Formulation and Stability of Cytokine Therapeutics

Lipiäinen, Tiina; Peltoniemi, Marikki; Sarkhel, Sanjay; Yrjönen, Teijo; Vuorela, Heikki; Urtti, Arto; Juppo, Anne

doi:10.1002/jps.24243

Cited by 61 publications

(49 citation statements)

References 128 publications

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“…5 Despite the high costs of protein production in mammalian cells compared with recombinant bacterial fermentation, it possesses substantial benets regarding the synthesized IFN-b. 6 The controlled release of IFN-b could provide important advantages, such as the decrease of dose and administration frequency, which would reduce the side effects and toxicity, overall the life quality of patients. This reduces the drug cost, immunogenicity and the appearance of neutralizing antibody.…”

Section: Introductionmentioning

confidence: 99%

Sustained in vitro interferon-beta release and in vivo toxicity of PLGA and PEG-PLGA nanoparticles

et al. 2020

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Section: Introductionmentioning

confidence: 99%

Sustained in vitro interferon-beta release and in vivo toxicity of PLGA and PEG-PLGA nanoparticles

et al. 2020

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“…Therapeutic agonists based on natural proteins are attractive immune modulators; however, they are not ideal pharmaceutical agents due to poor pharmacokinetics (PK), poor tolerability, and pleiotropic activity that may be exacerbated by frequent dose administration [7, 8]. The cytokine interleukin-2 (IL2) is an endogenous agonist of the IL2 pathway and is a well-described stimulator of CD8 + T cell (CD8 T) and NK cells [9].…”

Section: Introductionmentioning

confidence: 99%

Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of NKTR-214, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy

et al. 2017

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Cytokines are potent immune modulating agents but are not ideal medicines in their natural form due to their short half-life and pleiotropic systemic effects. NKTR-214 is a clinical-stage biologic that comprises interleukin-2 (IL2) protein bound by multiple releasable polyethylene glycol (PEG) chains. In this highly PEG-bound form, the IL2 is inactive; therefore, NKTR-214 is a biologic prodrug. When administered in vivo, the PEG chains slowly release, creating a cascade of increasingly active IL2 protein conjugates bound by fewer PEG chains. The 1-PEG-IL2 and 2-PEG-IL2 species derived from NKTR-214 are the most active conjugated-IL2 species. Free-IL2 protein is undetectable in vivo as it is eliminated faster than formed. The PEG chains on NKTR-214 are located at the region of IL2 that contacts the alpha (α) subunit of the heterotrimeric IL2 receptor complex, IL2Rαβγ, reducing its ability to bind and activate the heterotrimer. The IL2Rαβγ complex is constitutively expressed on regulatory T cells (Tregs). Therefore, without the use of mutations, PEGylation reduces the affinity for IL2Rαβγ to a greater extent than for IL2Rβγ, the receptor complex predominant on CD8 T cells. NKTR-214 treatment in vivo favors activation of CD8 T cells over Tregs in the tumor microenvironment to provide anti-tumor efficacy in multiple syngeneic models. Mechanistic modeling based on in vitro and in vivo kinetic data provides insight into the mechanism of NKTR-214 pharmacology. The model reveals that conjugated-IL2 protein derived from NKTR-214 occupy IL-2Rβγ to a greater extent compared to free-IL2 protein. The model accurately describes the sustained in vivo signaling observed after a single dose of NKTR-214 and explains how the properties of NKTR-214 impart a unique kinetically-controlled immunological mechanism of action.

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“…10 Traditional protein therapy involving direct injection is largely hampered by rapid diffusion and the short half-life of proteins. 11 For example, the apparent in vivo half-life of i.p. injected IL-10 was approximately 2 h in mice.…”

Section: Introductionmentioning

confidence: 99%

Modulating inflammation in a cutaneous chronic wound model by IL-10 released from collagen–silica nanocompositesviagene delivery

2018

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Cutaneous chronic wounds remain a major clinical challenge which requires the development of novel wound dressings. Previously, we showed that collagen-silica nanocomposites consisting of polyethyleneimine (PEI)-DNA complexes associated with silica nanoparticles (SiNP), collagen hydrogel and 3T3 fibroblasts, can work as a local "cell factory". Indeed, the "in-gel" transfection leads to a sustained production and release of biomolecules. Herein, we further explored the possibility for nanocomposites to deliver interleukin-10 (IL-10), a potent anti-inflammatory cytokine, which favors tissue repair. Its anti-inflammatory effect was evaluated in an in vitro inflammation model carried out by LPS (lipopolysaccharide) activation of macrophages embedded in collagen gel. The IL-10 synthesis from nanocomposites was detected over one week in the range of 200-400 pg mL and reached a maximum at day 5 without any observed cytotoxic effects. PEI-SiNP outperformed free PEI and PEI-SiNP, implying that the introduction of SiNP improved the transfection efficiency of low M of PEI. In addition, the structure and mechanical properties of collagen-silica nanocomposites were stable over one week. Subsequently, the ability of nanocomposites to modulate inflammation was tested in a 3D model of inflammation. The decrease of TNF-α and IL-1β gene expression by 20-80% indicated successful inhibition of inflammation by IL-10 released from nanocomposites. Taken together, the nanocomposites are capable of producing effective doses of IL-10 which inhibit the synthesis of pro-inflammatory cytokines and favor the expression of wound healing cytokines. Therefore, the as-constructed 3D gene delivery system represents a promising strategy for the controlled release of therapeutic biomolecules favoring cutaneous wound healing.

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Formulation and Stability of Cytokine Therapeutics

Cited by 61 publications

References 128 publications

Sustained in vitro interferon-beta release and in vivo toxicity of PLGA and PEG-PLGA nanoparticles

Sustained in vitro interferon-beta release and in vivo toxicity of PLGA and PEG-PLGA nanoparticles

Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of NKTR-214, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy

Modulating inflammation in a cutaneous chronic wound model by IL-10 released from collagen–silica nanocompositesviagene delivery

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