Mother-to-Child Signaling through Breast Milk Biomolecules.

Breastfeeding-or lactation-is a unique and defining reproductive trait of mammals that nourishes offspring by supplying nutrient-rich breast milk [...].

Impact of Food-Derived Bioactive Compounds on Intestinal Immunity.

The gastrointestinal system is responsible for the digestion and the absorption of nutrients. At the same time, it is essentially involved in the maintenance of immune homeostasis. The strongest antigen contact in an organism takes place in the digestive system showing the importance of a host to develop mechanisms allowing to discriminate between harmful and harmless antigens. An efficient intestinal barrier and the presence of a large and complex part of the immune system in the gut support the host to implement this task. The continuous ingestion of harmless antigens via the diet requires an efficient immune response to reliably identify them as safe. However, in some cases the immune system accidentally identifies harmless antigens as dangerous leading to various diseases such as celiac disease, inflammatory bowel diseases and allergies. It has been shown that the intestinal immune function can be affected by bioactive compounds derived from the diet. The present review provides an overview on the mucosal immune reactions in the gut and how bioactive food ingredients including secondary plant metabolites and probiotics mediate its health promoting effects with regard to the intestinal immune homeostasis.

A structure-based engineering approach to abrogate pre-existing antibody binding to biotherapeutics.

Development of biotherapeutics is hampered by the inherent risk of immunogenicity, which requires extensive clinical assessment and possible re-engineering efforts for mitigation. The focus in the pre-clinical phase is to determine the likelihood of developing treatment-emergent anti-drug antibodies (TE-ADA) and presence of pre-existing ADA in drug-naïve individuals as risk-profiling strategies. Pre-existing ADAs are routinely identified during clinical immunogenicity assessment, but their origin and impact on drug safety and efficacy have not been fully elucidated. One specific class of pre-existing ADAs has been described, which targets neoepitopes of antibody fragments, including Fabs, VH, or VHH domains in isolation from their IgG context. With the increasing number of antibody fragments and other small binding scaffolds entering the clinic, a widely applicable method to mitigate pre-existing reactivity against these molecules is desirable. Here is described a structure-based engineering approach to abrogate pre-existing ADA reactivity to the C-terminal neoepitope of VH(H)s. On the basis of 3D structures, small modifications applicable to any VH(H) are devised that would not impact developability or antigen binding. In-silico B cell epitope mapping algorithms were used to rank the modified VHH variants by antigenicity; however, the limited discriminating capacity of the computational methods prompted an experimental evaluation of the engineered molecules. The results identified numerous modifications capable of reducing pre-existing ADA binding. The most efficient consisted of the addition of two proline residues at the VHH C-terminus, which led to no detectable pre-existing ADA reactivity while maintaining favorable developability characteristics. The method described, and the modifications identified thereby, may provide a broadly applicable solution to mitigate immunogenicity risk of antibody-fragments in the clinic and increase safety and efficacy of this promising new class of biotherapeutics.

Interplay of Anti-Viral Vaccines with Biologic Agents and Immunomodulators in Individuals with Autoimmune and Autoinflammatory Diseases.

Vaccines are an essential part of a preventative healthcare strategy. However, response to vaccines may be less predictable in immunocompromised people. While outcomes for individuals with autoimmune and autoinflammatory diseases have dramatically improved with treatment using immunomodulating and biologic agents, infections have caused significant morbidity in these people today often more than due to their underlying diseases. Immune-based biologic therapies contribute to these infectious complications. This review addresses anti-viral vaccines, their effectiveness and safety in patients treated with approved biologic agents and immune targeted therapy with a focus on vaccines against influenza, human papillomavirus, hepatitis B virus and varicella zoster virus. Preliminary information regarding SARS-CoV-2 anti-viral vaccines is addressed. Additionally, we present recommendations regarding the safe use of vaccines in immunocompromised individuals with the goal to enhance awareness of the safety and efficacy of these anti-viral vaccines in these high-risk populations.

Behçet disease: From pathogenesis to novel therapeutic options.

Behçet disease (BD) is a complex, multi-systemic inflammatory condition mainly hallmarked by oral and genital ulcers which can also affect the vessels, gastrointestinal tract, central nervous system and even the axial skeleton. Without a clear classification among autoimmune or autoinflammatory conditions, BD has been recently classified as a MHC-I-opathy. BD aetiology is still obscure, but it is thought that certain microorganisms can elicit an aberrant adaptive immune response in the presence of a permissive genetic background. Altered T-cell homeostasis, mostly Th1/Th17 expansion and Treg impairment, could lead to an overactivation of the innate immunity, which underlies tissue damage and thus, signs and symptoms. Immunosuppression and/or immunomodulation are central to the BD management. A complex armamentarium ranging from classical synthetic disease-modifying antirrheumatic drugs to new-era biologic agents or small molecules is available in BD, with different therapeutic outcomes depending on disease manifestations. However, the precise disease mechanisms that underlie BD symptoms are not fully deciphered, which may limit their therapeutic potential and add a significant layer of complexity to the treatment decision-making process. The aim of the present review is to provide an exhaustive overview of the latest breakthroughs in BD pathogenesis and therapeutic options.

Immunogenicity of biologic agents in rheumatology.

Biologic agents have become a core component of therapeutic strategies for many inflammatory rheumatic diseases. However, perhaps reflecting the specificity and generally high affinity of biologic agents, these therapeutics have been used by rheumatologists with less consideration of their pharmacokinetics than that of conventional synthetic DMARDs. Immunogenicity was recognized as a potential limitation to the use of biologic agents at an early stage in their development, although regulatory guidance was relatively limited and assays to measure immunogenicity were less sophisticated than today. The advent of biosimilars has sparked a renewed interest in immunogenicity that has resulted in the development of increasingly sensitive assays, an enhanced appreciation of the pharmacokinetic consequences of immunogenicity and the development of comprehensive and specific guidance from regulatory authorities. As a result, rheumatologists have a greatly improved understanding of the field in general, including the factors responsible for immunogenicity, its potential clinical consequences and the implications for everyday treatment. In some specialties, immunogenicity testing is becoming a part of routine clinical management, but definitive evidence of its cost-effectiveness in rheumatology is awaited.

Immunogenicity-unwanted immune responses to biological drugs - can we predict them?

INTRODUCTION: Biological agents (BAs) target molecules involved in disease mechanisms and have modified the natural history of several immune-mediated disorders. All BAs are immunogenic, resulting in the formation of antidrug antibodies (ADAs), which can neutralize drug activity leading to loss of response and potential relapse, or serious adverse events such as infusion hypersensitivity reactions. The production of ADAs is the result of a specific adaptive immune response in which T and B cells are involved. AREAS COVERED: Factors conditioning the immunogenicity of BAs, including drug-, treatment- and patient-related factors are currently the subject of many studies. Among them, a lot of attention is dedicated to define the impact of BAs structure, the effect of targeting (soluble or membrane) molecules, the impact of interruption of therapy as well as the role of genetic (HLA and non-HLA) predisposing factors and disease activity. EXPERT OPINION: Knowledge of factors capable of influencing the immunogenicity of BAs may help to understand, in a predictive manner and at the single patient level, the presence of risk factors influencing the production of ADAs and their impact on clinical outcomes.

Laboratory Monitoring of Biological Therapies in Rheumatology: The Role of Immunogenicity.

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.

Immunogenicity of biologic agents in juvenile idiopathic arthritis: a systematic review and meta-analysis.

OBJECTIVE: The clinical impact of anti-drug antibodies (ADAbs) in paediatric patients with JIA remains unknown. This systematic review and meta-analysis aimed to summarize the prevalence of ADAbs in JIA studies; investigate the effect of ADAbs on treatment efficacy and adverse events; and explore the effect of immunosuppressive therapy on antibody formation. METHODS: PubMed, Embase and the Cochrane Library were systematically searched to identify relevant clinical trials and observational studies that reported prevalence of ADAbs. Studies were systematically reviewed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses and appropriate proportional and pairwise meta-analyses were performed. RESULTS: A total of 5183 references were screened; 28 articles, involving 26 studies and 2354 JIA patients, met eligibility criteria. Prevalence of ADAbs ranged from 0% to 82% across nine biologic agents. Overall pooled prevalence of ADAbs was 16.9% (95% CI, 9.5, 25.9). Qualitative analysis of included studies indicated that antibodies to infliximab, adalimumab, anakinra and tocilizumab were associated with treatment failure and/or hypersensitivity reactions. Concomitant MTX uniformly reduced the risk of antibody formation during adalimumab treatment (risk ratio 0.33; 95% CI 0.21, 0.52). CONCLUSION: The association of ADAbs with treatment failure and hypersensitivity reactions indicates their clinical relevance in paediatric patients with JIA. Based on our findings, we recommend a preliminary course of action regarding immunogenicity of biologic agents in patients with JIA. Further strategies to predict, prevent, detect and manage immunogenicity could optimize treatment outcomes and personalize treatment with biologic therapies.

A Model-Based Approach to Quantify the Time-Course of Anti-Drug Antibodies for Therapeutic Proteins.

A mathematical antidrug antibody (ADA) model was developed to quantitatively assess immunogenicity for therapeutic proteins. The ADA model was built with antibody titer data in subjects from 10 clinical trials. The time course of the antibody titers was quantitatively characterized with a two-component semimechanistic model describing the double peaks of ADA titers. The relationship between antibody titer and incidence was also explored. The ADA incidences in subjects from 12 clinical trials were used for internal and external validations. The ADA titers reasonably predicted the incidence of antibody. The model-predicted elimination rate constant for antibody titer was 14.1 × 10-3  day-1 and 8.1 × 10-3  day-1 in healthy subjects and patients, respectively. This research provided a useful tool to quantitatively evaluate immunogenicity and its impact for therapeutic proteins.