PEGylation prolongs the pulmonary retention of an anti-IL-17A Fab’ antibody fragment after pulmonary delivery in three different species

Preclinical evaluation of topically-administered PEGylated Fab’ lung toxicity

“…The murine Fab’ anti-IL17A containing a single free cysteine at the hinge region to react selectively with one molecule of PEG by thiol PEGylation was provided by UCB Pharma (United Kingdom). The Fab’ was conjugated to one molecule of a two-armed 40 kDa PEG (abbreviated as PEG40-Fab’ anti-IL17A or PEG40 Fab’) by thiol-directed PEGylation, as previously reported (Freches et al, 2017). The attachment of one PEG chain per Fab’ fragment was confirmed by molecular weight analysis using sodium dodecyl sulfate polyacrylamide gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (Freches et al, 2017).…”

“…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.…”

Site-specific PEGylation of an anti-CEA/CD3 bispecific antibody improves its antitumor efficacy

“…Such opposite effects of PEGylation on proteins in vitro and in vivo have also been shown for other proteins. 18,28,45…”

“…Their short in vivo half-life makes them less than optimal for clinical application. [17][18][19] To improve the in vivo half-life of proteins, various strategies have been explored to modulate their pharmacokinetic (PK) profiles, including conjugation to polyethylene glycol (PEG; PEGylation), N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers, proteins (such as albumin), and more recently, polyglutamic acid and PASylation. [19][20][21][22][23] Since the first introduction of PEG as an immunoprotective agent by Abuchowski et al [23][24][25] and the pioneering work of Davis 26 in the late 1970s, the covalent attachment of biocompatible nontoxic PEG to therapeutic proteins has become a common technique for improving the PK properties to reduce renal clearance.…”

Developing inhaled protein therapeutics for lung diseases

“…Furthermore, conjugation of a PEG chain to an anti-IL-17A Fab’ antibody fragment increased pulmonary retention in all three species tested (mice, rats, and rabbits) following intratracheal administration. Unconjugated fragments were cleared from the lungs within 24 h while large amounts of PEGylated fragments still remained for up to 48 h [ 89 ].…”