Subcutaneous delivery of biotherapeutics: challenges at the injection site

Sequeira, Joana; Santos, Ana Cláudia; Serra, João P.; Estevens, Catarina; Seiça, Raquel; Veiga, Francisco; Ribeiro, Antônio J.

doi:10.1080/17425247.2019.1568408

Cited by 40 publications

(26 citation statements)

References 60 publications

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“…There are also reports of possible depuration of this antigen at the injection site by immune cells. These antigen-presenting cells migrate to the SC space after the injection, process the administered protein, and present it to the T cells present in the lymphatic vessels as a “first pass” immune interaction before reaching the systemic circulation [ 27 ]. Thus, the migratory potential of these cutaneous dendritic cells drives the immunogenicity of proteins administered by SC [ 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

Peptide vaccines designed with the aid of immunoinformatic against Caseous Lymphadenitis promotes humoral and cellular response induction in mice

Droppa-Almeida¹,

Silva²,

Gaspar³

et al. 2021

PLoS ONE

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Caseous Lymphadenitis (CLA) is a chronic disease that affects also small ruminants. CLA is caused by Corynebacterium pseudotuberculosis and is responsible for high economic losses due to the formation of superficial and visceral granulomas, the latter is considered as asymptomatic CLA causing high levels of dissemination. Several vaccination strategies, in which the use of synthetic peptides stands out. Thus, this work aimed to evaluate the protective potential of peptide vaccines designed to determine the immunodominant epitopes of CP40 against CLA in mice. The animals were divided into eight groups separated in controls (G1—PBS, G2—Saponin and G9—rCP40) and experimental (G3—pep1, G4- pep2, G5-pep3, G6-pep4, G7-pep5 and G8-pep6), these were vaccinated on days 0 and 15 by a subcutaneous route. 60 days after the first immunization, all animals were challenged with C. pseudotuberculosis. On days 0, 15, 60, and 120 after the first immunization, blood samples were taken to measure immunoglobulins. On the same day of the challenge, the splenocytes were isolated and assayed for the production of IL-2, IL-4, IL-6, IFN-γ, TNF-α, IL-17, and IL-10. After vaccinations, the animals were challenged and all of them were affected by the disease which led to their death. The G6 and G8 groups provided 10% protection and the G7 provided 20%. The G3 and G4 groups provided 30% and 40% protection respectively. The peptides showed the production of Total IgG antibodies and cytokines (IL-2, IL-4, IL-6, IFN-γ, and TNF-α), indicating a possible activation of the Th1 type response. However, groups G3, G5, G6, and G8 showed production of IL-17. None of the study groups showed IL-10 production. The immunogenicity of the peptides was not enough to protect these animals and it is believed that the use of adjuvants based on PAMPs may improve the immune response offered by these peptides.

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Section: Discussionmentioning

confidence: 99%

Peptide vaccines designed with the aid of immunoinformatic against Caseous Lymphadenitis promotes humoral and cellular response induction in mice

Droppa-Almeida¹,

Silva²,

Gaspar³

et al. 2021

PLoS ONE

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“…1,13,15,16,[22][23][24] Biologicals currently requiring high volume subcutaneous administration include but are not limited to trastuzumab for HER2-positive breast cancer, rituximab for non-Hodgkin's lymphoma and various immunoglobulins for primary immunodeficiency. 1,5,8,[13][14][15] While multiple devices are in development to accommodate large volume subcutaneous (LVSC) injection formulations, limited options are commercially available. 16,[25][26][27] Some formulations indicated for LVSC delivery may utilize multiple injections or permeation enhancers.…”

Section: Introductionmentioning

confidence: 99%

Clinical evaluation of large volume subcutaneous injection tissue effects, pain, and acceptability in healthy adults

Woodley

Morel

Sutter

et al. 2021

Clinical Translational Sci

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“… 4 , 5 In addition, aggregated protein drugs may lose their activity, and their delivery to the target tissues may be compromised. 6 , 7 Thus, it is important to ensure product stability. To control the quality of biologics, stringent regulations have been set by, for example, the U.S. Food and Drug Administration and European Medicines Agency, obligating manufacturers to constantly test the product stability and the level of aggregation.…”

Section: Introductionmentioning

confidence: 99%

Sensitive, homogeneous, and label-free protein-probe assay for antibody aggregation and thermal stability studies

Valtonen

Vuorinen

Eskonen

et al. 2021

mAbs

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Protein aggregation is a spontaneous process affected by multiple external and internal properties, such as buffer composition and storage temperature. Aggregation of protein-based drugs can endanger patient safety due, for example, to increased immunogenicity. Aggregation can also inactivate protein drugs and prevent target engagement, and thus regulatory requirements are strict regarding drug stability monitoring during manufacturing and storage. Many of the current technologies for aggregation monitoring are time- and material-consuming and require specific instruments and expertise. These types of assays are not only expensive, but also unsuitable for larger sample panels. Here we report a label-free time-resolved luminescence-based method using an external Eu 3+ -conjugated probe for the simple and fast detection of protein stability and aggregation. We focused on monitoring the properties of IgG, which is a common format for biological drugs. The Protein-Probe assay enables IgG aggregation detection with a simple single-well mix-and-measure assay performed at room temperature. Further information can be obtained in a thermal ramping, where IgG thermal stability is monitored. We showed that with the Protein-Probe, trastuzumab aggregation was detected already after 18 hours of storage at 60°C, 4 to 8 days earlier compared to SYPRO Orange- and UV250-based assays, respectively. The ultra-high sensitivity of less than 0.1% IgG aggregates enables the Protein-Probe to reduce assay time and material consumption compared to existing techniques.

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Subcutaneous delivery of biotherapeutics: challenges at the injection site

Cited by 40 publications

References 60 publications

Peptide vaccines designed with the aid of immunoinformatic against Caseous Lymphadenitis promotes humoral and cellular response induction in mice

Peptide vaccines designed with the aid of immunoinformatic against Caseous Lymphadenitis promotes humoral and cellular response induction in mice

Clinical evaluation of large volume subcutaneous injection tissue effects, pain, and acceptability in healthy adults

Sensitive, homogeneous, and label-free protein-probe assay for antibody aggregation and thermal stability studies

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