Formation Of Anti-drug Antibodies Research Articles

Subcutaneous engineered factor VIIa marzeptacog alfa (activated) in hemophilia with inhibitors: Phase 2 trial of pharmacokinetics, pharmacodynamics, efficacy, and safety

BackgroundMarzeptacog alfa (activated) (MarzAA), a novel recombinant activated human factor VII (FVIIa) variant, was developed to provide increased procoagulant activity, subcutaneous (SC) administration, and longer duration of action in people with hemophilia. ObjectivesTo investigate if daily SC administration of MarzAA in subjects with inhibitors can provide effective prophylaxis. MethodsThis multicenter, open‐label phase 2 trial (NCT03407651) enrolled men with severe congenital hemophilia with an inhibitor. All subjects had a baseline annualized bleeding rate (ABR) of ≥12 events/year. Subjects received a single 18 μg/kg intravenous dose of MarzAA to measure 24‐hour pharmacokinetics (PK) and pharmacodynamics (PD), single 30 μg/kg SC dose to measure 48‐hour PK/PD, then daily SC 30 μg/kg MarzAA for 50 days. If spontaneous bleeding occurred, the dose was sequentially escalated to 60, 90, or 120 μg/kg, with 50 days at the final effective dose without spontaneous bleeding to proceed to a 30‐day follow‐up. The primary end point was reduction in ABR. Secondary end points were safety, tolerability, and antidrug antibody (ADA) formation. ResultsIn the 11 subjects, the mean ABR significantly reduced from 19.8 to 1.6, and the mean proportion of days with bleeding significantly reduced from 12.3% to 0.8%. Of a total of 517 SC doses, six injection site reactions in two subjects were reported. No ADAs were detected. One fatal unrelated serious adverse event occurred: intracerebral hemorrhage due to untreated hypertension. ConclusionsThe data demonstrated that MarzAA was highly efficacious for prophylactic treatment in patients with inhibitors by significantly decreasing bleed frequency and duration of bleeding episodes.

Immunogenicity of the Novel Glucagon Analogue Dasiglucagon: Results of a Dedicated Immunogenicity Trial in Type 1 Diabetes.

Dasiglucagon is a next-generation glucagon analogue that is stable in aqueous formulation. This dedicated immunogenicity trial to support use as rescue treatment for severe hypoglycemia was conducted to evaluate the immunogenicity of repeated subcutaneous doses of dasiglucagon in subjects with type 1 diabetes. A total of 112 subjects were randomized 1:1 to receive three subcutaneous weekly doses of either 0.6 mg dasiglucagon or 1.0 mg recombinant glucagon (GlucaGen®) according to a double-blind parallel-group trial design. Subjects were followed for 15 weeks, with a multitiered testing approach planned for assessment of antidrug antibody (ADA) formation. For the primary immunogenicity endpoint, the overall ADA incidence was zero, as no subject demonstrated any treatment-induced or treatment-boosted ADA response at any time point in this trial involving three consecutive weekly doses of trial drug. No injection site reactions were reported for subjects receiving dasiglucagon. There were no unexpected safety findings for the trial.

Small Molecule Drugs in Inflammatory Bowel Diseases.

Inflammatory bowel diseases (IBDs), mainly represented by Crohn’s disease (CD) and Ulcerative Colitis (UC), are chronic disorders with an unclear pathogenesis. This incurable and iterative intestinal mucosal inflammation requires the life-long use of anti-inflammatory drugs to prevent flares or relapses, which are the major providers of complications, such as small bowel strictures and intestinal perforations. The introduction of tumor necrosis factor (TNF)-alpha inhibitors and other compounds, such as anti-IL12/23 and anti-alpha4/beta7 integrin monoclonal antibodies, has considerably improved the clinical management of IBDs. They are now the standard of care, being the first-line therapy in patients with aggressive disease and in patients with moderate to severe disease with an inadequate response to conventional therapy. However, for approximately one third of all patients, their efficacy remains insufficient by a lack or loss of response due to the formation of anti-drug antibodies or compliance difficulties with parenteral formulations. To address these issues, orally administered Small Molecules Drugs (SMDs) that use a broad range of novel pharmacological pathways, such as JAK inhibitors, sphingosine-1-phosphate receptor modulators, and phosphodiesterase 4 inhibitors, have been developed for CD and UC. This article provides an updated and complete review of the most recently authorized SMDs and SMDs in phase II/III development.

DOP74 Initial Clearance of infliximab is a predictor for the time of formation of anti-drug antibodies

Abstract Background Treating patients with biologics like infliximab (IFX), may cause the formation of antidrug antibodies (ADA). ADA are associated with faster drug clearance, reduced treatment efficacy and increased risk of infusion-related side effects. The aim of this study is to identify possible predictors for ADA-formation. Methods A time to first detection of ADA model was developed by using data from a Phase 3 clinical trial of biosimilar CT-P13 and originator infliximab comparing efficacy and safety in moderately to severely active Crohn’s disease (CD). We analyzed data from 220 patients initiating IFX. Seven subjects with ADA present at baseline were discarded. The following baseline covariates were evaluated in this analysis: age, weight, first estimated drug clearance, disease duration, dose, sex and concomitant immune-modulators. Continuous covariates were divided into lower quartile, inter-quartile range, and upper quartile bins. Kaplan-Meier survivor estimates were plotted by bin. The data was then modeled parametrically with NONMEM by constructing a full model which was further refined using the Wald’s Approximation Method algorithm. Hazard ratios and probability of ADA at time points of interest were calculated for significant covariates. Results Initial IFX clearance, concomitant immunomodulators and IFX dose were identified as being statistically significant predictors of the time to first ADA. The model suggested that the hazard of ADA increases by 61% for every increase on 0.1 L/day in clearance, it decreases by 41% with concomitant administration of immunomodulators and decreases by 29% for every increase in dose of 100 mg. Thus, for a patient with initial IFX clearance of 0.2 L/day, no immunomodulators and a dose of 328 mg, the average time to first ADA is 374 days (range 221–451). If clearance is 0.4 L/day under the same conditions, then ADA onset is 144.5 days (range 90–216). Increasing the starting dose to 428 mg would improve the time to onset to 203 days (range 110–337). Again, under the same conditions, adding immunomodulator would increase the time to onset to 354 days (range 214–451). Conclusion We have identified initial infliximab clearance as an independent predictor for onset of ADA in CD patients. Our results suggest that early assessment of clearance should guide treatment optimization with IFX in patients with CD, including the addition of concomitant immunosuppressants or increasing the dose during induction.

DOP73 Antibiotic use differentially affects the risk of antidrug antibody formation during anti-TNFα therapy in Inflammatory Bowel Disease

Abstract Background Anti-drug antibodies (ADA) to anti-TNF therapy drive loss of response to treatment. Links between intestinal microbial composition and response to anti-TNF therapy were demonstrated, and antibiotic use during anti-TNF therapy reduced the risk of ADA formation. Here, we aimed to assess the possible implications of specific antibiotic treatments on ADA formation in patients with inflammatory bowel disease (IBD) patients. Methods We performed a retrospective analysis of data from three health maintenance organizations, covering 89% of the Israeli population. All patients with IBD and available ADA levels were included. Survival analysis using Kaplan-Meier and multivariate Cox proportional hazards regression with drug use as time varying covariates methods were used to assess the association between specific antibiotic use and ADA development. C57BL and germ free mice were treated with respective antibiotics followed by immunization with infliximab. ADA were assessed after 14 days. Results We analyzed 1,946 patients treated with anti-TNF. Positive ADAs were detected in 363 patients (18.6%). Age, gender and concomitant use of immunomodulators where comparable in patients who eventually developed ADAs or not. However, infliximab and not adalimumab therapy, previous anti-TNF therapy and higher baseline C-reactive protein levels were significantly associated with ADA development in univariate analysis. Kaplan-Meier curves of prior antibiotic use demonstrated significant hazard of ADA development in patients who used cephalosporins or penicillins with beta-lactamase inhibitors (BLI) and reduced risk with prior use of fluoroquinolones, macrolides or metronidazole (Figure 1) with early risk divergence for most classes. Multivariable Cox proportional hazards model adjusted for multiple factors associated with ADA development was overall consistent with Kaplan-Meier estimates (Figure 2). In mice exposed to infliximab, increased ADA production by cefuroxime treatment and a non-significant reduction following azithromycin treatment was noticed (Figure 3). Germ free mice produced no ADA. Figure 1: Kaplan-Meier curves of cumulative risk of ADA development for prior use of specific antibiotics. P value for the log rank test is presented in each plot. Figure 2: Multivariable-adjusted HR with 95% CI of ADA for use of various antibiotic classes during anti-TNF therapy. Figure 3: Mean ADA levels in mice treated with anti-TNF and prior cefuroxime, azithromycin, or no antibiotic Conclusion ADA production is microbial dependent. The risk of ADA development during anti-TNF therapy can possibly be reduced by avoidance of cephalosporins and penicillins with BLI, or possibly reduced by treatment with fluoroquinolones or macrolides.

P597 Cycling Anti-TNF Therapy in Inflammatory Bowel Disease: Effectiveness and Durability of Switching from adalimumab to infliximab

Abstract Background Anti-TNF therapy remains the cornerstone of moderate to severe inflammatory bowel disease (IBD) treatment. There are few data regarding switching from subcutaneous (SubQ) to intravenous (IV) agents. We evaluated the clinical utility of cycling adalimumab (ADA) for infliximab (IFX) in IBD patients (pts) treated at a tertiary center. Methods This is a retrospective observational study where we evaluated pts with IBD who cycled from ADA to IFX from 2010 to 2018. Pts were followed for 1 year following IFX initiation. We reviewed baseline demographic and clinical data. Primary outcomes included changes in CRP and clinical disease activity indices which were statistically analyzed using Wilcoxon Signed Rank Test. Results 24 pts with Crohn’s disease (CD) and 11 with ulcerative colitis (UC) were included. Median age at time of IFX initiation in the overall cohort was 33 years with median disease duration of 10 years. Most pts in the UC cohort had pancolitis (63.6%), while the CD cohort mostly had ileocolonic disease (79.2%). Prior to IFX initiation, median baseline CRP was 8 (IQR 15), with median HBI of 3.5 (IQR 5), and SCCAI of 3.5 (IQR 4) in the CD and UC cohorts, respectively. Additional baseline demographics are in Table 1. Following median 12 months on ADA therapy in the overall cohort, 16 pts (45.7%) discontinued ADA due to primary or secondary loss of response, 8 pts (22.8%) due to anti-drug antibody formation, and 11 pts (31.4%) due to adverse events or unclear causes. At the time of starting IFX therapy, 17 pts (48.6%) were using steroids, while 24 pts (68.6%) were on immunomodulatory therapy. In the overall cohort, after cycling to IFX, median CRP was lower at 8 weeks (4; IQR 9), 26 weeks (3; IQR 11), and 52 weeks (5; IQR 10) as compared to baseline; only the 8 week CRP reached statistical significance (P=0.0447, 0.0662, and 0.0876, respectively). In the CD cohort, median CRP was significantly lower at 8 weeks (7; IQR 6; P=0.0314) and 52 weeks (5; IQR 7; P=.0410) as compared to baseline (12.5; IQR 14). Although signals of median HBI and SCCAI scores trended lower after 8 weeks, 26 weeks, and 52 weeks of IFX therapy, these did not reach statistical significance. A total of 15 pts (43.0%) stopped IFX prior to one year. Subgroup analysis of 5 pts who developed anti-ADA antibodies demonstrated statistically significant reduction of median CRP (10; IQR 22.5; P=.043) after 52 weeks of IFX therapy. Additional results are detailed in Table 2. Conclusion Cycling anti-TNF therapy from ADA to IFX offers clinical utility in preserving mechanistic benefit of TNF-α blockade in IBD pts leading to improvement of CRP, particularly in CD pts and those who developed immunogenicity to ADA.

Phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with tofacitinib in patients with advanced pancreatobiliary cancer.

3051 Background: LMB-100 recombinant immunotoxin consists of a mesothelin-binding Fab for targeting a modified Pseudomonas exotoxin A payload to tumors. Previous clinical trials demonstrated that almost all patients formed anti-drug-antibodies (ADAs) to LMB-100 that made administration beyond cycle 2 ineffective. Tofacitinib is an oral JAK inhibitor that prevented formation of ADAs against a closely related immunotoxin in pre-clinical studies. The primary objective of the dose escalation cohort was assessment of safety and tolerability of LMB-100 given with tofacitinib to patients with mesothelin-expressing solid tumors. The primary objective of the expansion cohort was to determine whether co-administration of tofacitinib delays formation of neutralizing LMB-100 ADAs. Methods: Patients (n = 13) with pancreatic adenocarcinoma and other mesothelin-expressing solid tumors (n = 3; cholangiocarcinoma, appendix, cystadenocarcinoma) were treated for up to 3 cycles with LMB-100 as a 30-minute infusion on days 4, 6, and 8 at two dose levels (100 and 140 mcg/kg) and co-treated with oral tofacitinib for the first 10 days of the cycle (10 mg BID). Results: Dose level 1 of LMB-100 was started at 100 mcg/kg one dose level below the single agent MTD. Dose escalation to 140 mcg/kg (dose level 2) resulted in DLTs in 2 of the 3 patients treated: grade 3 cardiac toxicity and grade 4 hyponatremia, both attributed to capillary leak syndrome. Ultimately, 7 patients were treated at dose level 1 without DLTs and 100 mcg/kg was chosen as the LMB-100 dose for the expansion cohort. The last of 6 patients treated in the expansion cohort developed grade 4 pericardial effusion leading to early closure of the study for toxicity. No objective responses were seen. Of the 8 patients who received two cycles of treatment at MTD, 4 met prespecified criteria for ADA prevention, and 2 patients who went on to receive cycle 3 had detectable LMB-100 plasma drug levels after administration. Conclusions: LMB-100 was unable to be co-administered safely with tofacitinib. ADA formation was prevented in 2 patients through 3 cycles, a rare occurrence. Clinical trial information: NCT04034238.

Preclinical development of plant-based oral immune modulatory therapy for haemophilia B.

SummaryAnti‐drug antibody (ADA) formation is a major complication in treatment of the X‐linked bleeding disorder haemophilia B (deficiency in coagulation factor IX, FIX). Current clinical immune tolerance protocols are often not effective due to complications such as anaphylactic reactions against FIX. Plant‐based oral tolerance induction may address this problem, as illustrated by the recent first regulatory approval of orally delivered plant cells to treat peanut allergy. Our previous studies showed that oral delivery of plant cells expressing FIX fused to the transmucosal carrier CTB (cholera toxin subunit B) in chloroplasts suppressed ADA in animals with haemophilia B. We report here creation of the first lettuce transplastomic lines expressing a coagulation factor, in the absence of antibiotic resistance gene. Stable integration of the CTB‐FIX gene and homoplasmy (transformation of ˜10 000 copies in each cell) were maintained in both T1 and T2 generation marker‐free plants. CTB‐FIX expression in lyophilized leaves of T1 and T2 marker‐free plants was 1.0–1.5 mg/g dry weight, confirming that the marker excision did not affect antigen levels. Oral administration of CTB‐FIX to Sprague Dawley rats at 0.25, 1 or 2.5 mg/kg did not produce overt adverse effects or toxicity. The no‐observed‐adverse‐effect level (NOAEL) is at least 2.5 mg/kg for a single oral administration in rats. Oral administration of CTB‐FIX at 0.3 or 1.47 mg/kg either mixed in food or as an oral suspension to Beagle dogs did not produce any observable toxicity. These toxicology studies should facilitate filing of regulatory approval documents and evaluation in haemophilia B patients.

Fucosylation and Sialylation of Fc-Fragment of anti-Tumour Necrosis Factor Alpha Antibodies do not Influence Their Immunogenicity in Monocyte-Derived Dendritic Cells.

Antibodies targeting tumor necrosis factor-alpha [TNF-alpha] are a mainstay in the treatment of inflammatory bowel disease. However, they fail to demonstrate efficacy in a considerable proportion of patients. On the other hand, glycosylation of antibodies might influence not only their immunogenicity but also their structure and function. We investigated whether specific glycosylation patterns of the Fc-fragment would affect the immunogenicity of anti-TNF-alpha antibody in monocyte-derived dendritic cells. The effect of a specific Fc-glycosylation pattern on antibody uptake by monocyte-derived dendritic cells [mo-DCs] and how this process shapes the immunologic profile of mo-DCs was investigated. Three N-glycoforms of the anti-TNF-alpha antibody adalimumab, that differed in the content of fucose or sialic acid, were tested: [1] mock treated Humira, abbreviated 'Fuc-G0', where the N-glycan mainly consist of fucose and N-acetylglucosamine [GlcNAc], without sialic acid; [2] 'Fuc-G2S1/G2S2' with fucose and alpha 2,6 linked sialic acid; and [3] 'G2S1/G2S2' with alpha 2,6 linked sialic acid, without fucose. Our data demonstrated that neither fucosylation nor sialylation of anti-TNF-Abs [Fuc-G0, FucG2S1/G2S2, G2S1/G2S2] influence their uptake by mo-DCs. Additionally, none of the differentially glycosylated antibodies altered CD80, CD86, CD273, CD274 levels on mo-DCs stimulated in with lipopolysaccharide in the presence of antibodies. Next, we evaluated the levels of cytokines in the supernatant of mo-DCs stimulated with lipopolysaccharide in the presence of Fuc-G0, Fuc-G2S1/G2S2 or G2S1/G2S2-glycosylated anti-TNF antibodies. Only IL-2 and IL-17 levels were downregulated, and IL-5 production was upregulated by uptake of Fuc-G0 antibodies, as compared to control without antibodies. The specific modification in the Fc-glycosylation pattern of anti-TNF-alpha Abs does not affect their immunogenicity under the tested conditions. As this study was limited to mo-DCs, further investigation is required to clarify whether Ab uptake into mo-DCs might change the immunological profile of T- and B-cells, in order to ultimately reduce the formation of anti-drug antibodies and to improve the patient care.

Phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with tofacitinib in persons with pancreatobiliary cancer or other mesothelin expressing solid tumors.

TPS452 Background: LMB-100 recombinant immunotoxin consists of a mesothelin-binding Fab for targeting with a modified Pseudomonas exotoxin A payload. Formation of anti-drug antibodies (ADAs) is thought to contribute significantly to limited clinical efficacy of LMB-100 seen in prior clinical trials. Most patients develop clinically meaningful ADAs after 1-2 cycles of LMB-100, resulting in rapid neutralization of LMB-100 during subsequent cycles and undetectable plasma drug levels. Tofacitinib is an oral Janus Kinase-1 and -3 (JAK) inhibitor approved by the FDA for the treatment of rheumatoid arthritis and ulcerative colitis. Pre-clinical studies have shown that tofacitinib can prevent the formation of ADAs against recombinant immunotoxin (Onda et al. Journal of Immunology 2014), and that co-administration of tofacitinib with LMB-100 increases immunotoxin serum half- life in mice and anti-tumor efficacy (Simon et al. JCI Insight 2019). We hypothesize that co-administration of tofacitinib with LMB-100 will prevent or delay the formation of high titer ADAs to LMB-100, such that 2 effective cycles of immunotoxin can be administered to patients. Methods: This phase I clinical trial consists of a dose escalation phase using 3+3 design to determine the maximum tolerated dose (MTD) of LMB-100 that can be administered with tofacitinib in participants (n = 18 max) with mesothelin-expressing solid tumors, followed by a dose expansion phase at the MTD for participants (n = 15) with pancreatic adenocarcinoma or extrahepatic cholangiocarcinoma. The primary objective of the expansion phase is to determine whether co-administration of tofacitinib delays formation of neutralizing anti-LMB-100 ADAs for cycle 2 of treatment as measured by LMB-100 plasma drug levels. A positive outcome will be reached if percent of participants achieving threshold LMB-100 drug levels during cycle 2 increases from 50% to 80% (83.6% probability if >10 of 15 evaluable participants meet this milestone). Plasma drug levels during cycle 3 will also be analyzed as a secondary endpoint. Key inclusion criteria include adults with histologically confirmed previously treated solid tumor malignancies. Participants will receive tofacitinib 10 mg twice daily on days 1-10 and LMB-100 at 65, 100, or 140 mcg/kg on days 4, 6 and 8 of a 21-day cycle. The dose escalation phase has been completed and enrollment onto dose expansion phase is ongoing. Clinical trial information: NCT04034238.

The efficacy of immunomodulators in the prevention and suppression of anti-drug antibodies to anti-tumor necrosis factor therapy in inflammatory bowel disease.

The development of biological agents against tumor necrosis factor (TNF) has revolutionized the management of inflammatory bowel disease (IBD), frequently achieving induction and maintenance of remission in both ulcerative colitis and Crohn’s disease. However, a loss of response due to the development of anti-drug antibodies (ADA) is seen annually in approximately 20% of IBD patients receiving anti-TNF therapy. Current evidence suggests that the use of immunomodulators (IMM), such as thiopurines (azathioprine and 6-mercaptopurine) or methotrexate, may prevent or suppress ADA formation. In this article, we present a comprehensive review of the available literature regarding the efficacy of IMM in the prevention and suppression of ADA development to anti-TNF therapy in patients with IBD.

Industry experiences with immune-mediated findings in biotherapeutic nonclinical toxicology studies

With the growth of monoclonal antibodies and other proteins as major modalities in the pharmaceutical industry, there has been an increase in pharmacology and toxicity testing of biotherapeutics in animals. Animals frequently mount an immune response to human therapeutic proteins. This can result in asymptomatic anti-drug antibody formation, immune complexes that affect drug disposition and/or organ function such as kidney, cytokine release responses, fatal hypersensitivity, or a range of reactions in between. In addition, an increasing number of oncology therapeutics are being developed that enhance or directly stimulate immune responses by a variety of mechanisms, which could increase the risk of autoreactivity and an autoimmune-like syndrome in animals and humans. When evaluating the risk of biotherapeutics prior to entering the clinic, the nonclinical safety data may include any of these responses and it is critical to understand whether they represent a safety liability for humans. The DruSafe Leadership group of the IQ Consortium conducted a survey of industry to understand sponsors' experiences with these immune reactions in nonclinical studies related to both immunogenicity and pharmacologically-mediated immune perturbations. The survey covered what pathways were affected, how the immune responses were presented, how the company and health authorities interpreted the data and whether the immune responses were observed in the clinic. Additionally, the survey gathered information on association of these findings with anti-drug antibodies as well as sponsor's use of immunogenicity predictive tools. The data suggests that the ability of a biotherapeutic to activate the immune system, intended or not, plays a significant role on characteristics of the response and whether theys are translatable.

Immunogenicity of Biologic and Biosimilar Therapies for Psoriasis and Impact of Novel Immunoassays for Immunogenicity Detection.

Anti-drug antibodies (ADAs) may develop against originator biologic and biosimilar therapies used for the treatment of psoriasis and may be the cause of initial therapeutic non-response or diminished therapeutic response over time. Comparing immunogenicity between therapeutic agents is challenging owing to the variation in assays used for detection, among other reasons. Using the results of a PubMed search for psoriasis clinical trials disclosing the rates of ADAs for originator biologic and biosimilar therapies approved for the treatment of psoriasis within the last 5 years, this review discusses the rates and potential clinical impact of ADA formation in patients with psoriasis managed with originator biologic and biosimilar therapies, along with novel methods of ADA testing. Anti-drug antibodies are detectable in all biologic and biosimilar therapies approved for the treatment of psoriasis in the last 5 years, and the effect of ADAs on clinical response varies by agent. Novel immunoassays used for the detection of ADAs may have increased sensitivity compared with traditional assays, although the increased rate of detection may not correlate with decreased clinical response and the decision to test for the presence of ADAs may vary from patient to patient. Though ADA formation seems ubiquitous with the use of biologic agents for the treatment of psoriasis, the increased rates of ADAs detected by novel immunoassays may not necessarily correlate with decreased treatment efficacy.

Immunogenicity of antitumor necrosis factor therapy in patients with spondyloarthritis

Abstract Objectives To evaluate the serum dosage of the biomedicine (DBM) and the incidence of antidrug antibody (ADA) against antitumor necrosis factor (TNF) in spondyloarthritis, and to demonstrate the influence of these parameters on the clinical efficiency. Methods We conducted a cross-sectional multicentric study including patients with spondylarthritis (SpA) under antiTNF (infliximab [INF], etanercept [ETA] and adalimumab [ADL]) for at least 6 months. A dosage of the ADA and DBM were practiced by the immuno-enzymatic essay. Result Seventy one patients were recruited. Disease modifying antirheumatic drugs (DMARDs) were associated with anti-TNF in 30%. ADA was positive in 54% for INF, 33% for ADL and 0% for ETA with a significant difference(p<0.0001). Immunogenicity was correlated to a bad therapeutic response (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]≥4)(p=0.04). The DBM was inversely correlated with the rate of ADA for patients treated with INF(p<0.0001) and ADL(p<0.0001). The DBM was also inversely correlated with BASDAI of INF(p=0.03) and ADL (p=0.01). ADA was significantly associated with an anterior switch of anti TNF(p=0.04), the use of INF(p=0.002), presence of coxitis(p=0.01) and higher body mass index (BMI)(p=0.007). DMARDs associated with anti TNF were not a protective factor for positive ADA. In a multivariate study, only INF and BMI were independent factors of positive ADA. Conclusion The ADA formation lowered the DBM and favored the therapeutic failure.

Immunogenicity of antitumor necrosis factor therapy in patients with spondyloarthritis.

Objectives To evaluate the serum dosage of the biomedicine (DBM) and the incidence of antidrug antibody (ADA) against antitumor necrosis factor (TNF) in spondyloarthritis, and to demonstrate the influence of these parameters on the clinical efficiency. Methods We conducted a cross-sectional multicentric study including patients with spondylarthritis (SpA) under antiTNF (infliximab [INF], etanercept [ETA] and adalimumab [ADL]) for at least 6months. A dosage of the ADA and DBM were practiced by the immuno-enzymatic essay. Result Seventy one patients were recruited. Disease modifying antirheumatic drugs (DMARDs) were associated with anti-TNF in 30%. ADA was positive in 54% for INF, 33% for ADL and 0% for ETA with a significant difference(p<0.0001). Immunogenicity was correlated to a bad therapeutic response (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]≥4)(p=0.04). The DBM was inversely correlated with the rate of ADA for patients treated with INF(p<0.0001) and ADL(p<0.0001). The DBM was also inversely correlated with BASDAI of INF(p=0.03) and ADL (p=0.01). ADA was significantly associated with an anterior switch of anti TNF(p=0.04), the use of INF(p=0.002), presence of coxitis(p=0.01) and higher body mass index (BMI)(p=0.007). DMARDs associated with anti TNF were not a protective factor for positive ADA. In a multivariate study, only INF and BMI were independent factors of positive ADA. Conclusion The ADA formation lowered the DBM and favored the therapeutic failure.

Long-Term Durability, Safety and Efficacy of Fitusiran Prophylaxis in People with Hemophilia a or B, with or without Inhibitors - Results from the Phase II Study

Long-Term Durability, Safety and Efficacy of Fitusiran Prophylaxis in People with Hemophilia a or B, with or without Inhibitors - Results from the Phase II Study

Factors Associated with the Immunogenicity of Anti-Tumor Necrosis Factor Agents in Pediatric Patients with Inflammatory Bowel Disease.

Background/AimsAnti-drug antibodies (ADAs) can develop during treatment with anti-tumor necrosis factor (TNF) agents. We aimed to investigate the factors associated with immunogenicity of anti-TNF agents in pediatric patients with inflammatory bowel disease (IBD) and observe the clinical course of ADA-positive patients.MethodsPediatric IBD patients receiving maintenance treatment with anti-TNF agents who had been tested for ADAs against infliximab (IFX) or adalimumab (ADL) were included in this cross-sectional study. Factors associated with ADA positivity were investigated by analyzing clinicodemographic, laboratory, and treatment-related factors.ResultsA total of 76 patients (Crohn’s disease, 65; ulcerative colitis, 11) were included. Among these, 59 and 17 patients were receiving IFX and ADL, respectively. ADAs were found in 10 patients (13.2%), all of whom were receiving IFX. According to multivariable logistic regression analysis, the IFX trough level (TL) was associated with ADA positivity (odds ratio, 0.25; 95% confidence interval [CI], 0.08 to 0.51; p=0.002). According to the receiver operating characteristic analysis, the optimal cutoff of the IFX TLs for stratifying patients based on the presence of ADAs against IFX was 1.88 μg/mL (area under curve, 0.941; 95% CI, 0.873 to 1.000; sensitivity, 80.0%; specificity, 95.9%; p<0.001). Among the 10 patients with ADAs against IFX, five patients (50%) switched to ADL within 1 year, while five patients (50%) kept receiving IFX. Transient ADAs were observed in three patients (30%).ConclusionsIFX TL was the only factor associated with ADA formation in pediatric IBD patients receiving IFX. Future studies based on serial and proactive therapeutic drug monitoring are required in the future.

Anti-drug antibody formation in Japanese Fabry patients following enzyme replacement therapy

Enzyme replacement therapy (ERT) for Fabry disease (deficiency of α-galactosidase A, α-Gal) with recombinant α-Gals (agalsidase alfa and agalsidase beta) is widely available and improves some of the clinical manifestations and biochemical findings. However, recent reports suggest that recurrent administration of recombinant enzymes often induces the formation of anti-drug antibodies, which may have a negative impact on the outcome of the therapy. We examined the formation of anti-drug antibodies using blood samples from 97 Japanese Fabry patients following ERT and tried to characterize them by means of enzyme-linked immunosorbent assay (ELISA), serum-mediated α-Gal inhibition, and immunochromatographic (IC) assay, followed by GLA gene analysis and measurement of plasma globotriaosylsphingosine (lyso-Gb3). ELISA revealed that 20/35 (57%) classic Fabry males were antibody (Immunoglobulin G, IgG) -positive (Ab+) at 6 months after the initiation of ERT, although only two of the seventeen (12%) later-onset Fabry males and none of the 45 Fabry females were. The Ab+ state was maintained at least until 24 months after the initiation of ERT in most of the cases, the exceptions being two patients who acquired immune tolerance during ERT. As many Ab+ patients have nonsense mutations, attention should be paid to the formation of anti-drug antibodies in Fabry patients harboring such gene mutations, who hardly produce α-Gal protein. Serum-mediated α-Gal inhibition was seen in most of the Ab+ patients and the antibodies affected the reduction of the plasma lyso-Gb3 level following ERT, suggesting that the antibodies inhibit the enzyme activity. There was a correlation between the results of the IC test and those of the ELISA. As the former is easy and rapid, it should be useful as a bed-side test.

Assessment of clinically relevant immunogenicity for mAbs; are we over reporting ADA?

Immunogenicity is recognized as a possible clinical risk due to the development of anti drug antibodies (ADAs) that can adversely impact drug safety and efficacy. Although robust assays are currently used to assess the ADA, there is a debate on how best to generate the most appropriate immunogenicity data. There are several factors that can trigger ADA formation including the immunity status of the target population and the severity of the disease indication. Immunogenicity testing has defaulted to the most conservative approach regardless of the inherent risk of the molecule or the patient population. For low-risk biotherapeutics such as human monoclonal antibodies, ADA data that provide clinically relevant information should be prioritized when establishing immunogenicity monitoring plans.

The Molecular Mechanisms That Underlie the Immune Biology of Anti-drug Antibody Formation Following Treatment With Monoclonal Antibodies.

Monoclonal antibodies (mAbs) are a crucial asset for human health and modern medicine, however, the repeated administration of mAbs can be highly immunogenic. Drug immunogenicity manifests in the generation of anti-drug antibodies (ADAs), and some mAbs show immunogenicity in up to 70% of patients. ADAs can alter a drug’s pharmacokinetic and pharmacodynamic properties, reducing drug efficacy. In more severe cases, ADAs can neutralize the drug’s therapeutic effects or cause severe adverse events to the patient. While some contributing factors to ADA formation are known, the molecular mechanisms of how therapeutic mAbs elicit ADAs are not completely clear. Accurate ADA detection is necessary to provide clinicians with sufficient information for patient monitoring and clinical intervention. However, ADA assays present unique challenges because both the analyte and antigen are antibodies, so most assays are cumbersome, costly, time consuming, and lack standardization. This review will discuss aspects related to ADA formation following mAb drug administration. First, we will provide an overview of the prevalence of ADA formation and the available diagnostic tools for their detection. Next, we will review studies that support possible molecular mechanisms causing the formation of ADA. Finally, we will summarize recent approaches used to decrease the propensity of mAbs to induce ADAs.