Immunogenicity to Biologics: Mechanisms, Prediction and Reduction

Sethu, Swaminathan; Govindappa, Karthik; Alhaidari, Mohammad; Pirmohamed, Munir; Park, Kevin; Sathish, Jean G.

doi:10.1007/s00005-012-0189-7

Cited by 110 publications

(140 citation statements)

References 165 publications

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“…A single intravenous dose of idarucizumab, a monoclonal antibody fragment, has a low potential to stimulate ADA formation. Nevertheless, the use of a biologic agent may be a potential risk factor for immunogenicity in the form of ADA production 44. A pooled analysis of data from three phase 1 studies found that pre‐existing and treatment‐emergent antidrug antibodies were present at low levels and had no impact on the PK/PD of idarucizumab in adults 45.…”

Section: Discussionmentioning

confidence: 99%

Rationale and design of a phase III safety trial of idarucizumab in children receiving dabigatran etexilate for venous thromboembolism

Albisetti¹,

Schlosser²,

Brueckmann³

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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Essentials There is no data on the use of idarucizumab in children with venous thromboembolism (VTE).We present the design of a trial that will assess the safety of idarucizumab in children with VTE.Patients will be recruited from two ongoing trials in children treated with dabigatran for VTE.Idarucizumab provides additional re‐assurance when rapid reversal of dabigatran effects is needed. BackgroundThe incidence of venous thromboembolism (VTE) in children has been increasing. Anticoagulants are the mainstay of treatment but are associated with bleeding events that may be life‐threatening. Idarucizumab is a fragment antigen‐binding (fab) that provides immediate, complete, and sustained reversal of dabigatran's anticoagulant effects in adults.Objective and MethodsThis phase III, open‐label, single‐arm, multicenter, multinational trial will assess the safety of idarucizumab in children participating in two ongoing trials investigating dabigatran etexilate. Eligible patients will be children with VTE (aged 0–≤18 years; n = ~5) with life‐threatening or uncontrolled bleeding (group A), and children who require emergency surgery/urgent procedures for a condition other than bleeding (group B). Patients will receive idarucizumab up to 5 g as two consecutive intravenous infusions over 5‐10 minutes each, as two 10‐15‐minute drips or as two bolus injections (15 minutes apart) and will be monitored for 30 days. The primary endpoint will be the safety of idarucizumab assessed by the occurrence of drug‐related adverse events (including immune reactions) and all‐cause mortality. Secondary endpoints will be the reversal of dabigatran anticoagulant effects assessed by changes in diluted thrombin time and ecarin clotting time, time to achieve complete reversal and the duration of the reversal and bleeding severity (group A). The formation of antidrug antibodies at 30 days post‐dose and cessation of bleeding will also be assessed.ConclusionThis study will report the safety of idarucizumab in children with VTE who require rapid reversal of the anticoagulant effects of dabigatran. Clinical trial registration: NCT02815670.

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Section: Discussionmentioning

confidence: 99%

Rationale and design of a phase III safety trial of idarucizumab in children receiving dabigatran etexilate for venous thromboembolism

Albisetti¹,

Schlosser²,

Brueckmann³

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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show abstract

“…Especially, determination of epitope specificity is recommended for nonendogenous fusion molecules, such as antibody-drug conjugates. Second, for multi-regional clinical trials, the frequency of ADA formation could differ among ethnicities as some reports showed an association of highly variable human leukocyte antigen types with ADA formation [20].…”

Section: Study Sample Analysismentioning

confidence: 99%

Immunogenicity of Therapeutic Protein Products: Current Considerations for Anti-Drug Antibody Assay in Japan

et al. 2017

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Immunogenicity assessment is an important issue for ensuring the safety and efficacy of therapeutic protein products. Although the reliability of the anti-drug antibody (ADA) assay is one of the key points, there are some difficulties in assessing its validity because the analytes are polyclonal antibodies with variable and unknown characteristics. To elucidate the points to consider for the ADA assay, a Japanese research group was established that discusses the issues raised on the immunogenicity assessment. In this review, we first introduce the current situation regarding the development and immunogenicity assessment of therapeutic protein products in Japan. We then present our current view and recommendations on the ADA assay by considering its unique features. Therapeutic proteins such as monoclonal antibodies are currently essential in the treatment of cancer, autoimmune disease and other diseases. Many therapeutic protein products intended to address unmet medical needs are being developed worldwide, including in Japan, and therefore, ensuring their safety and efficacy is of paramount importance. Since protein has its intrinsic feature of immunogenicity owing to its structure containing potential B-cell and T-cell epitopes, therapeutic proteins have the potential to induce ADA even if the protein has the same amino acid sequence as endogenous human proteins. Proteins can be recognized as antigens by B cells and are also incorporated and digested by antigen-presenting cells. This process leads to the production of T-cell epitope peptides that are presented on major histocompatibility (MHC) II molecules. Various patient-and product-specific factors are suggested to affect the process of ADA induction [1]. The emergence of ADA in patients can potentially lead to loss of efficacy and/or adverse events. Therefore, immunogenicity risk assessment and risk-mitigating strategies are required during the development of therapeutic protein products [2].The appropriateness of the ADA assay is a key issue in immunogenicity assessment. The ligand-binding assay (LBA) is often used for detecting ADA in biological samples. Unlike the assay used for drug concentration analysis, the ADA assay has unique features, for example: the actual characteristics of the analyte (human ADA) are variable and unknown; there is no real reference standard: the experimentally prepared positive control for ADA is used as a surrogate reference standard to evaluate and control the assay performance; and the evaluated validation parameters such as sensitivity and drug tolerance limit (DTL) vary depending on the characteristics, mainly the affinity of the used positive control. In addition, matrix components that interfere with the assay in the study samples may vary depending on the disease and/or the individual patients. Therefore, it is practically impossible to completely assess the validity of the ADA assay, and the assay is associated with certain risks of obtaining an inappropriate result. As mentioned in the European Medicines Agency (EMA...

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“…63 As an alternative therapeutic strategy to TNF-a inhibitors, treatments that manipulate leukocyte adhesion, costimulatory signaling and cytokine receptors are emerging as potential treatments for IBD. The current therapeutic approach for fistulising CD, in case of uncomplicated perianal fistulae, is based on seton placement, while abscesses and other complications require surgical intervention combined with medical therapy, which usually includes anti-TNF, antibiotics and thiopurines.…”

Section: Current Therapeutic Strategiesmentioning

confidence: 99%

The role of adipose stem cells in inflammatory bowel disease: From biology to novel therapeutic strategies

Francesco

Romano

Zarantonello

et al. 2016

Cancer Biology & Therapy

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Inflammatory bowel diseases are an increasing phenomenon in western countries and in growing populations. The physiopathology of these conditions is linked to intestinal stem cells homeostasis and regenerative potential in a chronic inflammatory microenvironment. Patients with IBD present an increased risk of developing colorectal cancer (CRC), or colitis associated cancer (CAC). Conventional treatment for IBD target the inflammatory process (and include anti-inflammatory and immunosuppressive drugs) with biological agents emerging as a therapeutic approach for non-responders to traditional therapy. Conventional treatment provides scarce results and present severe complications. The intestinal environment may host incoming stem cells, able to engraft in the epithelial damaged sites and differentiate. Therefore, stem cell therapies represent an emerging alternative in inflammatory bowel diseases, with current investigations on the use of haematopoietic and mesenchymal stem cells, in particular adipose stem cells, apparently fundamental as regenerators and as immune-modulators. Here, we discuss stem cells in intestinal homeostasis and as therapeutic agents for the treatment of inflammatory bowel diseases.

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Immunogenicity to Biologics: Mechanisms, Prediction and Reduction

Cited by 110 publications

References 165 publications

Rationale and design of a phase III safety trial of idarucizumab in children receiving dabigatran etexilate for venous thromboembolism

Rationale and design of a phase III safety trial of idarucizumab in children receiving dabigatran etexilate for venous thromboembolism

Immunogenicity of Therapeutic Protein Products: Current Considerations for Anti-Drug Antibody Assay in Japan

The role of adipose stem cells in inflammatory bowel disease: From biology to novel therapeutic strategies

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