Antidrug antibodies (ADAs) may change pharmacokinetic or pharmacodynamic profiles of biologic therapies, potentially decreasing efficacy.
To evaluate the potential effects of brodalumab ...immunogenicity on safety, efficacy, and retreatment.
Data from 1 phase 2 and 3 phase 3 studies of brodalumab in psoriasis were analyzed.
Overall, 2.7% of patients had positive test results for binding ADAs after receiving brodalumab; ADAs were transient in 1.4% of patients, and there were no neutralizing ADAs. Among ADA-positive patients, 60.0% (3/5) achieved a static physician's global assessment score of 0 or 1 at week 12 in the group receiving the brodalumab 210 mg every 2 weeks, compared with 79.1% (1131/1429) of ADA-negative patients. All patients (100%) who experienced return of disease and were retreated with brodalumab 210 mg every 2 weeks (none were ADA positive) achieved at least a 75% improvement in Psoriasis Area And Severity Index, ≥90% of whom regained response by week 8 of retreatment. Hypersensitivity reactions were less frequent with brodalumab than with placebo. Injection site reactions occurred in 1.8% of patients treated with brodalumab versus 2% of patients treated with ustekinumab.
Retreatment could be assessed in only 1 phase 3 brodalumab study.
Brodalumab compares favorably with other biologics in terms of immunogenicity and high rates of efficacy recapture upon retreatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The management of patients with moderate to severe inflammatory bowel disease was transformed with the arrival of anti-tumor necrosis factor (TNF) therapy. Nevertheless, a considerable number of ...patients do not respond to anti-TNF induction therapy (primary nonresponse) or lose response to treatment over time after initially experiencing clinical improvement (secondary loss of response). Studies suggest that these outcomes are often due to inadequate drug concentrations. Therapeutic drug monitoring (TDM) is a practical tool that can be used to better define the etiologies of and help manage primary nonresponse or secondary loss of response. Proactive TDM, or drug titration to a target trough concentration, can improve the efficacy of anti-TNF treatment and lead to favorable clinical outcomes. However, in patients with adequate anti-TNF drug concentrations and active disease, alternate pathways of inflammation (not driven by TNFa agents) are at play, and therapies with another mechanism of action should be employed.
Advances in Anticancer Immunotoxin Therapy Alewine, Christine; Hassan, Raffit; Pastan, Ira
The oncologist (Dayton, Ohio),
February 2015, Volume:
20, Issue:
2
Journal Article
Peer reviewed
Open access
Immunotoxins are a novel class of antibody‐conjugated therapeutics currently in clinical development for a variety of malignancies. They consist of an antibody‐based targeting domain fused to a ...bacterial toxin payload for cell killing. Immunotoxins kill cells by inhibiting protein synthesis, a unique mechanism of action that is toxic to both dividing and nondividing cells. Recent advances in the design and administration of immunotoxins are overcoming historical challenges in the field, leading to renewed interest in these therapeutics.
Immunotoxins are a novel class of antibody‐based therapeutics currently in clinical development. This review of the field will help physicians better inform patients about the potential benefits and toxicities of these experimental treatments.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The chimeric antibodies anti-CD20 rituximab (Rtx) and anti-TNFα infliximab (Ifx) induce antidrug antibodies (ADAs) in many patients with inflammatory diseases. Because of the key role of CD4 T ...lymphocytes in the initiation of antibody responses, we localized the CD4 T cell epitopes of Rtx and Ifx. With the perspective to anticipate immunogenicity of therapeutic antibodies, identification of the CD4 T cell epitopes was performed using cells collected in healthy donors. Nine T cell epitopes were identified in the variable chains of both antibodies by deriving CD4 T cell lines raised against either Rtx or Ifx. The T cell epitopes often exhibited a good affinity for human leukocyte antigen (HLA)-DR molecules and were part of the peptides identified by MHC-associated peptide proteomics assay from HLA-DR molecules of dendritic cells (DCs) loaded with the antibodies. Two-third of the T cell epitopes identified from the healthy donors stimulated peripheral blood mononuclear cells from patients having developed ADAs against Rtx or Ifx and promoted the secretion of a diversity of cytokines. These data emphasize the predictive value of evaluating the T cell repertoire of healthy donors and the composition of peptides bound to HLA-DR of DCs to anticipate and prevent immunogenicity of therapeutic antibodies.
In oncology, an increasing number of targeted anticancer agents and immunotherapies are of biological origin. These biological drugs may trigger immune responses that lead to the formation of ...antidrug antibodies (ADAs). ADAs are directed against immunogenic parts of the drug and may affect efficacy and safety. In other medical fields, such as rheumatology and hematology, the relevance of ADA formation is well established. However, the relevance of ADAs in oncology is just starting to be recognized, and literature on this topic is scarce. In an attempt to fill this gap in the literature, we provide an up‐to‐date status of ADA formation in oncology. In this focused review, data on ADAs was extracted from 81 clinical trials with biological anticancer agents. We found that most biological anticancer drugs in these trials are immunogenic and induce ADAs (63%). However, it is difficult to establish the clinical relevance of these ADAs. In order to determine this relevance, the possible effects of ADAs on pharmacokinetics, efficacy, and safety parameters need to be investigated. Our data show that this was done in fewer than 50% of the trials. In addition, we describe the incidence and consequences of ADAs for registered agents. We highlight the challenges in ADA detection and argue for the importance of validating, standardizing, and describing well the used assays. Finally, we discuss prevention strategies such as immunosuppression and regimen adaptations. We encourage the launch of clinical trials that explore these strategies in oncology.
Implications for Practice:
Because of the increasing use of biologicals in oncology, many patients are at risk of developing antidrug antibodies (ADAs) during therapy. Although clinical consequences are uncertain, ADAs may affect pharmacokinetics, patient safety, and treatment efficacy. ADA detection and reporting is currently highly inconsistent, which makes it difficult to evaluate the clinical consequences. Standardized reporting of ADA investigations in the context of the aforementioned parameters is critical to understanding the relevance of ADA formation for each drug. Furthermore, the development of trials that specifically aim to investigate clinical prevention strategies in oncology is needed.
Because of the increasing use of biologicals in oncology, many patients are at risk of developing antidrug antibodies (ADAs) during therapy. ADAs may affect pharmacokinetics, patient safety, and treatment efficacy. To gain a better understanding of the clinical relevance, ADAs should be routinely investigated using consistent detection and reporting methods.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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•A rapid, sensitive, and specific flow cytometry assay was developed to detect anti-PEG IgG and IgM in human blood plasma.•Using the method, anti-PEG IgG or IgM were detected in 65% ...of plasma samples from 300 healthy blood donors.•The presence of anti-PEG IgG and IgM was confirmed using three validation assays.•The highest prevalence of both anti-IgG and anti-IgM was in individuals 18–24 years of age.•No correlation was found between anti-PEG IgG and IgM concentrations.
Polyethylene glycol (PEG) is a biocompatible polymer used in biotherapeutics to increase bioavailability, reduce the frequency of administration, and optimize pharmacokinetics. Anti-PEG antibodies have been detected in healthy individuals and may decrease efficacy and alter the pharmacokinetics of PEGylated therapeutics; however, the prevalence of anti-PEG antibodies is unclear. In this study, a flow cytometry assay was optimized to detect anti-PEG IgG and IgM in human blood plasma. Three hundred (300) plasma samples from healthy blood donors were screened; anti-PEG IgG or IgM was detected in 65.3% of the total population, with 21.3% having anti-PEG IgG, 19.0% having anti-PEG IgM, and 25.0% having both anti-PEG IgG and IgM. The presence of anti-PEG IgG and IgM was confirmed using a 0.5% Tween-20 interference assay, a 20 kDa PEGylated polystyrene bead binding assay, and Western blotting of purified plasma from human IgG and IgM purification columns. The concentrations of anti-PEG IgG and IgM in positive samples ranged from 39 ng/mL to 18.7 μg/mL and 26 ng/mL to 11.6 μg/mL, respectively. The highest prevalence of both anti-IgG and anti-IgM was in individuals 18–24 years of age. The prevalence of anti-PEG IgG and IgM tended to be higher in women but did not differ among races. Age, sex, and race were not associated with the concentrations of anti-PEG IgG or IgM. No correlation was found between anti-PEG IgG and IgM concentrations. Our study indicates that flow cytometry can be used to detect anti-PEG IgG and IgM antibodies in human plasma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The safety of 2 single domain antibodies (dAbs) was evaluated by inhalation toxicology studies in the cynomolgus monkey. In the first case study, a 14-day repeat-dose study evaluating an anti-thymic ...stromal lymphopoietin (anti-TSLP) dAb resulted in minimal mononuclear inflammatory cell infiltrates in the lungs, increases in lymphocytes in bronchoalveolar lavage fluid, and development of antidrug antibodies (ADAs). In a 6-week inhalation study, there was an increase in incidence and/or severity of mononuclear cell infiltrates in the lung, increased cellularity in the tracheobronchial lymph node (TBLN), and development of ADA. The second case study evaluated a change in duration of inhalation dosing, a different route of exposure (intravenous or IV), and recovery following an off-dose period with an anti-tumor necrosis factor receptor 1 dAb. A 7-day repeat-dose inhalation study and a 14-day IV study produced no microscopic effects in the lung, whereas a 14-day inhalation study resulted in moderate increases in pulmonary perivascular/peribronchiolar/alveolar lymphocytic infiltrates and increased cellularity in the TBLN, with partial and full recovery, respectively, after 14 days. The lung and lymph node findings seen after inhalation of either dAb were considered secondary to the immunogenic response to a human protein and were considered nonadverse.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Background:
The treatment for Crohn’s disease (CD) has increasingly required the use of biological agents. Safe and affordable tests have led to the active implementation of therapeutic drug ...monitoring (TDM) in clinical practice, which, although not yet widely available across all health services, has been proven effective.
Objective:
To analyze serum infliximab (IFX) and antidrug antibody (ADA) levels in CD patients, compare two tests, as well as construct a prediction of neural network using a combination of clinical, epidemiological, and laboratory variables.
Design:
Cross-sectional observational study.
Method:
A cross-sectional observational study was conducted on 75 CD patients in the maintenance phase of IFX treatment. The participants were allocated into two groups: CD in activity (CDA) and in remission (CDR). Disease activity was defined by endoscopic or radiological criteria. Serum IFX levels were measured by enzyme-linked immunosorbent assay (ELISA) and rapid lateral flow assay; ADA levels were measured by ELISA. A nonparametric test was used for statistical analysis; p value of ⩽0.05 was considered significant. Differences between ELISA and rapid lateral flow results within the measurement range were assessed by the Wilcoxon test, Passing–Bablok regression, and Bland–Altman method. Prediction models were created using four neural network sets. Neural networks and performance receiver operating characteristic curves were created using the Keras package in Python software.
Results:
Most participants exhibited supratherapeutic IFX levels (>7 mg/mL). Both tests showed no difference in IFX levels between the CDA and CDR groups ( p > 0.05). The use of immunosuppressive therapy did not affect IFX levels ( p > 0.05). Only 14.66% of patients had ADA levels >5 AU/mL, and all ADA-positive participants exhibited subtherapeutic IFX levels in both tests. The median results of both tests showed significant differences and moderate agreement ( r = −0.6758, p < 0.001). Of the four neural networks developed, two showed excellent performance, with area under the curve (AUCs) of 82–92% and 100%.
Conclusion:
Most participants exhibited supratherapeutic IFX levels, with no significant serum level difference between the groups. There was moderate agreement between tests. Two neural network sets showed disease activity and the presence of ADA, noninvasively determined in patients using IFX by presenting an AUC of >80%.
Plain language summary
Infliximab drug monitoring in Crohn’s disease
Crohn’s disease (CD) is a chronic condition that affects the gastrointestinal tract, with potential effects anywhere between the mouth and the anus. The primary treatment goal is symptom control and disease remission. The objective of this study was to analyze blood levels of infliximab (IFX), a commonly used medication for CD treatment. We also evaluated the level of antibodies that the body can produce against this medication to justify nonresponse to the drug. IFX levels were compared in 75 patients with CD in activity and in remission and using two different tests. The results showed that most patients had serum IFX above the recommended level (> 7 mg/mL). Neither of these tests showed differences in IFX levels when we evaluated disease activity or when the patients used immunosuppressants. Both tests showed antibodies against IFX in 14.66% of patients, all of whom had IFX levels below the therapeutic level. We compared two tests, ELISA and rapid test, and observed a difference between them, with moderate agreement. Normal serum IFX levels were higher with the rapid test than with the ELISA; however, they presented linear relationship. We also created prediction models using neural networks (artificial intelligence), which demonstrated excellent performance in noninvasively predicting disease activity and the presence of antibodies against IFX, achieving an area under the curve between 82% and 100%.
Background & Aims Few agents are available for the treatment of inflammatory bowel diseases, and patients frequently become unresponsive to biologics. We investigated the feasibility of reinitiating ...infliximab therapy for patients who previously received only episodic therapy with, lost response to, or had infusion reactions to infliximab. We also aimed to identify factors associated with the success and safety of restarting infliximab, such as antibodies to infliximab and trough levels of the drug. Methods From the inflammatory bowel disease biobank, we identified 128 consecutive patients (105 patients with Crohn's disease, 23 patients with ulcerative colitis) who restarted infliximab after a median 15-month discontinuation (range, 6–125 mo; 28 patients for loss of response or infusion reactions, 100 patients for remission or pregnancy). We also analyzed serum samples that had been collected during the first period of infliximab therapy (T-1), when therapy was reinitiated (T0), and at later time points (T+1, T+2) for trough levels and antibodies to infliximab. We investigated correlations among response to treatment, infusion reactions, treatment modalities, trough levels, and antibodies to infliximab. Results Reinitiation of infliximab therapy produced a response in 84.5% of patients at week 14, 70% of patients at 1 year, and in 61% of patients at more than 4 years. Fifteen patients had acute infusion reactions and 10 patients had delayed infusion reactions. The absence of antibodies to infliximab at T+1 (hazard ratio HR, 0.14; 95% confidence interval CI, 0.026–0.74; P = .021) and reinitiation with concomitant immunomodulator therapy were associated with short-term responses (HR, 6.0; 95% CI, 1.3–27; P = .019). Pregnancy or remission as reason for discontinuation (HR, 2.70; 95% CI, 1.09–6.67; P = .033) and higher trough levels at T+1 (HR, 2.94; 95% CI, 1.18–7.69; P = .021) were associated with long-term response. Undetectable antibodies to infliximab at T+1 were associated with the safety of reinitiating therapy (HR for infusion reaction with detectable antibodies to infliximab, 7.7; 95% CI, 1.88–31.3; P = .004). Conclusions Reinitiating infliximab therapy can be safe and effective for patients with Crohn's disease or ulcerative colitis after a median 15-month discontinuation period.
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