Molecular Landscape of Anti-Drug Antibodies Reveals the Mechanism of the Immune Response Following Treatment With TNFα Antagonists

Vaisman-Mentesh, Anna; Rosenstein, Shai; Yavzori, Miri; Dror, Yael; Fudim, Ella; Ungar, Bella; Kopylov, Uri; Picard, Orit; Kigel, Aya; Ben‐Horin, Shomron; Benhar, Itai; Wine, Yariv

doi:10.3389/fimmu.2019.02921

Cited by 47 publications

(37 citation statements)

References 54 publications

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“…The mAb target may also have high importance for the MOA of ADA formation. We recently found that repeated administration of infliximab (a TNFα antagonist) results in a vaccine-like response, where ADA formation is governed by the extrafollicular T cell-independent immune response ( 96 ). The administration of infliximab blocks TNFα and shifts the immune response toward the marginal zone (MZ) instead of the germinal center (GC), as observed in TNFα knockout mice ( 97 ).…”

Section: Drug and Patient Characteristics Contributing To Ada Formatimentioning

confidence: 99%

“…We recently reported on a newly developed quantitative bio-immunoassay for quantifying ADA specific to TNFα antagonists. The bio-immunoassay was further modified to easily assess the neutralization capacity of ADA using an in vitro assay ( 96 ). This assay can be readily used in a clinical setting that performs routine ADA measurements.…”

Section: Assays For Immunogenicity Assessment and Tools For Immunogenmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Drug and Patient Characteristics Contributing To Ada Formatimentioning

confidence: 99%

Section: Assays For Immunogenicity Assessment and Tools For Immunogenmentioning

confidence: 99%

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

et al. 2020

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“…Additionally, infusion reactions are associated with therapy discontinuation [ 38 ]. Systemic administration may induce anti-drug antibodies (ADA), which in turn is associated with infusion reactions as well as loss of efficacy [ 39 , 40 , 41 ].…”

Section: Introductionmentioning

confidence: 99%

Review: Local Tumor Necrosis Factor-α Inhibition in Inflammatory Bowel Disease

et al. 2020

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Crohn’s disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characterized by intestinal inflammation. Increased intestinal levels of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) are associated with disease activity and severity. Anti-TNF-α therapy is administered systemically and efficacious in the treatment of IBD. However, systemic exposure is associated with adverse events that may impede therapeutic treatment. Clinical studies show that the efficacy correlates with immunological effects localized in the gastrointestinal tract (GIT) as opposed to systemic effects. These data suggest that site-specific TNF-α inhibition in IBD may be efficacious with fewer expected side effects related to systemic exposure. We therefore reviewed the available literature that investigated the efficacy or feasibility of local TNF-α inhibition in IBD. A literature search was performed on PubMed with given search terms and strategy. Of 8739 hits, 48 citations were included in this review. These studies ranged from animal studies to randomized placebo-controlled clinical trials. In these studies, local anti-TNF-α therapy was achieved with antibodies, antisense oligonucleotides (ASO), small interfering RNA (siRNA), microRNA (miRNA) and genetically modified organisms. This narrative review summarizes and discusses these approaches in view of the clinical relevance of local TNF-α inhibition in IBD.

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“…For sample collection, peripheral blood mononuclear cells (PBMCs) and total B cells have been generally used because of their accessibility. [ 9–11 ] However, because antibody repertoire properties are divergent between antigen‐specific B cells and plasma cells, [ 12 ] specific B cell populations or B cells located in targeted tissues should be enriched for more precise studies. Considering that as few as 2% of total B cells are circulating in peripheral blood, [ 13 ] this population can only provide a narrow view of the adaptive immune response to antigens; therefore, lymph nodes, spleen, and red bone marrow are preferential as the sources of B cells if accessible.…”

Section: Overview Of Ig‐seq Pipelinementioning

confidence: 99%

Deep Mining of Human Antibody Repertoires: Concepts, Methodologies, and Applications

Tian

et al. 2020

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of V-J genes in the immunoglobulin light chains variable regions (V L), during the early stages of B cell maturation in the bone marrow; [1] 2) junctional diversity resulting from exonuclease trimmings and the random addition of palindrome (P) or non-template encoded (N) nucleotides in the process of rearrangement; [2] and 3) B cell proliferation after antigen stimulation in order to produce high-affinity antibodies and eliminate the antigen through subsequent class switch recombination (CSR) and somatic hypermutation (SHM). [3,4] It is estimated that there are over 10 13 BCRs in the human antibody repertoire. [5] This astronomical size prevents a global analysis of the antibody repertoire using conventional DNA sequencing. However, advancements in highthroughput sequencing (HTS) for Ig-Seq have improved the ability to characterize the antibody repertoire on a large scale. [6] Over a decade of development, a variety of new technologies and approaches have improved Ig-Seq methods, resulting in improved understanding of B-cell immunology and accumulation of massive antibody sequence data. In this review, an overview of Ig-Seq and advanced methodologies applied to HTS of antibody repertoires will be discussed. We will describe the wide applications of Ig-Seq in basic and clinical immunology, and strategies for functional antibody discovery from antibody repertoires. Finally, we will provide our perspective on the future directions and challenges in human antibody repertoire deep mining. 2. Overview of Ig-Seq Pipeline Although multiple strategies have been used for studying antibody repertoires, each strategy follows a similar workflow including sample collection, library preparation and sequencing, data cleaning, sequence alignment, and high-level processing (Figure 1). For sample collection, peripheral blood mononuclear cells (PBMCs) and total B cells have been generally used because of their accessibility. [9-11] However, because antibody repertoire properties are divergent between antigen-specific B cells and plasma cells, [12] specific B cell populations or B cells located in targeted tissues should be enriched for more precise studies. Considering that as few as 2% of total B cells are circulating in The ability of the human adaptive immune system to respond to antigens relies upon the tremendous diversity of T cell receptors (TCR) and B cell receptors (BCR). The entirety of an individual's BCRs, often referred to as an antibody repertoire, shapes the humoral immune system. Therefore, technologies to identify and characterize antibody repertoires are critical for understanding fundamental aspects of the development and maintenance of the humoral immune system. Recently, innovative methodologies and technologies devoted to high-throughput sequencing of antibody repertoires (Ig-Seq) have broadened the understanding of humoral immunity. This review provides an overview of the Ig-Seq pipeline from sample collection, library preparation, and sequencing, to data cleaning, sequence alignment, and highlevel processing....

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Molecular Landscape of Anti-Drug Antibodies Reveals the Mechanism of the Immune Response Following Treatment With TNFα Antagonists

Cited by 47 publications

References 54 publications

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

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

Review: Local Tumor Necrosis Factor-α Inhibition in Inflammatory Bowel Disease

Deep Mining of Human Antibody Repertoires: Concepts, Methodologies, and Applications

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