Targeting interleukin-4 to the arthritic joint

Spieler, Valerie; Ludwig, Marie-Gabrielle; Dawson, Janet; Tigani, Bruno; Littlewood‐Evans, Amanda; Safina, Caterina; Ebersbach, Hilmar; Seuwen, Klaus; Raschig, Martina; Mors, Björn Ter; Müller, Thomas; Meinel, Lorenz; Lühmann, Tessa

doi:10.1016/j.jconrel.2020.07.005

Cited by 20 publications

(27 citation statements)

References 34 publications

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“…We engineered two mutants of IFN-α2a by amber codon (UAG) suppression using a pyrrolysyl-tRNA synthethase/tRNAPyl CUA pair originating from Methanosarcina barkeri and as demonstrated before. ,,,− Positions #31 or #134 were chosen for mutation, as these lysine residues are surface-accessible for bioconjugation as demonstrated in the IFN-α2a tertiary structure (Figures A and S11).…”

Section: Resultsmentioning

confidence: 99%

Molecular Insights into Site-Specific Interferon-α2a Bioconjugates Originated from PEG, LPG, and PEtOx

et al. 2021

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Conjugation of biologics with polymers modulates their pharmacokinetics, with polyethylene glycol (PEG) as the gold standard. We compared alternative polymers and two types of cyclooctyne linkers (BCN/DBCO) for bioconjugation of interferon-α2a (IFN-α2a) using 10 kDa polymers including linear mPEG, poly(2-ethyl-2-oxazoline) (PEtOx), and linear polyglycerol (LPG). IFN-α2a was azide functionalized via amber codon expansion and bioorthogonally conjugated to all cyclooctyne linked polymers. Polymer conjugation did not impact IFN-α2a’s secondary structure and only marginally reduced IFN-α2a’s bioactivity. In comparison to PEtOx, the LPG polymer attached via the less rigid cyclooctyne linker BCN was found to stabilize IFN-α2a against thermal stress. These findings were further detailed by molecular modeling studies which showed a modulation of protein flexibility upon PEtOx conjugation and a reduced amount of protein native contacts as compared to PEG and LPG originated bioconjugates. Polymer interactions with IFN-α2a were further assessed via a limited proteolysis (LIP) assay, which resulted in comparable proteolytic cleavage patterns suggesting weak interactions with the protein′s surface. In conclusion, both PEtOx and LPG bioconjugates resulted in a similar biological outcome and may become promising PEG alternatives for bioconjugation.

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Section: Resultsmentioning

confidence: 99%

Molecular Insights into Site-Specific Interferon-α2a Bioconjugates Originated from PEG, LPG, and PEtOx

et al. 2021

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“…Key barriers to the successful development of RA treatment include a limited understanding of early cartilage degradation pathways and the ineffectiveness of therapeutic drug delivery to inherent chondrocytes without vascular cartilage. In previous studies, Frideriki et al injected infliximab into the intraperitoneal cavity to treat CIA rat models [35], and Spieler et al directed interleukin-4 to arthritic joints in a mouse model of antigen-induced arthritis [36]. In these studies, although certain therapeutic effects were achieved in the development of arthritis, there was still a lack of specific targets and treatment efficiency.…”

Section: Discussionmentioning

confidence: 99%

Efficient Treatment of Rheumatoid Arthritis by Degradable LPCE Nano-Conjugate-Delivered p65 siRNA

et al. 2022

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Rheumatoid arthritis (RA) is one of the most common autoimmune diseases worldwide, causing severe cartilage damage and disability. Despite the recent progress made in RA treatment, limitations remain in achieving early and efficient therapeutic intervention. Advanced therapeutic strategies are in high demand, and siRNA-based therapeutic technology with a gene-silencing ability represents a new approach for RA treatment. In this study, we created a cationic delivery micelle consisting of low-molecular-weight (LMW) polyethylenimine (PEI)–cholesterol–polyethylene glycol (PEG) (LPCE) for small interfering RNA (siRNA)-based RA gene therapy. The carrier is based on LMW PEI and modified with cholesterol and PEG. With these two modifications, the LPCE micelle becomes multifunctional, and it efficiently delivered siRNA to macrophages with a high efficiency greater than 70%. The synthesized LPCE exhibits strong siRNA protection ability and high safety. By delivering nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 siRNA, the p65 siRNA/LPCE complex efficiently inhibited macrophage-based cytokine release in vitro. Local administration of the p65 siRNA/LPCE complex exhibited a fast and potent anti-inflammatory effect against RA in a mouse model. According to the results of this study, the functionalized LPCE micelle that we prepared has potential gene therapeutic implications for RA.

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“…GCE by codon reassignment or alphabet expansion represents a remarkable academic achievement, and the process of commercialization is now underway. In addition to the commercialization efforts described above, an increasing number of early efforts have been reported from academic laboratories, focusing on the use of the Tyr or Pyl analog OTS(CUA) variants to optimize the properties of a broad range of potential therapeutics, including hGH, INF-α2b, erythropoietin, , urate oxidase, ,, FGF2, interleukin-4, − insulin-like growth factor I, bone morphogenic protein 2, GLP-1, and ribosomally synthesized macrocyclic peptides, ,,− which represent exciting future commercialization possibilities.…”

Section: Challenges and Future Directionsmentioning

confidence: 99%

Genetic Code Expansion: Inception, Development, Commercialization

Manandhar¹,

Chun²,

Romesberg³

2021

J. Am. Chem. Soc.

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Virtually all natural proteins are built from only 20 amino acids, and while this makes possible all the functions they perform, the ability to encode other amino acids selected for specific purposes promises to enable the discovery and production of proteins with novel functions, including therapeutic proteins with more optimal drug-like properties. The field of genetic code expansion (GCE) has for years enabled the production of such proteins for academic purposes and is now transitioning to commercialization for the production of more optimal protein therapeutics. Focusing on E. coli, we review the history and current state of the field. We also provide a review of the first generation commercialization efforts, the lessons learned, and how those lessons are guiding new efforts. With continued academic and industrial progress, GCE methodologies promise to make possible the routine optimization of proteins for therapeutic use in a way that has only previously been possible with small-molecule therapeutics.

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Targeting interleukin-4 to the arthritic joint

Cited by 20 publications

References 34 publications

Molecular Insights into Site-Specific Interferon-α2a Bioconjugates Originated from PEG, LPG, and PEtOx

Molecular Insights into Site-Specific Interferon-α2a Bioconjugates Originated from PEG, LPG, and PEtOx

Efficient Treatment of Rheumatoid Arthritis by Degradable LPCE Nano-Conjugate-Delivered p65 siRNA

Genetic Code Expansion: Inception, Development, Commercialization

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