Immunogenicity of murine mPEG-red blood cells and the risk of anti-PEG antibodies in human blood donors

Le, Yevgeniya; Toyofuku, Wendy M.; Scott, Mark D.

doi:10.1016/j.exphem.2016.11.001

Cited by 15 publications

(17 citation statements)

References 56 publications

(144 reference statements)

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“…58 Protein A is known to deplete serum/plasma from IgG 1 , IgG 2 , IgG 3 and to some extent IgM. 43 Indeed, binding of naturally occurring IgM antibodies against a component of the pristine surface (e.g., anti-PEG and anti-dextran IgM) 44 could trigger complement activation through the classical pathway. Among tested cohort of donors and nanoparticles, however, we excluded a major role of the classical pathway in complement activation.…”

Section: Discussionmentioning

confidence: 99%

Immunoglobulin deposition on biomolecule corona determines complement opsonization efficiency of preclinical and clinical nanoparticles

et al. 2019

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Deposition of complement factors (opsonisation) on nanoparticles may promote clearance from the blood by macrophages and trigger proinflammatory responses, but the mechanisms regulating the efficiency of complement activation are poorly understood. We previously demonstrated that opsonisation of superparamagnetic iron oxide nanoworms (SPIO NWs) with the third complement protein (C3) was dependent on the biomolecule corona. Here we show that natural antibodies play a critical role in C3 opsonisation of SPIO NWs and a range of clinically approved nanopharmaceuticals. The dependency of C3 opsonisation on immunoglobulin binding is predominantly universal and is observed regardless of the complement activation pathway. Few surface-bound immunoglobulin molecules trigger complement activation and opsonisation. While the total amount of nanoparticle-absorbed protein does not determine C3 deposition efficiency, the biomolecule corona per se enhances immunoglobulin binding to all nanoparticle types. We therefore show that natural antibodies represent a link between biomolecule corona and C3 opsonisation, and may determine individual complement responses to nanomedicines.

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Section: Discussionmentioning

confidence: 99%

Immunoglobulin deposition on biomolecule corona determines complement opsonization efficiency of preclinical and clinical nanoparticles

et al. 2019

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“…For example, the engineering of PEG to the RBC membrane concealed glycophorin A epitopes from antibody detection and even inhibited the invasion of the malaria parasite [49]. Chronic transfusions of murine RBCs conjugated to mPEG revealed a normal in vivo circulation time with no evidence of antibody response against PEG [50]. However, excessive modification can have a deleterious impact on cell integrity and biocompatibility, and thus maintaining a balance between epitope shielding and membrane deformability is crucial [51].…”

Section: Rbc Loading: Effects On Cargoesmentioning

confidence: 99%

Vascular Drug Delivery Using Carrier Red Blood Cells: Focus on RBC Surface Loading and Pharmacokinetics

et al. 2020

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Red blood cells (RBC) have great potential as drug delivery systems, capable of producing unprecedented changes in pharmacokinetics, pharmacodynamics, and immunogenicity. Despite this great potential and nearly 50 years of research, it is only recently that RBC-mediated drug delivery has begun to move out of the academic lab and into industrial drug development. RBC loading with drugs can be performed in several ways-either via encapsulation within the RBC or surface coupling, and either ex vivo or in vivo-depending on the intended application. In this review, we briefly summarize currently used technologies for RBC loading/coupling with an eye on how pharmacokinetics is impacted. Additionally, we provide a detailed description of key ADME (absorption, distribution, metabolism, elimination) changes that would be expected for RBC-associated drugs and address unique features of RBC pharmacokinetics. As thorough understanding of pharmacokinetics is critical in successful translation to the clinic, we expect that this review will provide a jumping off point for further investigations into this area.Pharmaceutics 2020, 12, 440 2 of 21 of the research enterprise encompassing the design of drug delivery systems (DDS)-liposomes, antibody-drug conjugates, and polymeric nanocarriers, to name a few.Nevertheless, approaches to use RBCs as carriers for pharmacological agents have recently gained significant and rapidly growing attention. Progress in this field is rapidly diversifying and accelerating towards potentially clinically useful products. Many groups are now investigating the use of RBCs in drug delivery and are making significant contributions, leading to breakthrough findings and upbeat investments. Several RBC-based drug delivery approaches have entered clinical trials, including RBC-encapsulated asparaginase (Erytech, Phase 3) and dexamethasone (EryDel, Phase 3). Novel advanced strategies are emerging, including genetic molecular modifications of RBC [2,3], modulation of the immune system by RBC-coupled antigens [3,4], and vascular transfer of RBC-coupled nanocarriers (RBC hitchhiking) [5][6][7].Both encapsulation into and coupling to the surface of RBC fundamentally transform the key parameters of absorption, distribution, metabolism, and elimination (ADME) of drugs and drug delivery systems (DDS), including diverse nanocarriers. To our knowledge, studies of the pharmacokinetics (PK) and pharmacodynamics (PD) of RBC-based DDS are lacking, despite great relevance for industrial development and clinical utility.In order to help to close this gap of knowledge, in this paper we undertook the first attempt to define specific, salient parameters controlling behavior of RBC/DDS in the body. Our goal is to provide the modular framework for experimental and theoretical pre-clinical and clinical investigations of ADME-PK-PD features of RBC-based drug delivery.

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“…This may initiate macrophage recognition of PEGylated NPs through complement opsonization. 9–13 Furthermore, PEG can undergo oxidative degradation, and this may increase its complement activation property. 14 A number of animal and clinical studies have also indicated that PEGylated NPs may induce cardiopulmonary disturbances and distress.…”

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confidence: 99%

C1q-Mediated Complement Activation and C3 Opsonization Trigger Recognition of Stealth Poly(2-methyl-2-oxazoline)-Coated Silica Nanoparticles by Human Phagocytes

et al. 2018

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Poly(2-methyl-2-oxazoline) (PMOXA) is an alternative promising polymer to poly(ethylene glycol) (PEG) for design and engineering of macrophage-evading nanoparticles (NPs). Although PMOXA-engineered NPs have shown comparable pharmacokinetics and in vivo performance to PEGylated stealth NPs in the murine model, its interaction with elements of the human innate immune system has not been studied. From a translational angle, we studied the interaction of fully characterized PMOXA-coated vinyltriethoxysilane-derived organically modified silica NPs (PMOXA-coated NPs) of approximately 100 nm in diameter with human complement system, blood leukocytes, and macrophages and compared their performance with PEGylated and uncoated NP counterparts. Through detailed immunological and proteomic profiling, we show that PMOXA-coated NPs extensively trigger complement activation in human sera exclusively through the classical pathway. Complement activation is initiated by the sensing molecule C1q, where C1q binds with high affinity ( K = 11 ± 1 nM) to NP surfaces independent of immunoglobulin binding. C1q-mediated complement activation accelerates PMOXA opsonization with the third complement protein (C3) through the amplification loop of the alternative pathway. This promoted NP recognition by human blood leukocytes and monocyte-derived macrophages. The macrophage capture of PMOXA-coated NPs correlates with sera donor variability in complement activation and opsonization but not with other major corona proteins, including clusterin and a wide range of apolipoproteins. In contrast to these observations, PMOXA-coated NPs poorly activated the murine complement system and were marginally recognized by mouse macrophages. These studies provide important insights into compatibility of engineered NPs with elements of the human innate immune system for translational steps.

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Immunogenicity of murine mPEG-red blood cells and the risk of anti-PEG antibodies in human blood donors

Cited by 15 publications

References 56 publications

Immunoglobulin deposition on biomolecule corona determines complement opsonization efficiency of preclinical and clinical nanoparticles

Immunoglobulin deposition on biomolecule corona determines complement opsonization efficiency of preclinical and clinical nanoparticles

Vascular Drug Delivery Using Carrier Red Blood Cells: Focus on RBC Surface Loading and Pharmacokinetics

C1q-Mediated Complement Activation and C3 Opsonization Trigger Recognition of Stealth Poly(2-methyl-2-oxazoline)-Coated Silica Nanoparticles by Human Phagocytes

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