• anti-drug antibodies
• infliximab
• long-term follow-up
• rheumatic diseases
• survival

• Rheumatoid arthritis
• biological treatment
• dosage reduction
• tumor necrosis factor-alpha inhibitors
• withdrawal

• Humans
• Arthritis, Rheumatoid/drug therapy
• Arthritis, Rheumatoid/immunology
• Antirheumatic Agents/therapeutic use
• Antirheumatic Agents/adverse effects
• Antirheumatic Agents/administration & dosage
• Tumor Necrosis Factor-alpha/antagonists & inhibitors
• Tumor Necrosis Factor-alpha/immunology
• Quality of Life

• Adalimumab
• Antidrug antibodies
• Methotrexate
• PK-PD model
• Psoriasis

• Humans
• Adalimumab/therapeutic use
• Methotrexate/therapeutic use
• Prospective Studies
• Antibodies, Monoclonal, Humanized/therapeutic use
• Psoriasis/drug therapy
• Treatment Outcome

• Adalimumab
• Anti-TNF
• Crohn’s disease
• Inflammatory Bowel disease
• Infliximab
• Markers
• Ulcerative colitis

• Adult
• Humans
• Infliximab/therapeutic use
• Tumor Necrosis Factor Inhibitors/therapeutic use
• Tumor Necrosis Factor-alpha/therapeutic use
• Inflammatory Bowel Diseases/drug therapy
• Colitis, Ulcerative/drug therapy
• Biomarkers

• Humans
• Antibody Formation
• Antigens
• Antibodies
• B-Lymphocytes
• Biological Products/pharmacology

• P30 CA014599 NCI NIH HHS
• T32 AI007090 NIAID NIH HHS
• UL1 TR000430 NCATS NIH HHS

• Crohn's disease
• Inflammatory diseases
• TNF alpha blockers
• anti-drug antibodies
• disease activity
• immunogenicity
• rheumatoid arthritis.
• trough serum concentration

• Humans
• Male
• Female
• Adult
• Middle Aged
• Cross-Sectional Studies
• Infliximab/therapeutic use
• Infliximab/immunology
• Adalimumab/therapeutic use
• Adalimumab/immunology
• Adalimumab/blood
• Tunisia/epidemiology
• Antirheumatic Agents/therapeutic use
• Tumor Necrosis Factor-alpha/antagonists & inhibitors
• Tumor Necrosis Factor-alpha/immunology
• Arthritis, Rheumatoid/drug therapy
• Arthritis, Rheumatoid/immunology
• Arthritis, Rheumatoid/blood
• Antibodies/blood
• Treatment Outcome
• Aged
• Crohn Disease/drug therapy
• Crohn Disease/immunology
• Crohn Disease/blood
• Spondylarthritis/drug therapy
• Spondylarthritis/immunology
• Spondylarthritis/blood

• Anti-drug antibody
• Concentration
• Enzyme-linked immunosorbent assay
• Infliximab
• Therapeutic drug monitoring

• adaptive immunity
• cell targeting
• innate immunity
• targeted vaccines
• vaccine

• Vaccines/immunology
• Drug Design
• Immunity
• Immune System/cytology
• Humans
• Animals

• T32 AI153020 NIAID NIH HHS
• Division of Intramural Research, National Institute of Allergy and Infectious Diseases

• Fc-γ receptor
• adalimumab
• anti-drug antibody
• etanercept
• infliximab
• rheumatoid arthritis
• rituximab

• Humans
• Adalimumab/therapeutic use
• Antibodies, Monoclonal/therapeutic use
• Arthritis, Rheumatoid/drug therapy
• Arthritis, Rheumatoid/genetics
• Biological Products/therapeutic use
• Cross-Sectional Studies
• Etanercept/therapeutic use
• Infliximab/therapeutic use
• Polymorphism, Single Nucleotide
• Rituximab/therapeutic use

• HLA-DQA1*05
• anti-TNF therapy
• anti-drug antibodies
• inflammatory bowel disease (IBD)
• pharmacogenomics
• rs2097432

• MHC-II
• deep learning
• immunogenicity
• protein language model
• transfer learning

• AbbVie Inc.

• Biomarkers
• Cytokines/therapeutic use
• Humans
• Immunologic Factors/therapeutic use
• Inflammation
• Inflammatory Bowel Diseases/drug therapy

• Antibodies, Monoclonal/therapeutic use
• Antineoplastic Agents, Immunological
• Haplotypes
• Humans
• Neoplasms/drug therapy

Monoclonal antibodies that block the interaction between programmed cell death 1 (PD-1) and its ligand (PD-L1) have revolutionized cancer immunotherapy. However, immunogenic responses to these new therapies—such as the development of antidrug antibodies (ADAs) and neutralizing antibodies (NAbs)—may represent a significant challenge to both efficacy and safety in some patients. Dostarlimab (TSR-042) is an approved, humanized, anti-PD-1 monoclonal antibody that has shown efficacy in multiple solid tumor types. Here, we report the results of an immunogenicity analysis of dostarlimab monotherapy in patients enrolled in the GARNET trial, a multicenter, open-label, single-arm phase 1 study. Overall, 477 of 478 patients (99.8%) were included in the analysis of dostarlimab antibody prevalence, and 349 out of 478 enrolled patients (73.0%) were evaluable for treatment-emergent antibodies to dostarlimab. The incidence of treatment-emergent ADAs was 2.5% at the recommended therapeutic dose (500 mg Q3W for the first 4 doses, 1000 mg Q6W until discontinuation), which is comparable to other anti-PD-(L)1 drugs. NAbs were detected in only 1.3% of patients. In the small percentage of patients who developed ADAs, there was no evidence of altered efficacy or safety of dostarlimab at the recommended dosing regimen. These findings demonstrated that treatment with dostarlimab was associated with a low risk of eliciting clinically meaningful ADAs over the course of this study, and dostarlimab is already approved by health authorities.

• Antibody
• Immuno-oncology
• Immunogenicity
• PD-1

• Psoriasis
• anti-drug antibodies
• biologic disease modifying therapies
• immunotherapy

• Anti-TNF drug trough levels
• Anti-drug antibodies
• Biologics
• Children
• Juvenile idiopathic arthritis (JIA)

• Healthy volunteers
• Humanized rabbit monoclonal antibody
• Immunogenicity
• Safety

• antibodies
• drug monitoring
• enzyme-linked immunosorbent assay
• immunoassay
• inflammatory bowel diseases
• infliximab
• point-of-care systems

• Portuguese IBD Study Group (GEDII)
• fundação para a ciência e a tecnologia

• Antibodies
• inflammatory bowel disease
• peripheral arthritis
• rheumatoid arthritis
• spondyloarthritis
• tumoral necrosis factor.

Biological drugs, such as proteins and immunogens, are increasingly used to treat various diseases, including tumors and autoimmune diseases, and biological molecules have almost completely replaced synthetic drugs in rheumatology. Although biological treatments such as anti-tumor necrosis factor (TNF) drugs seem to be quite safe, they cause some undesirable effects, such as the onset of infections due to weakening of the immune system. Given the biological nature of these drugs, they might be recognized as extraneous; this would induce an immune reaction that neutralizes their effectiveness or lead to more serious consequences. Laboratories play a pivotal role in appropriate therapeutic management. The aim of this review was to underline the production of anti-drug antibodies during treatment with biological drugs and highlight the role of laboratories in ensuring appropriate use of these drugs.

• Anti-drug antibodies
• Anti-tumor necrosis factor (TNF) drugs
• Antibodies
• Biological drugs

Tumor necrosis factor inhibitors (TNFi) have significantly improved treatment outcome of rheumatic diseases since their incorporation into treatment protocols two decades ago. Nevertheless, a substantial fraction of patients experiences either primary or secondary failure to TNFi due to ineffectiveness of the drug or adverse reactions. Secondary failure and adverse events can be related to the development of anti-drug antibodies (ADA). The earliest studies that reported ADA toward TNFi mainly used drug-sensitive assays. Retrospectively, we recognize this has led to an underestimation of the amount of ADA produced due to drug interference. Drug-tolerant ADA assays also detect ADA in the presence of drug, which has contributed to the currently reported higher incidence of ADA development. Comprehension and awareness of the assay format used for ADA detection is thus essential to interpret ADA measurements correctly. In addition, a concurrent drug level measurement is informative as it may provide insight in the extent of underestimation of ADA levels and improves understanding the clinical consequences of ADA formation. The clinical effects are dependent on the ratio between the amount of drug that is neutralized by ADA and the amount of unbound drug. Pharmacokinetic modeling might be useful in this context. The ADA response generally gives rise to high affinity IgG antibodies, but this response will differ between patients. Some patients will not reach the phase of affinity maturation while others generate an enduring high titer high affinity IgG response. This response can be transient in some patients, indicating a mechanism of tolerance induction or B-cell anergy. In this review several different aspects of the ADA response toward TNFi will be discussed. It will highlight the ADA assays, characteristics and regulation of the ADA response, impact of immunogenicity on the pharmacokinetics of TNFi, clinical implications of ADA formation, and possible mitigation strategies.

• antidrug antibodies
• assay
• drug levels
• immunogenicity
• tumor necrosis factor inhibitors

• anti-CD20 monoclonal antibody
• immuno-monitoring
• immunogenicity
• membranous nephropathy
• rituximab

• Anti-Infliximab antibodies
• Atherosclerosis
• Infliximab
• Rheumatic disease

• Antibodies, Neutralizing/blood
• Antibodies, Neutralizing/metabolism
• Cells, Cultured
• Coronary Vessels/drug effects
• Coronary Vessels/immunology
• Coronary Vessels/metabolism
• Endothelial Cells/drug effects
• Endothelial Cells/immunology
• Endothelial Cells/metabolism
• Humans
• Inflammation Mediators/metabolism
• Infliximab/immunology
• Interleukin-1beta/pharmacology
• Serum Amyloid A Protein/pharmacology
• Tumor Necrosis Factor Inhibitors/immunology
• Tumor Necrosis Factor-alpha/pharmacology

Pembrolizumab is a potent, humanized, monoclonal anti–programmed death 1 antibody that has demonstrated effective antitumor activity and acceptable safety in multiple tumor types. Therapeutic biologics can result in the development of antidrug antibodies (ADAs), which may alter drug clearance and neutralize target binding, potentially reducing drug efficacy; such immunogenicity may also result in infusion reactions, anaphylaxis, and immune complex disorders. Pembrolizumab immunogenicity and its impact on exposure, safety, and efficacy was assessed in this study.

Pembrolizumab immunogenicity was assessed in 3655 patients with advanced or metastatic cancer treated in 12 clinical studies. Patients with melanoma, non–small cell lung cancer, head and neck squamous cell carcinoma, colorectal cancer, urothelial cancer, and Hodgkin lymphoma were treated with pembrolizumab at 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. An additional study involving 496 patients with stage III melanoma treated with 200 mg adjuvant pembrolizumab every 3 weeks after complete resection was analyzed separately.

Of 3655 patients, 2000 were evaluable for immunogenicity analysis, 36 (1.8%) were treatment-emergent (TE) ADA-positive; 9 (0.5%) of these TE-positive patients had antibodies with neutralizing capacity. The presence of pembrolizumab-specific ADAs did not impact pembrolizumab exposure, nor did pembrolizumab immunogenicity affect the incidence of drug-related adverse events (AEs) or infusion-related reactions. There was no clear relationship between the presence of pembrolizumab-specific ADAs and changes in tumor size across treatment regimens. Of the 496 patients treated with pembrolizumab as adjuvant therapy, 495 were evaluable, 17 (3.4%) were TE ADA–positive; none had neutralizing antibodies.

The incidence of TE (neutralizing positive) ADAs against pembrolizumab was low in patients with advanced tumors. Furthermore, immunogenicity did not appear to have any clinically relevant effects on the exposure, safety, or efficacy of pembrolizumab.

ClinicalTrials.gov, NCT01295827 (February 15, 2011), NCT01704287 (October 11, 2012), NCT01866319 (May 31, 2013), NCT01905657 (July 23, 2013), NCT02142738 (May 20, 2014), NCT01848834 (May 8, 2013), NCT02255097 (October 2, 2014), NCT02460198 (June 2, 2015), NCT01953692 (October 1, 2013), NCT02453594 (May 25, 2015), NCT02256436 (October 3, 2014), NCT02335424 (January 9, 2015), NCT02362594 (February 13, 2015).

The online version of this article (10.1186/s40425-019-0663-4) contains supplementary material, which is available to authorized users.

• Advanced tumors
• Efficacy
• Immunogenicity
• Pembrolizumab
• Safety
• Treatment-emergent ADA

• Biosimilares
• Biosimilars
• Posicionamiento
• Position paper
• Review
• Revisión
• Sociedad Española de Reumatología
• Spanish Society of Rheumatology

• TNF-alpha
• anti-TNF biologics
• autoimmune disease
• chronic inflammation
• rheumatoid arthritis
• shark IgNAR
• variable new antigen receptors (VNARs)

Crotamine is a single-chain polypeptide with cell-penetrating properties, which is considered a promising molecule for clinical use. Nevertheless, its biosafety data are still scarce. Herein, we assessed the in vivo proinflammatory properties of crotamine, including its local effect and systemic serum parameters. Sixty male Wistar rats were intradermically injected with 200, 400 and 800 µg crotamine and analyzed after 1, 3 and 7 days. Local effect of crotamine was assessed by determination of MPO and NAG activities, NO levels and angiogenesis. Systemic inflammatory response was assessed by determination of IL-10, TNF-α, CRP, NO, TBARS and SH groups. Crotamine induced macrophages and neutrophils chemotaxis as evidenced by the upregulation of both NAG (0.5–0.6 OD/mg) and MPO (0.1–0.2 OD/mg) activities, on the first and third day of analysis, respectively. High levels of NO were observed for all concentrations and time-points. Moreover, 800 μg crotamine resulted in serum NO (64.7 μM) and local tissue NO (58.5 μM) levels higher or equivalent to those recorded for their respective histamine controls (55.7 μM and 59.0 μM). Crotamine also induced a significant angiogenic response compared to histamine. Systemically, crotamine induced a progressive increase in serum CRP levels up to the third day of analysis (22.4–45.8 mg/mL), which was significantly greater than control values. Crotamine (400 μg) also caused an increase in serum TNF-α, in the first day of analysis (1095.4 pg/mL), however a significant increase in IL-10 (122.2 pg/mL) was also recorded for the same time-point, suggesting the induction of an anti-inflammatory effect. Finally, crotamine changed the systemic redox state by inducing gradual increase in serum levels of TBARS (1.0–1.8 μM/mL) and decrease in SH levels (124.7–19.5 μM/mL) throughout the experimental period of analysis. In summary, rats intradermally injected with crotamine presented local and systemic acute inflammatory responses similarly to histamine, which limits crotamine therapeutic use on its original form.

• Crotalus durissus terrificus
• cell-penetrating peptide
• crotamine
• inflammation

• Animals
• C-Reactive Protein/immunology
• Crotalid Venoms/toxicity
• Inflammation/chemically induced
• Inflammation/immunology
• Injections, Intradermal
• Interleukin-10/immunology
• Male
• Neovascularization, Physiologic
• Nitric Oxide/immunology
• Rats, Wistar
• Tumor Necrosis Factor-alpha/immunology

• immunogenicity
• microparticle(s)
• monoclonal antibody(s)
• nanoparticle(s)
• particle size
• protein aggregation

• Anti-drug antibody
• IL-17 inhibitor
• brodalumab
• ixekizumab
• secukinumab

• Anti-drug antibody assay
• Collaborative study
• Confirmatory assay cut point
• Drug tolerance
• Precision
• Screening assay cut point
• Selectivity
• Sensitivity

• Antibodies, Monoclonal, Humanized/blood
• Humans
• Immunosuppressive Agents/blood

• Ipilimumab
• anti-drug antibodies
• cancer
• checkpoint inhibitors
• immunogenicity
• malignant melanoma

• Annual relapse rate
• Anti-Rituximab antibody
• EDSS
• Human anti-chimeric antibody
• Neuromyelitis optica spectrum disorders
• Rituximab

The management of chronic inflammatory diseases, such as inflammatory bowel disease, psoriasis, and rheumatoid arthritis has significantly improved over the last decade with the clinical availability of anti-TNF-α biologics. Despite this undoubted treatment success, a combination of acquired resistance together with an increased risk of systemic complications, means that a significant number of patients either fail to find a suitable targeted therapy or frustratingly discover that an approach that did work is no longer efficacious. Here, we report the isolation and characterization of a new class of super-neutralizing anti-TNF-α biologics formats, the building blocks of which were originally derived as variable new antigen receptor (VNAR) domains from an immunized nurse shark. These parental small, stable VNAR monomers recognize and neutralize tumor necrosis factor (TNF)-α, in cell-based assays, at nanomolar concentrations. However, the simple, single-chain molecular architecture of VNARs allows for easy and multiple reformatting options. Through reformatting, we achieved a 50,000-fold enhancement in in vitro efficacy with super-neutralizing fusion proteins able to block TNF-α induced cytotoxicity in the 2–5 pM range while retaining other functionality through the addition of fusion proteins known to extend serum half-life in vivo. In an in vitro intestinal epithelial barrier dysfunction efficacy model, the lead VNAR domains, restored barrier function and prevented paracellular flux with comparable efficacy to adalimumab (Humira^®). In addition, all multivalent VNAR constructs restored trans-epithelial electrical resistance (TEER) to approximately 94% of the untreated control. Reformatted VNAR domains should be considered as a new class of biologic agents for the treatment of hTNF-α driven diseases; either used systemically with appropriate half-life extension or alternatively where site-specific delivery of small and stable neutralizers may provide improvements to current therapy options.

• anti-TNF biologics
• bi-paratopic/bi-specific binding domain
• chronic inflammation
• cytokine neutralization
• phage display
• shark IgNAR
• tumor necrosis factor-α
• variable new antigen receptor