Identification of B cell epitopes enhanced by protein unfolding and aggregation

Eyes, Timothy; Austerberry, James; Dearman, Rebecca J.; Johannissen, Linus O.; Kimber, Ian; Smith, Noel; Thistlethwaite, Angela; Derrick, Jeremy P.

doi:10.1016/j.molimm.2018.11.020

Cited by 18 publications

(17 citation statements)

References 46 publications

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“…Subvisible aggregates of single-chain variable fragment (scFv) and ovalbumin induced significantly higher IgG2a titers compared to monomeric protein by SC injection in BALB/c mice, although total IgG and IgG1 titers were comparable. Skewing towards T H 1-type immune response by aggregates was also suggested by cytokine profiles in DC co-culture experiments [ 156 , 157 ]. Additionally, T H 1-type immune response was observed for bevacizumab heat-triggered aggregates in a human artificial lymph node (HuALN) model, where delayed immune reactions can be monitored by long-term exposure of the system up to 28 days [ 158 ].…”

Section: Immunogenicity Of the Subcutaneous Route Of Administrationmentioning

confidence: 99%

Immunogenicity Challenges Associated with Subcutaneous Delivery of Therapeutic Proteins

Jarvi

Balu‐Iyer

2021

BioDrugs

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The subcutaneous route of administration has provided convenient and non-inferior delivery of therapeutic proteins compared to intravenous infusion, but there is potential for enhanced immunogenicity toward subcutaneously administered proteins in a subset of patients. Unwanted anti-drug antibody response toward proteins or monoclonal antibodies upon repeated administration is shown to impact the pharmacokinetics and efficacy of multiple biologics. Unique immunogenicity challenges of the subcutaneous route have been realized through various preclinical and clinical examples, although subcutaneous delivery has often demonstrated comparable immunogenicity to intravenous administration. Beyond route of administration as a treatment-related factor of immunogenicity, certain product-related risk factors are particularly relevant to subcutaneously administered proteins. This review attempts to provide an overview of the mechanism of immune response toward proteins administered subcutaneously (subcutaneous proteins) and comments on product-related risk factors related to protein structure and stability, dosage form, and aggregation. A two-wave mechanism of antigen presentation in the immune response toward subcutaneous proteins is described, and interaction with dynamic antigen-presenting cells possessing high antigen processing efficiency and migratory activity may drive immunogenicity. Mitigation strategies for immunogenicity are discussed, including those in general use clinically and those currently in development. Mechanistic insights along with consideration of risk factors involved inspire theoretical strategies to provide antigen-specific, long-lasting effects for maintaining the safety and efficacy of therapeutic proteins.

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Section: Immunogenicity Of the Subcutaneous Route Of Administrationmentioning

confidence: 99%

Immunogenicity Challenges Associated with Subcutaneous Delivery of Therapeutic Proteins

Jarvi

Balu‐Iyer

2021

BioDrugs

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“…Conformational stability affects whether a protein stays in its folded state, and (partial) unfolding may expose hydrophobic regions which promote protein-protein interactions and thus propagate aggregation. [62][63][64] Protein stability and thus aggregation are affected by various stresses that can occur during production, processing, storage and transportation of therapeutic proteins. 57,59 Such stresses include changes in temperature, 65 pH and ionic strength 66 during manufacture and processing, mechanical agitation stresses, such as pumping and shaking during processing and transportation, 67,68 and freeze-thawing stress from storage.…”

Section: Reviewmentioning

confidence: 99%

Aggregation of protein therapeutics enhances their immunogenicity: causes and mitigation strategies

Lundahl

Fogli²,

Colavita

et al. 2021

RSC Chem. Biol.

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“…hypothesis. On the other hand, in vivo studies are currently focusing on the oligomeric antibodies and their immunogenicity (68,69). Indeed, nanometric-sized aggregates could be found in preparations and are hardly ever detected and eliminated before the administration of the therapeutic antibody (38,41).…”

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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Identification of B cell epitopes enhanced by protein unfolding and aggregation

Cited by 18 publications

References 46 publications

Immunogenicity Challenges Associated with Subcutaneous Delivery of Therapeutic Proteins

Immunogenicity Challenges Associated with Subcutaneous Delivery of Therapeutic Proteins

Aggregation of protein therapeutics enhances their immunogenicity: causes and mitigation strategies

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

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