Immunogenicity Challenges Associated with Subcutaneous Delivery of Therapeutic Proteins

Jarvi, Nicole L.; Balu‐Iyer, Sathy V.

doi:10.1007/s40259-020-00465-4

Cited by 55 publications

(45 citation statements)

References 209 publications

(329 reference statements)

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“…This has been proposed to be due to efficient antigen presentation in the immune response to subcutaneous proteins [57]. While enhanced immunogenic potential has been demonstrated for some SC biologic drugs, the prevalence of ADAb formation is similar for SC and IV formulations for other biologics [57,58]. The latter has been suggested for tocilizumab and abatacept, which are used in both SC and IV formulations in IJDs [59][60][61][62].…”

Section: Route and Mode Of Administrationmentioning

confidence: 99%

“…Subcutaneous (SC) drug administration is commonly perceived to be associated with enhanced immunogenic potential, as compared with intravenous (IV) administration. This has been proposed to be due to efficient antigen presentation in the immune response to subcutaneous proteins [ 57 ]. While enhanced immunogenic potential has been demonstrated for some SC biologic drugs, the prevalence of ADAb formation is similar for SC and IV formulations for other biologics [ 57 , 58 ].…”

Section: Factors Affecting Adab Developmentmentioning

confidence: 99%

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Assessing Immunogenicity of Biologic Drugs in Inflammatory Joint Diseases: Progress Towards Personalized Medicine

et al. 2022

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Biologic drugs have greatly improved treatment outcomes of inflammatory joint diseases, but a substantial proportion of patients either do not respond to treatment or lose response over time. Drug immunogenicity, manifested as the formation of anti-drug antibodies (ADAb), constitute a significant clinical problem. Anti-drug antibodies influence the pharmacokinetics of the drug, are associated with reduced clinical efficacy, and an increased risk of adverse events such as infusion reactions. The prevalence of ADAb differs among drugs and diseases, and the detection of ADAb also depends on the assay format. Most data exist for the tumor necrosis factor-alpha inhibitors infliximab and adalimumab, with a frequency of ADAb that ranges from 10 to 60% across studies. Measurement of ADAb and serum drug concentrations, therapeutic drug monitoring, has been suggested as a strategy to optimize therapy with biologic drugs. Although the recent randomized clinical Norwegian Drug Monitoring (NOR-DRUM) trials show promise towards a personalized medicine prescribing approach by therapeutic drug monitoring, several challenges remain. A plethora of assay formats, with widely differing properties, is currently used for measuring ADAb. Comparing results between different assays and laboratories is difficult, which complicates the development of cut-offs necessary for guidelines and the implementation of ADAb measurements in clinical practice. With the possible exception of infliximab, limited data on clinical relevance and cost effectiveness exist to support therapeutic drug monitoring as a routine clinical strategy to monitor biologic drugs in inflammatory joint diseases. The aim of this review is to provide an overview of the characteristics and prevalence of ADAb, predisposing factors to ADAb formation, commonly used assessment methods, clinical consequences of ADAb, and the potential implications of ADAb assessments for everyday treatment of inflammatory joint diseases.

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Section: Route and Mode Of Administrationmentioning

confidence: 99%

Section: Factors Affecting Adab Developmentmentioning

confidence: 99%

Assessing Immunogenicity of Biologic Drugs in Inflammatory Joint Diseases: Progress Towards Personalized Medicine

et al. 2022

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“…These processes increase the production of IgE antibodies, causing mast cells to flood the system with histamines; in extreme cases, this may result in anaphylaxis. In contrast, delivery to the avascular epidermis reduces systemic uptake, thereby increasing the relative production of IgG 4 antibodies-i.e., those responsible for immune tolerance [14][15][16]. Consequently, both the safety and efficacy of targeted allergen immunotherapy within the skin may be improved by localizing the antigen in the epidermis, ideally without requiring a hypodermic needle, as this would significantly decrease the rate of systemic uptake, elicit the desired immune response, and address needle-phobia concerns [17] (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Angled Insertion of Microneedles for Targeted Antigen Delivery to the Epidermis

et al. 2022

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Peanut and tree nut allergies account for most food-induced anaphylactic events. The standard allergy immunotherapy approach involves subcutaneous injection, which is challenging because severe adverse reactions can occur when antigens spread systemically. Allergen localization within the epidermis (i.e., the upper 20–100 µm of skin) should significantly reduce systemic uptake, because the epidermis is avascular. Microneedle (MN) patches provide a convenient method for drug delivery to the skin, but they generally target both epidermis and dermis, leading to systemic delivery. In this study, we adapted MN technology for epidermal localization by performing angled insertion of 250 µm–long MNs that limits MN insertion depth mostly to the epidermis. We designed a biplanar insertion device to aid the repeatability of angled insertions into porcine skin ex vivo at specified angles (90°, 45°, and 20°). When compared to 90° insertions, MN application at 20° decreased mean insertion depth from 265 ± 45 µm to 97 ± 15 µm. Image analysis of histological skin sections revealed that acute-angle insertion increased epidermal localization of delivery for antigen-coated MNs from 25% ± 13% to 70% ± 21%. We conclude that angled insertion of MNs can target antigen delivery to epidermis.

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“…It is a matter of debate whether the route of administration is associated with increased immunogenicity of a biologic drug, which in turn is known to increase the risk of adverse events and to decrease efficacy. [4][5][6] Additional factors that may play a role in immunogenicity include the pathogenesis of the specific disease, disease severity and inflammatory activity, the drug's mechanism of action, dose and dosing intervals, and product impurities. [4][5][6] Our data and the study by Ventress et al show that patients in remission can be switched from IV to SC vedolizumab safely and with preserved efficacy.…”

mentioning

confidence: 99%

“…[4][5][6] Additional factors that may play a role in immunogenicity include the pathogenesis of the specific disease, disease severity and inflammatory activity, the drug's mechanism of action, dose and dosing intervals, and product impurities. [4][5][6] Our data and the study by Ventress et al show that patients in remission can be switched from IV to SC vedolizumab safely and with preserved efficacy. 1,7 However, patients with active disease or optimised IV dosing were under-represented in these studies.…”

mentioning

confidence: 99%