Fate of PEGylated antibody fragments following delivery to the lungs: Influence of delivery site, PEG size and lung inflammation

Patil, Harshad P.; Freches, Danielle; Karmani, Linda; Duncan, Gregg A.; Ucakar, Bernard; Suk, Jung Soo; Gallez, Bernard; Vanbever, Rita

doi:10.1016/j.jconrel.2017.12.009

Cited by 43 publications

(39 citation statements)

References 30 publications

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“…PEG30-rhDNase is thus slowly absorbed in the systemic circulation and the resulting low levels are then gradually cleared from the body. [25] PEGylated rhDNase presented a 2 week residence time in the murine healthy lungs and one single dose of PEG30-rhDNase or PEG40-rhDNase presented a similar efficacy as one daily dose of unconjugated rhDNase during five consecutive days in -ENaC mice (Figures 1 and 4). Yet, it is not straightforward to foresee how these data will extrapolate to humans.…”

Section: Discussionmentioning

confidence: 83%

“…[24] Moreover, PEGylation has been suggested to decrease protein uptake by alveolar macrophages and respiratory epithelial cells. [14,25] The larger the PEG attached to rhDNase, the longer the residence time of the active enzyme in the murine lungs. While PEG20-rhDNase and PEG30-rhDNase could be detected in the lungs up to 15 days postdelivery, PEG40-rhDNase was detected up to day 20 (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

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PEGylation of Recombinant Human Deoxyribonuclease I Provides a Long‐Acting Version of the Mucolytic for Patients with Cystic Fibrosis

Guichard

Wilms

Mahri

et al. 2020

Advanced Therapeutics

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Inhalation of recombinant human deoxyribonuclease I (rhDNase) is a gold-standard therapy in the management of cystic fibrosis (CF). Yet, the rapid elimination of the mucolytic from the lungs requires its daily administration and rhDNase contributes to the high therapy burden of patients. Here, a long-acting version of rhDNase that is delivered once weekly instead of once daily is presented. Conjugation of rhDNase to a polyethylene glycol (PEG) chain sustains its presence and mucolytic activity within murine lungs for more than 15 days. One single dose of PEGylated rhDNase is as effective as 1 daily dose of unconjugated rhDNase during five days to decrease the DNA content in the lungs of-ENaC mice, a model of the CF lung disease. Moreover, once weekly administration of PEGylated rhDNase over four weeks decreases both the DNA content and the neutrophil counts in the lungs of-ENaC mice. PEGylated rhDNase is stable to jet nebulization. Finally, multiple high-dose administrations of PEGylated rhDNase for up to 3 months do not cause any significant pulmonary or systemic toxicity, nor accumulation of the rhDNase or PEG moieties in biological fluids. PEGylation of rhDNase may offer a convenient long-acting mucolytic to patients with CF.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

PEGylation of Recombinant Human Deoxyribonuclease I Provides a Long‐Acting Version of the Mucolytic for Patients with Cystic Fibrosis

Guichard

Wilms

Mahri

et al. 2020

Advanced Therapeutics

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“…In addition, urinary excretion has been reported as a major elimination route for PEG moieties of <50 kDa (Webster et al, 2007, Yamoaka et al, 1994). As suggested by Patil et al, following pulmonary administration of PEG40-Fab’ anti-IL17A, the mucociliary clearance could be an alternative pathway of elimination (Patil et al, 2018). Nevertheless, while the mechanisms of uptake and recycling out of the cells are not fully understood, we bring in vitro and in vivo evidence indicating that the integrity of the macrophage membranes in not altered as assessed by the low LDH levels released following incubation of macrophages with PEG40 and low LDH levels measured in the BAL of mice treated with PEG40-Fab’ anti-IL17A.…”

Section: Discussionmentioning

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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“…However, it is also known that PEGylation can modulate the inflammatory effect of nanoparticles. Previous work has shown that PEI caused higher levels of complement activation, whereas conjugation with high molecular weight PEG reduced the inflammatory reactions in vivo [ 56 , 57 , 58 ]. However, it is possible that the LPS is interacting with the PEI-LPEG to some degree.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Assessment of PEGylated PEI for Anti-IL-8/CxCL-1 siRNA Delivery to the Lungs

et al. 2020

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Inhalation offers a means of rapid, local delivery of siRNA to treat a range of autoimmune or inflammatory respiratory conditions. This work investigated the potential of a linear 10 kDa Poly(ethylene glycol) (PEG)-modified 25 kDa branched polyethyleneimine (PEI) (PEI-LPEG) to effectively deliver siRNA to airway epithelial cells. Following optimization with anti- glyceraldehyde 3-phosphate dehydrogenase (GAPDH) siRNA, PEI and PEI-LPEG anti-IL8 siRNA nanoparticles were assessed for efficacy using polarised Calu-3 human airway epithelial cells and a twin stage impinger (TSI) in vitro lung model. Studies were then advanced to an in vivo lipopolysaccharide (LPS)-stimulated rodent model of inflammation. In parallel, the suitability of the siRNA-loaded nanoparticles for nebulization using a vibrating mesh nebuliser was assessed. The siRNA nanoparticles were nebulised using an Aerogen® Pro vibrating mesh nebuliser and characterised for aerosol output, droplet size and fine particle fraction. Only PEI anti-IL8 siRNA nanoparticles were capable of significant levels of IL-8 knockdown in vitro in non-nebulised samples. However, on nebulization through a TSI, only PEI-PEG siRNA nanoparticles demonstrated significant decreases in gene and protein expression in polarised Calu-3 cells. In vivo, both anti-CXCL-1 (rat IL-8 homologue) nanoparticles demonstrated a decreased CXCL-1 gene expression in lung tissue, but this was non-significant. However, PEI anti-CXCL-1 siRNA-treated rats were found to have significantly less infiltrating macrophages in their bronchoalveolar lavage (BAL) fluid. Overall, the in vivo gene and protein inhibition findings indicated a result more reminiscent of the in vitro bolus delivery rather than the in vitro nebulization data. This work demonstrates the potential of nebulised PEI-PEG siRNA nanoparticles in modulating pulmonary inflammation and highlights the need to move towards more relevant in vitro and in vivo models for respiratory drug development.

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Fate of PEGylated antibody fragments following delivery to the lungs: Influence of delivery site, PEG size and lung inflammation

Cited by 43 publications

References 30 publications

PEGylation of Recombinant Human Deoxyribonuclease I Provides a Long‐Acting Version of the Mucolytic for Patients with Cystic Fibrosis

PEGylation of Recombinant Human Deoxyribonuclease I Provides a Long‐Acting Version of the Mucolytic for Patients with Cystic Fibrosis

Preclinical evaluation of topically-administered PEGylated Fab’ lung toxicity

In Vitro and In Vivo Assessment of PEGylated PEI for Anti-IL-8/CxCL-1 siRNA Delivery to the Lungs

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