacy and safety of biologicals, today used to treat several chronic inflammatory conditions. Specific patient groups may be more prone to develop ADAs. Rituximab is routinely used for ANCA-associated vasculitis (AAV) and as off-label therapy for systemic lupus erythematosus (SLE), but data on occurrence and predisposing factors to ADAs in these diseases is limited. Objectives To elucidate the rate of occurrence, and risk factors for ADAs against rituximab in SLE and AAV. Methods ADAs were detected using a bridging electrochemiluminescent (ECL) immunoassay in sera from rituximab-naive (AAV; n = 41 and SLE; n = 62) and rituximab-treated (AAV; n = 22 and SLE; n = 66) patients. Clinical data was retrieved from medical records. Disease activity was estimated by the SLE Disease Activity Index-2000 (SLEDAI-2 K) and the Birmingham Vasculitis Activity Score (BVAS). Results After first rituximab cycle, no AAV patients were ADA-positive compared to 37.8% of the SLE patients. Samples were obtained at a median (IQR) time of 5.5 (3.7-7.0) months (AAV), and 6.0 (5.0-7.0) months (SLE). ADA-positive SLE individuals were younger (34.0 (25.9-40.8) vs 44.3 (32.7-56.3) years, p = 0.002) and with more active disease (SLEDAI-2 K 14.0 (10.0-18.5) vs. 8.0 (6.0-14), p = 0.0017) and shorter disease duration (4.14 (1.18-10.08) vs 9.19 (5.71-16.93), p = 0.0097) compared to ADA-negative SLE. ADAs primarily occurred in nephritis patients, were associated with anti-dsDNA positivity but were not influenced by concomitant use of corticosteroids, cyclophosphamide or previous treatments. Despite overall reduction of SLEDAI-2 K (12.0 (7.0-16) to 4.0 (2.0-6.7), p < 0.0001), ADA-positive individuals still had higher SLEDAI-2 K (6.0 (4.0-9.0) vs 4.0 (2.0-6.0), p = 0.004) and their B cell count at 6 months follow-up was higher (CD19 + % 4.0 (0.5-10.0) vs 0.5 (0.4-1.0), p = 0.002). At retreatment, two ADA-positive SLE patients developed serum sickness (16.7%), and three had infusion reactions (25%) in contrast with one (5.2%) serum sickness in the ADA-negative group. Conclusions In contrast to AAV, ADAs were highly prevalent among rituximab-treated SLE patients already after the first course of treatment and were found to effect on both clinical and immunological responses. The high frequency in SLE may warrant implementations of ADA screening before retreatment and survey of immediate and late-onset infusion reactions.

Dunn, Nicky (author)
Immunogenicity of biological therapies : frequency, predictability and clinical relevance in chronic inflammatory diseases
2021
Doctoral thesis (other academic/artistic)abstract
- Over the past three decades, biologic therapies have revolutionised the treatment of chronic inflammatory diseases such as multiple sclerosis (MS), systemic lupus erythematosus (SLE), and anti-neutrophil cytoplasmic antibody (AAV)-associated vasculitis (AAV) and for many, are now a core component of management. However, unlike chemically synthesised smallmolecule drugs, biologicals are larger and are produced using complex processes in or from living organisms, resulting in a propensity to stimulate an unwanted immune response to itself or related proteins. Immunogenicity of biologicals can lead to the formation of antidrug antibodies (ADAs), which can potentially inhibit the biological activity of a treatment and impair its safety and efficacy. Since the early stages of development, immunogenicity of biological therapies has been recognised as a potential limitation to their use, and progression towards the use of more humanised biological therapies over the years has aimed to minimise this issue. However, despite these developments and their improvements to effector functions and tolerability, immunogenicity has not been mitigated and, in some cases, has worsened. Immunogenicity testing is a required safety component of clinical trials; however, these results often do not accurately reflect the real-world setting and can fail to elucidate the less overt, rare and long-term implications of ADAs. Moreover, in several countries, biological therapies are used as an off-label therapy for some disease indications. Variation in the development and relevance of ADA between treatments and diseases limits the ability to extrapolate data to off-label indications. Therefore, further real-world studies are required to ascertain the extent and significance of this issue. The objective of this thesis was to investigate the frequency, predictability and clinical implications of ADA to rituximab, an anti-CD20 chimeric monoclonal antibody (mAb) in patients with MS, SLE and AAV, as well as the long-term effects of neutralising antibodies (NAbs) to interferon beta (IFNβ), a recombinant therapeutic protein, in patients with MS. Paper I was a prospective cross-sectional study investigating the frequency and possible clinical implications of ADAs to rituximab in 339 treated patients with MS. ADA status and titre were determined using an in-house validated bridging electrochemiluminescence (ECL) immunoassay, and the results were compared with a commercial enzyme-linked immunosorbent assay (ELISA) kit. The ELISA was found to be less sensitive than the ECL, with a false-negative rate of 27%. Using the ECL, a high frequency of ADAs were observed with 37% of patients relapsing-remitting MS (RRMS) and 26% of patients with progressive forms of MS, ADA-positive. A strong association was observed with both ADA status and titre and incomplete B cell depletion, indicating an effect of ADAs on the pharmacodynamics of rituximab. No difference was observed in clinical outcomes or safety; however, a trend towards poorer drug survival was noted in patients who were ADA-positive. In paper II, the frequency and risk factors for ADAs to rituximab were explored in 66 patients with SLE and 22 patients with AAV following first rituximab exposure in a mixed retrospective/prospective observational study. ADAs to rituximab were also detected using the in-house validated bridging ECL immunoassay with disease-specific cut-points. Higher rates of ADAs to rituximab were detected in SLE (37.8%) compared with none in AAV patients following first exposure to rituximab. Patients with SLE who developed ADAs were younger and had more active disease clinically and serologically at baseline. Following rituximab re-treatment, ADA positivity was associated with higher B cell counts and immediate infusion reactions. Paper III was a single-centre retrospective study that aimed to build on the findings of paper II, evaluating the presence and dynamics of persistent ADAs over time, their association with circulating rituximab level, and clinical implications of ADAs to rituximab. In this study, 35 rituximab-treated SLE patients, with 114 sera samples taken at specific time points between 1 month and 3 years post rituximab treatment cycle(s), were included. SLE was associated with a high rate of persistent ADAs to rituximab (64.3%). ADA titres tended to be higher earlier after re-treatment with rituximab compared to first exposure. Both persistence and titre of ADAs were associated with lower drug levels. Moreover, we confirmed in vitro that these antibodies can have neutralising capacity. Persistently positive patients appeared to have poorer clinical outcomes after re-treatment however, larger studies are required to clearly elucidate this. Together with results from paper II, these results support the use of routine testing in SLE patients prior to re-treatment with rituximab. In paper IV, the long-term implications of high-titre NAbs to IFNβ were investigated in a observational cohort study including 3104 patients with MS patients with just under 20,000 years of follow up data from the Swedish MS registry. Patients with high-titre NAbs to IFNβ had higher disease activity at baseline, which when adjusting for this, was observed to persist both during IFNβ treatment and after treatment change. These results suggest the impact of high-titre NAbs on IFNβ treatment effectiveness may lead to persistently higher disease activity, which is not entirely mitigated by subsequent treatments. In patients who are more susceptible to developing high-titre NAbs, these results may support the use of a more efficacious treatment earlier to prevent these potential complications. In conclusion, the included papers contribute towards our understanding of the short- and long-term implications of the immunogenicity of rituximab and IFNβ, aiming to support bestpractice decisions surrounding routine testing and clinical management in the studied diseases. Where required, routine testing could ensure that patients exposed to these biological therapies are optimally treated by minimising disease and economic burden due to ineffective treatment, adverse events and disease progression owing to ADAs.

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