Browse
Submit Data
Databases
API
Help

Dataset Information

24 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Pre-treatment with high molecular weight free PEG effectively suppresses anti-PEG antibody induction by PEG-liposomes in mice.

ABSTRACT: Immune responses against polyethylene glycol (PEG) can lead to the rapid clearance of PEGylated drugs and are associated with increased risk of serious adverse events such as infusion reactions and anaphylaxis. Although select PEGylated therapeutics can induce anti-PEG antibodies (APA), there is currently no readily deployable strategy to mitigate their negative effects. Given the large number of PEGylated therapeutics that are either FDA-approved or in clinical development, methods that suppress APA induction to ensure the safety and efficacy of PEGylated drugs in patients would be a valuable clinical tool. We previously showed that infusion of high molecular weight (MW) free PEG can safely and effectively restore the circulation of PEG liposomes in animals with high pre-existing titers of APA, without stimulating additional APA production. Here, we explored the effectiveness of prophylaxis with free PEG or tolerogenic PEGylated liposomes as a strategy to reduce the amount of APA induced by subsequently administered PEGylated liposomes. Surprisingly, we found that a single administration of free PEG alone was capable of markedly reducing the APA response to PEG-liposomes for ~2 months; the effectiveness was comparable to, and frequently exceeded, interventions with different tolerogenic PEG-liposomes. These results support further investigations of free PEG prophylaxis as a potential strategy to ameliorate the APA response to sensitizing PEGylated therapeutics.

SUBMITTER: McSweeney MD

PROVIDER: S-EPMC7904660 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Overcoming anti-PEG antibody mediated accelerated blood clearance of PEGylated liposomes by pre-infusion with high molecular weight free PEG.

Project description:Antibodies that specifically bind polyethylene glycol (PEG), i.e. anti-PEG antibodies (APA), are associated with reduced efficacy and increased risk of serious adverse events for several PEGylated therapeutics. Here, we explored the concept of using free PEG molecules to saturate circulating APA. Surprisingly, we found that 40?kDa free PEG effectively restored the prolonged circulation of PEGylated liposomes in the presence of high titers of pre-existing APA for at least 48?h in mice. In contrast, lower molecular weight free PEG (?10?kDa) failed to restore circulation beyond a few hours. These in vivo results were consistent with estimates from a minimal physiologically based pharmacokinetic model. Importantly, the infusion of free PEG appeared to be safe in mice previously sensitized by injection of PEGylated liposomes, and free PEG did not elicit excess APA production even in mice with pre-existing adaptive immunity against PEG. Our results support further investigation of high molecular weight free PEG as a potential method to control and overcome high titers of APA, restoring the prolonged circulation of PEGylated liposomes and possibly other PEGylated therapeutics.

| S-EPMC6874909 | biostudies-literature

Pre-existing anti-polyethylene glycol antibody reduces the therapeutic efficacy and pharmacokinetics of PEGylated liposomes.

Project description:Rationale: Increasing frequency of human exposure to PEG-related products means that healthy people are likely to have pre-existing anti-PEG antibodies (pre-αPEG Ab). However, the influence of pre-αPEG Abs on the pharmacokinetics (PK) and therapeutic efficacy of LipoDox is unknown. Methods: We generated two pre-αPEG Ab mouse models. First, naïve mice were immunized with PEGylated protein to generate an endogenous αPEG Ab titer (endo αPEG). Second, monoclonal αPEG Abs were passively transferred (αPEG-PT) into naïve mice to establish a αPEG titer. The naïve, endo αPEG and αPEG-PT mice were intravenously injected with 111in-labeled LipoDox to evaluate its PK. Tumor-bearing naïve, endo αPEG and αPEG-PT mice were intravenously injected with 111in-labeled LipoDox to evaluate its biodistribution. The therapeutic efficacy of LipoDox was estimated in the tumor-bearing mice. Results: The areas under the curve (AUC)last of LipoDox in endo αPEG and αPEG-PT mice were 11.5- and 15.6- fold less, respectively, than that of the naïve group. The biodistribution results suggested that pre-αPEG Ab can significantly reduce tumor accumulation and accelerate blood clearance of 111In-labeled LipoDox from the spleen. The tumor volumes of the tumor-bearing endo αPEG and αPEG-PT mice after treatment with LipoDox were significantly increased as compared with that of the tumor-bearing naïve mice. Conclusions: Pre-αPEG Abs were found to dramatically alter the PK and reduce the tumor accumulation and therapeutic efficacy of LipoDox. Pre-αPEG may have potential as a marker to aid development of personalized therapy using LipoDox and achieve optimal therapeutic efficacy.

| S-EPMC5996368 | biostudies-literature

BAFF Inhibition Effectively Suppresses the Development of Anti-HLA.A2 Antibody in the Highly Sensitized Mouse Model.

Project description:B cell activating factor (BAFF) is a cytokine that plays a role in the survival, proliferation and differentiation of B cells. We proposed to observe the effects of BAFF inhibition on the humoral immune responses of an allosensitized mouse model using HLA.A2 transgenic mice. Wild-type C57BL/6 mice were sensitized with skin allografts from C57BL/6-Tg (HLA-A2.1)1Enge/J mice and were treated with anti-BAFF monoclonal antibody (mAb) (named Sandy-2) or control IgG1 antibody. HLA.A2-specific IgG was reduced in BAFF-inhibited mice compared to the control group (?-13.62 vs. ?27.07, p < 0.05). BAFF inhibition also resulted in increased pre-pro and immature B cell proportions and decreased mature B cells in the bone marrow (p < 0.05 vs. control). In the spleen, an increase in transitional B cells was observed with a significant decrease in marginal and follicular B cells (p < 0.05 vs. control). There was no significant difference in the proportions of long-lived plasma and memory B cells. Microarray analysis showed that 19 gene probes were significantly up- (>2-fold, p < 0.05) or down-regulated (?2-fold, p < 0.05) in the BAFF-inhibited group. BAFF inhibition successfully reduced alloimmune responses through the reduction in alloantibody production and suppression of B cell differentiation and maturation. Our data suggest that BAFF suppression may serve as a useful target in desensitization therapy.

| S-EPMC7830620 | biostudies-literature

Anti-Human VEGF Repebody Effectively Suppresses Choroidal Neovascularization and Vascular Leakage.

Project description:Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness among people over the age of 60. Vascular endothelial growth factor (VEGF) plays a major role in pathological angiogenesis in AMD. Herein, we present the development of an anti- human VEGF repebody, which is a small-sized protein binder consisting of leucine-rich repeat (LRR) modules. The anti-VEGF repebody selected through a phage-display was shown to have a high affinity and specificity for human VEGF. We demonstrate that this repebody effectively inhibits in vitro angiogenic cellular processes, such as proliferation and migration, by blocking the VEGF-mediated signaling pathway. The repebody was also shown to have a strong suppression effect on choroidal neovascularization (CNV) and vascular leakage in vivo. Our results indicate that the anti-VEGF repebody has a therapeutic potential for treating neovascular AMD as well as other VEGF-involved diseases including diabetic retinopathy and metastatic cancers.

| S-EPMC4807815 | biostudies-literature

Anti-EphA10 antibody-conjugated pH-sensitive liposomes for specific intracellular delivery of siRNA.

Project description:Therapeutic delivery of small interfering RNA (siRNA) is a major challenge that limits its potential clinical application. Here, a pH-sensitive cholesterol-Schiff base-polyethylene glycol (Chol-SIB-PEG)-modified cationic liposome-siRNA complex, conjugated with the recombinant humanized anti-EphA10 antibody (Eph), was developed as an efficient nonviral siRNA delivery system. Chol-SIB-PEG was successfully synthesized and confirmed with FTIR and (1)H-NMR. An Eph-PEG-SIB-Chol-modified liposome-siRNA complex (EPSLR) was prepared and characterized by size, zeta potential, gel retardation, and encapsulation efficiency. Electrophoresis results showed that EPSLR was resistant to heparin replacement and protected siRNA from fetal bovine serum digestion. EPSLR exhibited only minor cytotoxicity in MCF-7/ADR cells. The results of flow cytometry and confocal laser scanning microscopy suggested that EPSLR enhanced siRNA transfection in MCF-7/ADR cells. Intracellular distribution experiment revealed that EPSLR could escape from the endo-lysosomal organelle and release siRNA into cytoplasm at 4 hours posttransfection. Western blot experiment demonstrated that EPSLR was able to significantly reduce the levels of MDR1 protein in MCF-7/ADR cells. The in vivo study of DIR-labeled complexes in mice bearing MCF-7/ADR tumor indicated that EPSLR could reach the tumor site rather than other organs more effectively. All these results demonstrate that EPSLR has much potential for effective siRNA delivery and may facilitate its therapeutic application.

| S-EPMC4993279 | biostudies-literature

Characterization of pre-existing anti-PEG and anti-AGAL antibodies towards PRX-102 in patients with Fabry disease.

Project description:Polyethylene glycol (PEG)ylated drugs are used for medical treatment, since PEGylation either decreases drug clearance or/and shields the protein from undesirable immunogenicity. PEGylation was implemented in a new enzyme replacement therapy for Fabry disease (FD), pegunigalsidase-alfa (PRX-102). However, exposure to PEG via life-style products and vaccination can result in the formation of anti-PEG antibodies. We demonstrate the de novo formation of functional anti-PEG antibodies in a healthy male after the second mRNA-based vaccination against SARS-CoV-2. Consequently, we analyzed the frequency and inhibitory function of anti-PEG and anti-α-Galactosidase A (AGAL) antibodies in 102 FD patients (46.9% males). We identified 29 out of 87 (33.3%) patients with low anti-PEG titers. Sera from patients without anti-AGAL antibodies [n=70] showed a higher rescued AGAL activity of agalsidase-beta and PRX-102 [both p<0.0001] compared to those with anti-AGAL antibodies [n=15]. Sera from anti-AGAL antibody-negative and -positive patients had less inhibitory effects on PRX-102 (rescued activity: 89 ± 6% versus 85 ± 7% and 49 ± 26% versus 25 ± 32%; both p<0.0001). Enzyme stability assays demonstrated that AUCs in anti-AGAL-negative sera (n=20) were 7.6-fold higher for PRX-102, while AUCs of both enzymes in anti-AGAL-positive sera (n=6) were decreased. However, AUC for PRX-102 was 33% of non-anti-AGAL-positive sera treated PRX-102 and 5-fold higher compared to agalsidase-beta. Anti-PEG antibodies had no significant effects on serum half-life of PRX-102, probably due to low titers. Conceivably, therapy efficacy may be superior under next-generation PRX-102 therapy compared to current enzyme replacement therapies in terms of reduced inhibitory effects of anti-AGAL and minor inhibitory effects of anti-PEG antibodies.

| S-EPMC10561604 | biostudies-literature

Fc-Silent Anti-CD154 Domain Antibody Effectively Prevents Nonhuman Primate Renal Allograft Rejection.

Project description:The advent of costimulation blockade provides the prospect for targeted therapy with improved graft survival in transplant patients. Perhaps the most effective costimulation blockade in experimental models is the use of reagents to block the CD40/CD154 pathway. Unfortunately, successful clinical translation of anti-CD154 therapy has not been achieved. In an attempt to develop an agent that is as effective as previous CD154 blocking antibodies but lacks the risk of thromboembolism, we evaluated the efficacy and safety of a novel anti-human CD154 domain antibody (dAb, BMS-986004). The anti-CD154 dAb effectively blocked CD40-CD154 interactions but lacked crystallizable fragment (Fc) binding activity and resultant platelet activation. In a nonhuman primate kidney transplant model, anti-CD154 dAb was safe and efficacious, significantly prolonging allograft survival without evidence of thromboembolism (Median survival time 103 days). The combination of anti-CD154 dAb and conventional immunosuppression synergized to effectively control allograft rejection (Median survival time 397 days). Furthermore, anti-CD154 dAb treatment increased the frequency of CD4+ CD25+ Foxp3+ regulatory T cells. This study demonstrates that the use of a novel anti-CD154 dAb that lacks Fc binding activity is safe without evidence of thromboembolism and is equally as potent as previous anti-CD154 agents at prolonging renal allograft survival in a nonhuman primate preclinical model.

| S-EPMC5409881 | biostudies-literature

Effect of PEG pairing on the efficiency of cancer-targeting liposomes.

Project description:Standardized poly(ethylene glycol)-modified (PEGylated) liposomes, which have been widely used in research as well as in pre-clinical and clinical studies, are typically constructed using PEG with a molecular weight of 2000 Da (PEG(2000)). Targeting ligands are also generally conjugated using various functionalized PEG(2000)). However, although standardized protocols have routinely used PEG(2000), it is not because this molecular weight PEG has been optimized to enhance tumor uptake of nanoparticles. Herein, we investigated the effect of various PEG lipid pairings--that is, PEG lipids for targeting-ligand conjugation and PEG lipids for achieving 'stealth' function--on in vitro cancer cell- and in vivo tumor-targeting efficacy. A class of high-affinity peptides (aptides) specific to extra domain B of fibronectin (APT(EDB)) was used as a representative model for a cancer-targeting ligand. We synthesized a set of aptide-conjugated PEGylated phospholipids (APT(EDB)?PEG(2000))?DSPE and APT(EDB)?PEG(2000))?DSPE) and then paired them with methoxy-capped PEGylated phospholipids with diverse molecular weights (PEG(2000)), PEG(2000)), PEG(2000)), and PEG(2000))) to construct various aptide-conjugated PEGylated liposomes. The liposomes with APT(EDB)?PEG(2000))/PEG(2000)) and APT(EDB)?PEG(2000))/PEG(2000)) pairings had the highest uptake in EDB-positive cancer cells. Furthermore, in a U87MG xenograft model, APT(EDB)?PEG(2000))/PEG(2000)) liposomes retarded tumor growth to the greatest extent, followed closely by APT(EDB)?PEG(2000))/PEG(2000)) liposomes. Among the PEGylated liposomes tested, pairs in which the methoxy-capped PEG length was about half that of the targeting ligand-displaying PEG exhibited the best performance, suggesting that PEG pairing is a key consideration in the design of drug-delivery vehicles.

| S-EPMC4402498 | biostudies-literature

Evading pre-existing anti-hinge antibody binding by hinge engineering.

Project description:Antigen-binding fragments (Fab) and F(ab')2 antibodies serve as alternative formats to full-length anti-bodies in therapeutic and immune assays. They provide the advantage of small size, short serum half-life, and lack of effector function. Several proteases associated with invasive diseases are known to cleave antibodies in the hinge-region, and this results in anti-hinge antibodies (AHA) toward the neoepitopes. The AHA can act as surrogate Fc and reintroduce the properties of the Fc that are otherwise lacking in antibody fragments. While this response is desired during the natural process of fighting disease, it is commonly unwanted for therapeutic antibody fragments. In our study, we identify a truncation in the lower hinge region of the antibody that maintains efficient proteolytic cleavage by IdeS protease. The resulting neoepitope at the F(ab')2 C-terminus does not have detectable binding of pre-existing AHA, providing a practical route to produce F(ab')2 in vitro by proteolytic digestion when the binding of pre-existing AHA is undesired. We extend our studies to the upper hinge region of the antibody and provide a detailed analysis of the contribution of C-terminal residues of the upper hinge of human IgG1, IgG2 and IgG4 to pre-existing AHA reactivity in human serum. While no pre-existing antibodies are observed toward the Fab of IgG2 and IgG4 isotype, a significant response is observed toward most residues of the upper hinge of human IgG1. We identify a T225L variant and the natural C-terminal D221 as solutions with minimal serum reactivity. Our work now enables the production of Fab and F(ab')2 for therapeutic and diagnostic immune assays that have minimal reactivity toward pre-existing AHA.

| S-EPMC5098439 | biostudies-literature

siRNA-containing liposomes modified with polyarginine effectively silence the targeted gene.

Project description:Development of RNA interference (RNAi) technology utilizing the short interfering RNA sequences (siRNA) based 'targeted' therapeutics has focused on creating methods for delivering siRNAs to cells and for enhancing siRNA stability in vitro and in vivo. Here, we describe a novel approach for siRNA cellular delivery using siRNA encapsulated into liposomes additionally bearing arginine octamer (R8) molecules attached to their outer surface (R8-liposomes). The R8-liposomal human double minute gene 2 (HDM2)-siRNA demonstrated a significant stability against degradation in the blood serum (siRNA-loaded R8-liposomes remained intact even after 24-h incubation), and higher transfection efficiency into all three tested lung tumor cell lines. siRNA delivery successfully proceeds in the presence of plasma proteins, and R8-liposomes demonstrate low non-specific toxicity. The mechanism of action of R8-liposome-encapsulated siRNA is associated with the RNAi-mediated degradation of the target mRNA. siRNA in R8-liposomes effectively inhibited the targeted gene and significantly reduced the proliferation of cancer cells. The approach offers the potential for siRNA delivery for various in vitro and in vivo applications.

| S-EPMC7114600 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data