Optimal PEGylation can Improve the Exposure of Interferon in the Lungs Following Pulmonary Administration

McLeod, Victoria M.; Chan, Linda J.; Ryan, Gemma; Porter, Christopher John; Kaminskas, Lisa M.

doi:10.1002/jps.24353

Cited by 25 publications

(17 citation statements)

References 51 publications

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“…In this context, PEGylation represents a promising approach to sustain the presence of biopharmaceuticals in the lungs and to enhance their overall therapeutic efficiency (Guichard et al, 2017a). Recently, using preclinical animal models, others and our groups have reported the feasibility and the efficacy of the pulmonary administration of PEGylated compounds, such as Fab’ (fragment antigen-binding) and biopharmaceutical and chemotherapeutic agents (Cantin et al, 2002, Freches et al, 2017, Koussoroplis et al, 2013, Koussoroplis et al, 2014, Luo et al, 2016, Mcleod et al, 2015). However, the safety of administering PEG or PEGylated compounds directly to the lungs by inhalation and the potential impact on the pulmonary tissue has not been studied in an extensive manner yet.…”

Section: Introductionmentioning

confidence: 99%

Preclinical evaluation of topically-administered PEGylated Fab’ lung toxicity

Freches

Rocks²,

Patil

et al. 2019

International Journal of Pharmaceutics: X

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Section: Introductionmentioning

confidence: 99%

Preclinical evaluation of topically-administered PEGylated Fab’ lung toxicity

Freches

Rocks²,

Patil

et al. 2019

International Journal of Pharmaceutics: X

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“…Galenic optimization for protein nebulization is complex, and could be achieved by different excipients such as PEG 8000, n-Dodecyl-β-D-maltoside, l-arginine and trehalose (Mahjoubi et al, 2015;Sécher et al, 2019). The use of pegylated IFNs could also be considered to both increase stability and extend action at the local level (Mcleod et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Rationale for COVID-19 Treatment by Nebulized Interferon-β-1b–Literature Review and Personal Preliminary Experience

et al. 2020

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The inflammatory response to COVID-19 is specifically associated with an impaired type I interferon (IFN) response and complete blockade of IFN-β secretion. Clinically, nebulization of IFN-α-2b has been historically used in China to treat viral pneumonia associated with SARS-CoV. Very recent data show that the use of inhaled type I IFN is associated with decreased mortality in Chinese COVID-19 patients. However, IFN nebulization is currently not standard in Europe and the United States. Therefore, our group has set up a project aimed to evaluate the possibility to nebulize IFN-β-1b (a drug currently used in Europe to treat multiple sclerosis via subcutaneous injections) and to assess the safety of this new mode of administration in SARS-CoV-2 infected patients. We present here literature data that allowed us to build our hypothesis and to develop collaboration between clinical pharmacists, intensivists and nebulization engineers in order to gain first pre-clinical and clinical experience of IFN-β-1b nebulization. After validation of the nebulization method and verification of droplet size compatible with nebulization, the method has been applied to four intensive care patients treated at our university hospital, for whom none of the COVID-19 therapies initially used in France led to significant clinical improvement. All patients exhibited negative viral carriage and experienced clinical improvement 7–16 days after having initiated nebulized IFN-β-1b inhalation therapy. No side effects were observed. All patients were alive within a 90-days follow-up. Although it is not possible to draw firm conclusions on treatment efficacy based on this case report, our study shows that pulmonary IFN-β-1b administration is feasible, with a good safety profile. This procedure, which presents the advantage of directly targeting the lungs and reducing the risks of systemic side effects, may represent a promising therapeutic strategy for the care of patients with severe COVID-19. However, our preliminary observation requires confirmation by randomized controlled trials.

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“…Preceding reports have highlighted the role of alveolar macrophages in the sequestration and clearance of proteins, PEGylated or not, after pulmonary delivery [12,23,27]. The contribution of alveolar macrophages in the uptake of native and PEGylated rhDNase was also suggested in vivo in our laboratory [7,16].…”

Section: Influence Of Pegylation and Peg Size On The Uptake Of Rhdnasmentioning

confidence: 97%

“…The absorption of proteins by the lungs is influenced, to a great extent, by their molecular size and nature, and the bioavailability does not exceed, in general, 5% for large proteins (molecular weight, MW ≥ 40 kDa) [19][20][21]. PEGylation has been shown to reduce the systemic absorption of recombinant human granulocyte-colony stimulating factor (rhGCSF, 18 kDa), IFNα2b (19 kDa), and recently rhDNase following pulmonary delivery in small animals [16,22,23]. The same trend has also been shown in vitro in Calu-3 human lung epithelial cells for PEGylated anti-IL-13 and anti-IL-17A (~ 47 kDa) [14].…”

Section: Introductionmentioning

confidence: 99%

PEGylation of recombinant human deoxyribonuclease I decreases its transport across lung epithelial cells and uptake by macrophages

Mahri

Hardy

Wilms

et al. 2021

International Journal of Pharmaceutics

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Conjugation to high molecular weight (MW) polyethylene glycol (PEG) was previously shown to largely prolong the lung residence time of recombinant human deoxyribonuclease I (rhDNase) and improve its therapeutic efficacy following pulmonary delivery in mice. In this paper, we investigated the mechanisms promoting the extended lung retention of PEG-rhDNase conjugates using cell culture models and lung biological media. Uptake by alveolar macrophages was also assessed in vivo. Transport experiments showed that PEGylation reduced the uptake and transport of rhDNase across monolayers of Calu-3 cells cultured at an air-liquid interface. PEGylation also decreased the uptake of rhDNase by macrophages in vitro whatever the PEG size as well as in vivo 4 h following intratracheal instillation in mice. However, the reverse was observed in vivo at 24 h. The uptake of rhDNase by macrophages was dependent on energy, time, and concentration and occurred at rates indicative of adsorptive endocytosis. The diffusion of PEGylated rhDNase in porcine tracheal mucus and cystic fibrosis sputa was slower compared with that of rhDNase. Nevertheless, no significant binding of PEGylated rhDNase to both media was observed. In conclusion, decreased transport across lung epithelial cells and uptake by macrophages appear to contribute to the longer retention of PEGylated rhDNase in the lungs.

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Optimal PEGylation can Improve the Exposure of Interferon in the Lungs Following Pulmonary Administration

Cited by 25 publications

References 51 publications

Preclinical evaluation of topically-administered PEGylated Fab’ lung toxicity

Preclinical evaluation of topically-administered PEGylated Fab’ lung toxicity

Rationale for COVID-19 Treatment by Nebulized Interferon-β-1b–Literature Review and Personal Preliminary Experience

PEGylation of recombinant human deoxyribonuclease I decreases its transport across lung epithelial cells and uptake by macrophages

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