Anti-PEG antibodies compromise the integrity of PEGylated lipid-based nanoparticles via complement

Senti, MarionaEstapé; Jongh, Caroline A. de; Dijkxhoorn, Kim; Verhoef, J.; Szebeni, János; Storm, Gert; Hack, C. E.; Schiffelers, Raymond M.; Fens, Marcel H.A.M.; Boross, Péter

doi:10.1016/j.jconrel.2021.11.042

Cited by 75 publications

(48 citation statements)

References 41 publications

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“…Polyethylene glycol is a hydrophilic, biocompatible polymer that is acknowledged to significantly reduce recognition and clearance of nanoparticles ( 34 , 35 ). Nevertheless, the generation of anti-PEG antibodies has been associated with considerably faster clearance of PEG-containing drugs and nanocarrier systems upon repeated administration, potentially hindering drug product efficacy ( 36 ). Therefore, to evaluate whether elevated levels of anti-PEG antibodies were detected at shorter intervals, mice were immunized with dose 1 of mRNA-1273 (1-µg and 10-µg dose levels) at varying dosing intervals and antibodies to PEG (IgG and IgM) were evaluated before dose 2.…”

Section: Resultsmentioning

confidence: 99%

Altering the mRNA-1273 dosing interval impacts the kinetics, quality, and magnitude of immune responses in mice

Garcia-Dominguez

Henry

et al. 2022

Front. Immunol.

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For a vaccine to achieve durable immunity and optimal efficacy, many require a multi-dose primary vaccination schedule that acts to first “prime” naive immune systems and then “boost” initial immune responses by repeated immunizations (ie, prime-boost regimens). In the context of the global coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 2-dose primary vaccination regimens were often selected with short intervals between doses to provide rapid protection while still inducing robust immunity. However, emerging post-authorization evidence has suggested that longer intervals between doses 1 and 2 for SARS-CoV-2 vaccines may positively impact robustness and durability of immune responses. Here, the dosing interval for mRNA-1273, a messenger RNA based SARS-CoV-2 vaccine administered on a 2-dose primary schedule with 4 weeks between doses, was evaluated in mice by varying the dose interval between 1 and 8 weeks and examining immune responses through 24 weeks after dose 2. A dosing interval of 6 to 8 weeks generated the highest level of antigen-specific serum immunoglobulin G binding antibody titers. Differences in binding antibody titers between mRNA-1273 1 µg and 10 µg decreased over time for dosing intervals of ≥4 weeks, suggesting a potential dose-sparing effect. Longer intervals (≥4 weeks) also increased antibody-dependent cellular cytotoxicity activity and numbers of antibody-secreting cells (including long-lived plasma cells) after the second dose. An interval of 6 to 8 weeks elicited the strongest CD8+ T-cell responses, while an interval of 3 weeks elicited the strongest CD4+ T-cell response. Overall, these results suggest that in a non-pandemic setting, a longer interval (≥6 weeks) between the doses of the primary series for mRNA-1273 may induce more durable immune responses.

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Section: Resultsmentioning

confidence: 99%

Altering the mRNA-1273 dosing interval impacts the kinetics, quality, and magnitude of immune responses in mice

Garcia-Dominguez

Henry

et al. 2022

Front. Immunol.

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“…This phenomenon has already been observed with PEGylated drugs, especially those given at low dose [ [9] , [10] , [11] ] and causes a decrease in the drug efficacy due to its very shortened residence time in the bloodstream. ABC has been observed with PEGylated drugs that weren't LNPs, but the binding of anti-PEG antibodies to PEGylated formulations has others consequences, namely activation of the complement cascade [ 41 ] and disruption of the LNP membrane, causing the formation of Membrane attack Complex (MAC) and leaking of the payload into the bloodstream [ 18 , 42 ]. The impact of high titers of either pre-existing or elicited anti-PEG antibodies have previously been linked to accelerated blood clearance, loss of therapeutic efficacy of pegylated pharmaceuticals administered intravenously and infusion reactions [ 18 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

Anti-PEG antibodies before and after a first dose of Comirnaty® (mRNA-LNP-based SARS-CoV-2 vaccine)

Bavli¹,

Chen

Gross³

et al. 2023

Journal of Controlled Release

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“…PEG-based surfactants typically display a stealth effect to ensure stability in the physiological milieu and reduce formation of protein corona, which is necessary to minimize undesired blood clearance . However, it has been shown that PEG can lead to antibody formation, thus accelerating blood clearance, , promoting researchers to explore PEG alternatives. ,, Therefore, we explored a class of amphiphilic proteins, hydrophobins, as possible nonimmunogenic stabilizers for obtaining PERFECTA formulations with reduced sizes and stealth properties (Figure c,g) . Hydrophobin-II (HFBII) displays a highly hydrophobic patch enabling, for example, the formation of HFBII films on hydrophobic and fluorinated switching surface. − This rationale was applied to disperse PERFECTA in HFBII aqueous solutions resulting in the formation of 50 nm PERFECTA solid NPs coated by a protein shell.…”

Section: Superfluorinated Tracer (Perfecta)mentioning

confidence: 99%

Multibranched-Based Fluorinated Materials: Tailor-Made Design of ¹⁹F-MRI Probes

et al. 2022

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Conspectus Future medicine is primarily aiming at the development of novel approaches for an early diagnosis of diseases and a personalized therapy for patients. For achieving these objectives, a key role is played by medical imaging. Among available noninvasive imaging techniques, Fluorine-19 (19F) Magnetic Resonance Imaging (MRI) is emerging as a powerful quantitative detection modality for clinical use both for molecular imaging and for cell tracking. The strength of using 19F-MRI is mainly related to the lack of endogenous organic fluorine in tissues, with no background, enabling the visualization of fluorinated tracers as hot-spot images, adding secondary independent information to the anatomical features provided by the grayscale 1H-MRI. The main challenge for 19F-MRI clinical application is the intrinsic reduced sensitivity of MRI. To improve sensitivity, undoubtedly the use of a high field MRI scanner and cryogenic radiofrequency probes is advantageous, but there is a clear need of developing increasingly effective fluorinated tracers. The ideal tracer should bear as many as possible magnetically equivalent fluorine atoms and show optimal magnetic resonance relaxivity properties (i.e., T 1 and T 2), which enable reduced acquisition time with the possibility to apply fast imaging methods. Moreover, it should be biocompatible with reduced tendency to bioaccumulate in tissues, which is one of the main drawbacks in using perfluorocarbons (PFCs), together with their difficulty to be chemically modified with functional groups. In fact, PFCs such as perfluorooctyl bromide (PFOB), perfluoro-15-crown-5-ether (PFCE), and linear perfluoropolyethers (PFPE) are currently the most used tracers in 19F-MRI preclinical and clinical studies, with the above-mentioned limitations. In this regard, molecules bearing short branched fluorinated chains gained a lot of attention for their high number of equivalent fluorines and expected capability of reducing bioaccumulation concerns. A valuable building block for branched fluorinated tracers is perfluoro-tert-butanol (PFTB), with nine magnetically equivalent fluorines and easy availability and modification. In this Account we will discuss the main challenges that 19F-MRI has to overcome for increasing its clinical use, highlighting on one hand the need of developing customized fluorinated materials for increasing sensitivity and enabling multimodal properties, and on the other hand, the importance of the ultrastructure of the final formulation for the final biological response (i.e., clearance). In this context, our group has been focusing on the synthesis and development of branched fluorinated tracers, for which the originator is a molecule called PERFECTA (from suPERFluorinatEdContrasT Agent), bearing 36 equiv 19F atoms, which showed not only optimal relaxometry properties but also a very specific and intense Raman signal. Thus, PERFECTA and its derivatives represent a new family of multimodal tracers enabling multiscale analysis, from whole body imaging (19F-MRI) to microsco...

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Anti-PEG antibodies compromise the integrity of PEGylated lipid-based nanoparticles via complement

Cited by 75 publications

References 41 publications

Altering the mRNA-1273 dosing interval impacts the kinetics, quality, and magnitude of immune responses in mice

Altering the mRNA-1273 dosing interval impacts the kinetics, quality, and magnitude of immune responses in mice

Anti-PEG antibodies before and after a first dose of Comirnaty® (mRNA-LNP-based SARS-CoV-2 vaccine)

Multibranched-Based Fluorinated Materials: Tailor-Made Design of ¹⁹F-MRI Probes

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Anti-PEG antibodies compromise the integrity of PEGylated lipid-based nanoparticles via complement

Cited by 75 publications

References 41 publications

Altering the mRNA-1273 dosing interval impacts the kinetics, quality, and magnitude of immune responses in mice

Altering the mRNA-1273 dosing interval impacts the kinetics, quality, and magnitude of immune responses in mice

Anti-PEG antibodies before and after a first dose of Comirnaty® (mRNA-LNP-based SARS-CoV-2 vaccine)

Multibranched-Based Fluorinated Materials: Tailor-Made Design of 19F-MRI Probes

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Product

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Multibranched-Based Fluorinated Materials: Tailor-Made Design of ¹⁹F-MRI Probes