Preclinical evaluation of topically-administered PEGylated Fab’ lung toxicity

Freches, D.; Rocks, Natacha; Patil, H. P.; Perin, Fabienne; Van Snick, J.; Vanbever, R.; Cataldo, Didier

doi:10.1016/j.ijpx.2019.100019

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Preclinical evaluation of topically-administered PEGylated Fab’ lung toxicity

Freches, D.; Rocks, Natacha; Patil, H. P. et al.

2019 • In International Journal of Pharmaceutics: X, 1

Peer Reviewed verified by ORBi

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https://hdl.handle.net/2268/259264

DOI
10.1016/j.ijpx.2019.100019

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Keywords :

Alveolar macrophages; Lung toxicity; Monoclonal antibodies; PEGylation; Pulmonary drug delivery; Article; J774A1 cell line

Abstract :

[en] PEGylation is a promising approach to increase the residence time of antibody fragments in the lungs and sustain their therapeutic effects. However, concerns arise as to the potential pulmonary toxicity of antibody fragments conjugated to high molecular weight (HMW) polyethylene glycol (PEG), notably after repeated administrations, and the possibility of PEG accumulation in the lungs. The purpose of this proof-of-concept study is to give insights about the safety of lung administration of a Fab’ anti-IL17A antibody fragment conjugated to two-armed 40 kDa PEG (PEG40). The presence of the PEG40 moiety inside alveolar macrophages remained stable for at least 24 h after intratracheal administration of PEG40-Fab’ to mice. PEG40 was then progressively cleared from alveolar macrophages. Incubation of PEG40 alone with macrophages in vitro did not significantly harm macrophages and did not affect phagocytosis or the production of inflammatory markers. After acute or chronic administration of PEG40-Fab’ to mice, no signs of significant pulmonary toxicity or inflammatory cell accumulation were observed. A vacuolization of alveolar macrophages not associated with any inflammation was noticed when PEG40, PEG40-Fab’, or unPEGylated Fab’ were administered. To conclude this preliminary proof of concept study, acute or repeated pulmonary administrations of PEGylated Fab’ appear safe in rodents. © 2019 The Authors

Disciplines :

Pharmacy, pharmacology & toxicology

Author, co-author :

Freches, D.; Advanced Drug Delivery & Biomaterials, Louvain Drug Research Institute, Université catholique de Louvain (UCLouvain), Brussels, Belgium

Rocks, Natacha ; Université de Liège - ULiège > Département de pharmacie > Pharmacie galénique

Patil, H. P.; Advanced Drug Delivery & Biomaterials, Louvain Drug Research Institute, Université catholique de Louvain (UCLouvain), Brussels, Belgium

Perin, Fabienne ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques

Van Snick, J.; Ludwig Cancer Research Ltd, Brussels Branch, Avenue Hippocrate 74, UCLouvain, 7459, Brussels, B-1200, Belgium

Vanbever, R.; Advanced Drug Delivery & Biomaterials, Louvain Drug Research Institute, Université catholique de Louvain (UCLouvain), Brussels, Belgium

Cataldo, Didier ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement

Language :

English

Title :

Preclinical evaluation of topically-administered PEGylated Fab’ lung toxicity

Publication date :

2019

Journal title :

International Journal of Pharmaceutics: X

eISSN :

2590-1567

Publisher :

Elsevier B.V.

Volume :

Peer reviewed :

Peer Reviewed verified by ORBi

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since 26 April 2021

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Bibliography

Ackland, G.L., Gutierrez Del Arroyo, A., Yao, T.S., Stephens, R.C., Dyson, A., Klein, N.J., Singer, M., Gourine, A.V., Low-molecular-weight polyethylene glycol improves survival in experimental sepsis. Crit. Care Med. 38 (2010), 629–636.
Baumann, A., Tuerck, D., Prabhu, S., Dickmann, L., Sims, J., Pharmacokinetics, metabolism and distribution of PEGs and PEGylated proteins: quo vadis?. Drug Discov. Today 19:10 (2014), 1623–1631.
Bendele, A., Seely, J., Richey, C., Sennello, G., Shopp, G., Short communication: renal tubular vacuolation in animals treated with polyethylene-glycol-conjugated proteins. Toxicol. Sci. 42 (1998), 152–157.
Burgess, E., Jones, E., Larsson, L., Morgan, F., Palframan, R., Scrimgeour, A., Main, M.J., A Randomised, Double-Blind, Placebo-Controlled, Dose-Escalation Study To Evaluate The Safety, Tolerability, Pharmacodynamics And Pharmacokinetics Of Single Inhaled Doses Of Vr942 (ucb4144) inHealthy Subjects And Repeated Doses In Mild Asthmatics. Am J Respir Crit Care Med, 2017(195), 2017, A4681.
Caliceti, P., Veronese, F.M., Pharmacokinetic and biodistribution properties of poly(ethyleneglycol)- protein conjugates. Adv. Drug Deliv. Rev. 55 (2003), 1261–1277.
Cantin, A.M., Woods, D.E., Cloutier, D., Dufour, E.K., Leduc, R., Polyethylene glycol conjugation at Cys 232 prolongs the half-life of α 1 proteinase inhibitor. Am. J. Respir. Cell. Mol. Biol. 27 (2002), 659–665.
Cataldo, D.D., Tournoy, K.G., Vermaelen, K., Munaut, C., Foidart, J.M., Louis, R., Noël, A., Pauwels, R.A., Matrix metalloproteinase-9 deficiency impairs cellular infiltration and bronchial hyperresponsiveness during allergen-induced airway inflammation. Am. J. Pathol. 161:2 (2002), 491–498.
Chapman, A.P., PEGylated antibodies and antibody fragments for improved therapy: a review. Adv. Drug Deliv. Rev. 54:4 (2002), 531–545.
Chun, L.F., Moazed, F., Calfee, C.S., Matthay, M.A., Gotts, J.E., Pulmonary toxicicy of e-cigarettes. Am. J. Physiol. Lung Cell. Mol. Physiol. 313:2 (2017), 193–206.
EMEA/664021/2009, 2009. Certolizumab pegol (CIMZIA).
Fernandes, C.A., Vanbever, R., Preclinical models for pulmonary drug delivery. Exp. Opin. Drug Deliv. 6:11 (2009), 1231–1245.
Forbes, B., O'Lone, R., Allen, P.P., Cahn, A., Clarke, C., Collinge, M., Dailey, L.A., Donnelly, L.E., Dybowski, J., Hassall, D., et al. Challenges for inhaled drug discovery and development: induced alveolar macrophages. Adv. Drug Deliv. Rev. 71 (2014), 15–33.
Freches, D., Patil, H.P., Machado Franco, M., Uyttenhove, C., Heywood, S., Vanbever, R., PEGylation prolongs the pulmonary retention of an anti-IL-17A Fab' antibody fragment after pulmonary delivery in three different species. Int. J. Pharm. 521 (2017), 120–129.
Guichard, M.J., Leal, T., Vanbever, R., PEGylation, an approach for improving the pulmonary delivery of biopharmaceuticals. Curr. Opin. Colloid. Interface Sci., 31(43–50), 2017, (a).
Gursahani, H., Riggs-Sauthier, J., Pfeiffer, J., Lechuga-Ballesteros, D., Fishburn, C.S., Absorption of polyethylene glycol (PEG) polymers: the effect of PEG size on permeability. J. Pharm. Sci. 98:8 (2009), 2847–2856.
Hoffman, E., Kumar, A., Kanabar, V., Arno, M., Preux, L., Millar, V., Page, C., Collins, H., Mudway, I., Dailey, L.A., et al. In vitro multiparameter assay development strategy toward differentiating macrophage responses to inhaled medicines. Mol. Pharm. 12:8 (2015), 2675–2687.
Ivens, I.A., Achanzar, W., Baumann, A., Brändli-Baiocco, A., Cavagnaro, J., Dempster, M., Depelchin, B.O., Rovira, A.R., Dill-Morton, L., Lane, J.H., et al. PEGylated biopharmaceuticals: current experience and considerations for nonclinical development. Toxicol. Pathol. 43:7 (2015), 959–983.
Jevsevar, S., Kunstelj, M., Porekar, V.G., PEGylation of therapeutic proteins. Biotechnol. J. 5 (2010), 113–128.
Kang, J.S., Deluca, P.P., Lee, K.C., Emerging PEGylated drugs. Expert. Opin. Emerg. Drugs 14 (2009), 363–380.
Klonne, D.R., Dodd, D.E., Losco, P.E., Troup, C.M., Tyler, T.R., Two-week aerosol inhalation study on polyethylene glycol (PEG) 3350 in F344-rats. Drug Chem. Toxicol. 12:1 (1989), 39–48.
Koussoroplis, S.J., Heywood, S., Uyttenhove, C., Barilly, C., Van Snick, J., Vanbever, R., Production, purification and biological characterization of mono-PEGylated anti-IL-17A antibody fragments. Int. J. Pharm. 454 (2013), 107–115.
Koussoroplis, S.J., Paulissen, G., Tyteca, D., Goldansaz, H., Todoroff, J., Barilly, C., Uyttenhove, C., Van Snick, J., Cataldo, D., Vanbever, R., PEGylation of antibody fragments greatly increases their local residence time following delivery to the respiratory tract. J. Control. Release 187 (2014), 91–100.
Lee, K.C., Chae, S.Y., Kim, T.H., Lee, S., Lee, E.S., Youn, Y.S., Intrapulmonary potential of polyethylene glycol-modified glucagon-like peptide-1s as a type 2 anti-diabetic agent. Regul. Pept. 152 (2009), 101–107.
Lee, W.S., Shim, S.R., Lee, S.Y., Yoo, J.S., Cho, S.K., Preclinical pharmacokinetics, interspecies scaling, and pharmacokinetics of a Phase I clinical trial of TTAC-0001, a fully human monoclonal antibody against vascular endothelial growth factor 2. Drug design, development and therapy 12 (2018), 495–504.
Luo, T., Loira-Pastoriza, C., Patil, H.P., Ucakar, B., Muccioli, G.G., Bosquillon, C., Vanbever, R., PEGylation of paclitaxel largely improves its safety and anti-tumor efficacy following pulmonary delivery in a mouse model of lung carcinoma. J. Control. Release 239 (2016), 62–71.
Malyala, P., Endotoxin limits in formulations for preclinical research. J. Pharm. Sci. 97:6 (2008), 2041–2044.
Mcleod, V.M., Chan, L.J., Ryan, G.M., Porter, C.J., Kaminskas, L.M., Optimal PEGylation can improve the exposure of interferon in the lungs following pulmonary administration. J. Pharm. Sci. 104:4 (2015), 1421–1430.
Moyers, J.S., Volk, C.B., Cao, J.X.C., Zhang, C., Ding, L., Kiselyov, V.V., Michael, M.D., Internalization and localization of basal insulin peglispro in cells. Mol. Cell. Endocrino. 454 (2017), 23–38.
Nikula, K.J., McCartney, J.E., McGovern, T., Miller, G.K., Odin, M., Pino, M.V., Reed, M.D., STP position paper: interpretating the significance of increased alveolar macrophages in rodents following inhalation of pharmaceutical materials. Toxicol. Pathol. 42:3 (2014), 472–486.
Patil, H.P., Freches, D., Karmani, L., Duncan, G., Ucakar, B., Suk, J.S., Hanes, J., Gallez, B., Vanbever, R., Fate of PEGylated antibody fragments following delivery to the lungs: influence of delivery site, PEG size and lung inflammation. J. Control. Release 272 (2018), 62–71.
Rudmann, D.G., Alston, J.T., Hanson, J.C., Heidel, S., High molecular weight polyethylene glycol cellular distribution and PEG-associated cytoplasmic vacuolation is molecular weight dependent and does not require conjugation to proteins. Toxicol. Pathol. 41 (2013), 970–983.
Turecek, P.L., Bossard, M.J., Schoetens, F., Ivens, I.A., PEGylation of biopharmaceuticals: a review of chemistry and nonclinical safety information of approved drugs. J. Pharm. Sci. 105 (2016), 460–475.
Uyttenhove, C., Marillier, R.G., Tacchini-Cottier, F., Charmoy, M., Caspi, R.R., Damsker, J.M., Goriely, S., Su, D., Van Damme, J., Struyf, S., et al. Amine-reactive OVA multimers for auto-vaccination against cytokinesand other mediators: perspectives illustrated for GCP-2 in L. major infection. J. Leukoc. Biol. 89:6 (2011), 1001–1007.
Vink, A., Coulie, P., Warnier, G., Renauld, J.C., Stevens, M., Donckers, D., Van Snick, J., Mouse plasmacytoma growth in vivo: enhancement by interleukin 6 (IL-6) and inhibition by antibodies directed against IL-6 or its receptor. J. Exp. Med. 172:3 (1990), 997–1000.
Webster, R., Didier, E., Harris, P., Siegel, N., Stadler, J., Tilbury, L., Smith, D., PEGylated proteins/ evaluation of their safety in the absence of definitive metabolism studies. Drug Metab. Dispos. 35:1 (2007), 9–16.
Yamoaka, T., Tabata, Y., Ikada, Y., Distribution and tissue uptake of poly(ethylene glycol) with different molecular weights after intravenous administration to mice. J. Pharm. Sci. 83 (1994), 601–606.
Youn, Y.S., Chae, S.Y., Lee, S., Jeon, J.E., Shin, H.G., Lee, K.C., 2007. Evaluation of therapeutic potentials of site-specific PEGylated glucagon-like peptide-1 isomers as a type 2 anti-diabetic treatment: insulinotropic activity, glucose-stabilizing capability, and proteolytic stability. Biochem. Pharmacol. 73, 84–93.
Youn, Y.S., Kwon, M.J., Na, D.H., Chae, S.Y., Lee, S., Lee, K.C., Improved intrapulmonary delivery of site-specific PEGylated salmon calcitonin: Optimization by PEG size selection. J. Control. Release 125 (2008), 68–75.
Young, M.A., Malavalli, A., Winslow, N., Vandegriff, K.D., Winslow, R.M., Toxicity and hemodynamic effects after single dose administration of MalPEG-hemoglobin (MP4) in rhesus monkeys. Transl. Res. 149 (2007), 333–342.
Zhang, C., Desai, R., Perez-Luna, V., Karuri, N., PEGylation of lysine residues improves the proteolytic stability of fibronectin while retaining biological activity. Biotechnol. J. 9 (2014), 1033–1043.