T-cell assays confirm immunogenicity of tungsten-induced erythropoietin aggregates associated with pure red cell aplasia

Rubic-Schneider, Tina; Kuwana, Masataka; Christen, Brigitte; Aßenmacher, Manuela; Hainzl, Otmar; Zimmermann, Frank; Fischer, R.; Koppenburg, Vera; Chibout, Salah-Dine; Wright, Timothy M.; Seidl, Andreas; Kammüller, Michael

doi:10.1182/bloodadvances.2016001842

Cited by 28 publications

(24 citation statements)

References 35 publications

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“…The second case affected a biosimilar epoetin [35,36]. A comparative efficacy study, undertaken to complete the data package for gaining approval for subcutaneous (SC) treatment of chronic kidney disease patients, was stopped in 2009 after two patients developed neutralizing antibodies.…”

Section: Evaluation Of Comparative Efficacy Studiesmentioning

confidence: 99%

The Path Towards a Tailored Clinical Biosimilar Development

Schiestl¹,

Ranganna

Watson

et al. 2020

BioDrugs

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Since the first approval of a biosimilar medicinal product in 2006, scientific understanding of the features and development of biosimilar medicines has accumulated. This review scrutinizes public information on development programs and the contribution of the clinical studies for biosimilar approval in the European Union (EU) and/or the United States (US) until November 2019. The retrospective evaluation of the programs that eventually obtained marketing authorization and/or licensure revealed that in 95% (36 out of 38) of all programs, the comparative clinical efficacy studies confirmed similarity. In the remaining 5% (2 out of 38), despite meeting efficacy outcomes, the biosimilar candidates exhibited clinical differences in immunogenicity that required changes to the manufacturing process and additional clinical studies to enable biosimilar approval. Both instances of clinical differences in immunogenicity occurred prior to 2010, and the recurrence of these cases is unlikely today due to state-of-the-art assays and improved control of process-related impurities. Biosimilar candidates that were neither approved in the EU nor in the US were not approved due to reasons other than clinical confirmation of efficacy. This review of the development history of biosimilars allows the proposal of a more efficient and expedited biosimilar development without the routine need for comparative clinical efficacy and/or pharmacodynamic studies and without any compromise in quality, safety, or efficacy. This proposal is scientifically valid, consistent with regulation of all biologics, and maintains robust regulatory standards in the assessment of biosimilar candidates. Note: The findings and conclusion of this paper are limited to biosimilar products developed against the regulatory standards in the EU and the US.

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Section: Evaluation Of Comparative Efficacy Studiesmentioning

confidence: 99%

The Path Towards a Tailored Clinical Biosimilar Development

Schiestl¹,

Ranganna

Watson

et al. 2020

BioDrugs

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“…Cell-based models presented in the previous section highlighted that aggregated antibodies could fulfill the two latter activation signals. However, the role of aggregates in the initiation of a specific T-cell response has been less explored (62), even though the specificity of the immune response to native monoclonal antibodies has been well documented over the past years, as described hereafter.…”

Section: Antibody Aggregates and The Generation Of De Novo Antigensmentioning

confidence: 99%

“…How could aggregation modulate the specific T-cell response detected for native antibodies? One study exploring the T-cell response to erythropoietin and heat-or tungsten-induced erythropoietin aggregates in an autologous moDC-T-cell coculture model that aggregates induced an increase in T-cell proliferation compared to native erythropoietin (62). This is the only study to date evaluating the specific T-cell activation in response to BP aggregates.…”

Section: The Role Of Antibody Aggregates In the Initiation Of A Specimentioning

confidence: 99%

Immunogenicity of Bioproducts: Cellular Models to Evaluate the Impact of Therapeutic Antibody Aggregates

2020

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Patients treated with bioproducts (BPs) frequently develop anti-drug antibodies (ADAs) with potential neutralizing capacities leading to loss of clinical response or potential hypersensitivity reactions. Many factors can influence BP immunogenicity and could be related to the patient, the treatment, as well as to the product itself. Among these latter factors, it is now well accepted that BP aggregation is associated with an increased potential for immunogenicity, as aggregates seem to be correlated with ADA development. Moreover, the presence of high-affinity ADAs suggests a CD4 T-cell dependent adaptive immune response and therefore a pivotal role for antigenpresenting cells (APCs), such as dendritic cells (DCs). In this review, we address the in vitro methods developed to evaluate how monoclonal antibodies could trigger the immunization process by focusing on the role of aggregated antibodies in the establishment of this response. In particular, we will present the different cell-based assays that have been used to assess the potential of antibodies and their aggregates to modulate cellular mechanisms leading to activation and the biological parameters (cellular activation markers, proliferation and secreted molecules) that can be measured to evaluate the different cell activation stages and their consequences in the propagation of the immune response. Indeed, the use of such strategies could help evaluate the risk of BP immunogenicity and their role in mitigating this risk.

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“…SC use of the reference medicine was subsequently re-instated, allowing such a study to be conducted; however, two patients developed neutralizing anti-erythropoietin antibodies following SC administration of HX575 in this trial. 14 Results of a thorough root–cause analysis indicated that atypical increased tungsten levels in pre-filled syringes precipitated immunogenic reactions with two batches of the study medication; 15 , 16 the manufacturing process of the syringe barrels was subsequently changed to consistently reduce the tungsten levels to specified low levels (introduction of low-tungsten syringes).…”

Section: Further Clinical Development and Recent Ema Approval Of Sc Hmentioning

confidence: 99%

HX575: established biosimilarity in the treatment of renal anemia and 10 years of clinical experience

Dellanna¹,

Goldsmith

Krendyukov

et al. 2017

DDDT

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Erythropoiesis-stimulating agents, such as recombinant human erythropoietin, are commonly used for the treatment of anemia in patients with chronic kidney disease (CKD). In 2007, HX575 (Binocrit®) became the first biosimilar epoetin alfa to be approved by the European Medicines Agency (EMA). The decision to approve a biosimilar is based on the totality of evidence obtained in a comprehensive comparability exercise that involves extensive analytical characterization, nonclinical studies and clinical studies. The development process for HX575 included extensive analytical characterization and comparison with the reference epoetin alfa. This was followed by a clinical development program, comprising Phase I pharmacokinetic/pharmacodynamic studies to show bioequivalence to the reference medicine and a confirmatory Phase III study to demonstrate therapeutic effectiveness in anemia related to CKD. In addition to the comparability exercises, extensive clinical experience over the last decade also confirms that HX575 provides an effective treatment for CKD-related anemia, with a favorable safety profile. Growing clinical experience with EMA-approved biosimilars, including HX575, should offer additional reassurance to health care professionals and patients that these agents are as effective and well tolerated as others in the therapeutic class.

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T-cell assays confirm immunogenicity of tungsten-induced erythropoietin aggregates associated with pure red cell aplasia

Abstract: • Tungsten-induced rhEPO aggregates in clinical lots are associated with rhEPOneutralizing antibodies and PRCA.• T-cell responses differentiate nonaggregated from aggregated rhEPO, confirming immunogenicity of tungsten-induced rhEPO aggregates.

Cited by 28 publications

References 35 publications

The Path Towards a Tailored Clinical Biosimilar Development

The Path Towards a Tailored Clinical Biosimilar Development

Immunogenicity of Bioproducts: Cellular Models to Evaluate the Impact of Therapeutic Antibody Aggregates

HX575: established biosimilarity in the treatment of renal anemia and 10 years of clinical experience

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