PEGylation of a Factor VIII–Phosphatidylinositol Complex: Pharmacokinetics and Immunogenicity in Hemophilia A Mice

Peng, Aaron; Kosloski, Matthew P.; Nakamura, Gisaku; Ding, Hong; Balu‐Iyer, Sathy V.

doi:10.1208/s12248-011-9309-2

Cited by 19 publications

(17 citation statements)

References 60 publications

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“…Transferrin embedded on ML surface was confirmed by spectrophotometry (Fig 4). Similar to the previous study of Xu et al [26], spectra of Transferrin embedded magnetic-liposomes showed red shift comparing with Transferrin. It should be noted that inclusion of less than 10% of PEG in formulation mixture results in homogenous PEGylation rather than forming thick corona which was noticed in the work of Gao et al [23] The shielding effect thick PEG corona may cause improper ligand bind and also may prevent proper interaction of ligand to the receptor on the cells.…”

Section: Resultssupporting

confidence: 89%

Enhanced blood–brain barrier transmigration using a novel transferrin embedded fluorescent magneto-liposome nanoformulation

Ding¹,

Sagar²,

Agudelo³

et al. 2014

Nanotechnology

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101

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Blood-brain barrier (BBB) is considered as the primary impediment barrier for most of drugs. Delivering therapeutic agents to brain is still a big challenge by now. In our study, a dual mechanism, receptor mediation combining with external non-invasive magnetic force, was incorporated together into ferrous magnet-based liposome for BBB transmigration enhancement. The homogenous magnetic nanoparticles (MNPs) with size of ~ 10 nm were synthesized and confirmed by TEM and XRD respectively. The classical magnetism assay showed presence of characteristic superparamagnetic property. These MNPs encapsulated in PEGylated fluorescent liposomes as magneto liposomes (ML) showed mono-dispersion ~ 130±10 nm diameter by dynamic laser scattering (DLS) using lipid-extrusion technique. Remarkably, this magnetite encapsulation efficiency of nearly 60% was achieved. And the luminescence and hydrodynamic size of ML was stable for over two months under 4 degree. Additionally, the integrity of ML structure remained unaffected through 120 rounds circulation mimicking human blood fluid. After biocompatibility confirmation by cytotoxicity evaluation, these fluorescent ML was further embedded with Transferrin and applied to in vitro BBB transmigration study in presence or absence of external magnetic force. Comparing with only by magnetic force- or Transferrin receptor-mediated transportation, their synergy resulted in 50–100% increased transmigration without affecting the BBB integrity. Consequently, confocal microscopy and iron concentration in BBB-composed cells further confirmed the higher cellular uptake of ML particles due to synergic effect. Thus, our multi-functional liposomal magnetic nanocarriers possess great potential in particles transmigration across BBB and may have bright future in drug delivery to brain.

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Section: Resultssupporting

confidence: 89%

Enhanced blood–brain barrier transmigration using a novel transferrin embedded fluorescent magneto-liposome nanoformulation

Ding¹,

Sagar²,

Agudelo³

et al. 2014

Nanotechnology

Self Cite

101

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“…33 In the face of the possible occurrence of bystander epitopes in bioengineered FVIII products, several manipulations introduced in the recombinant protein might minimize the risk of immunogenicity, 34 including modifying protein folding; using smaller peptides (ideally with a molecular weight Ͻ 2500) in lieu of full proteins, thus reducing the number of potential epitopes-a theoretical advantage for all truncated or deleted molecules 35,36 ; and extending the half-lives of coagulation proteins, thus reducing the frequency of administration and avoiding repeatedly boosting memory responses. 37 As an example, PEGylation may shield bystander epitopes 38 and protect the molecule from epitope-specific antibodies in inhibitor-positive subjects.…”

Section: Immunogenicity Of Therapeutic Proteinsmentioning

confidence: 99%

Clotting factor concentrate switching and inhibitor development in hemophilia A

Iorio

Puccetti

Makris

2012

Blood

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The development of alloantibodies or inhibitors is the most serious complication a patient with severe hemophilia can experience from treatment with clotting factor concentrates. Although common in previously untreated patients, inhibitor development is rare in multiply exposed, welltolerized patients. There has been a nonevidence-based reluctance to change concentrate because of a perceived greater inhibitor risk after the switch, even though most patients are now likely to be using a concentrate on which they did not begin. Inhibitors in previously treated patients are observed in approximately 2 per 1000 patient/years, which makes it difficult to study and compare rates among different products. Because the baseline inhibitor risk in previously treated patients may vary over time, it is important to compare the risk in patients switching to a new product with that in a parallel control group of nonswitching patients or within a case-controlled study.

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“…However, the immunogenic potential of chronic administration and long-term effects are not often adequately addressed during clinical trials (6). Few preclinical studies have shown that the sc route of administration does not increase immunogenicity (7)(8)(9). For example, the relative immunogenicity of Betaseron, interferon beta, is less for sc administration compared to iv administration (9).…”

Section: Immunogenicity Of Proteins Given Via Sc Routementioning

confidence: 99%

Immunogenicity of Subcutaneously Administered Therapeutic Proteins—a Mechanistic Perspective

Fathallah

Bankert

Balu‐Iyer

2013

AAPS J

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Abstract. The administration of therapeutic proteins via the subcutaneous route (sc) is desired for compliance and convenience, but could be challenging due to perceived immunogenic potential or unwanted immune responses. There are clinical and preclinical data supporting as well as refuting the generalized notion that sc is more immunogenic. We provide a mechanistic perspective of immunogenicity of therapeutic proteins administered via the sc route and discuss strategies and opportunities for novel therapeutic approaches to mitigate immunogenicity.KEY WORDS: biotechnology; immunogenicity; mitigation of immunogenicity; protein therapeutics; subcutaneous administration. IMMUNOGENICITY OF PROTEINS GIVEN VIA SC ROUTEThe subcutaneous (sc) route of administration of therapeutic proteins is desired over the intravenous (iv) route due to patient comfort and compliance. In addition, it could also prolong half-life of the therapeutic in circulation (1,2). However, this route of administration could be problematic due to a perceived potential for unwanted immunogenicity (3). As most of the vaccines are given via the sc route, it is expected that the sc route is more immunogenic than the iv route. However, a recent comparative clinical study of sc vs iv administration of abatacept, a fusion protein of Fc of human IgG and extracellular domain of CTLA-4, showed that the efficacy and immunogenicity are comparable between the two routes of administration (4,5). However, the immunogenic potential of chronic administration and long-term effects are not often adequately addressed during clinical trials (6). Few preclinical studies have shown that the sc route of administration does not increase immunogenicity (7-9). For example, the relative immunogenicity of Betaseron, interferon beta, is less for sc administration compared to iv administration (9). Based on clinical experience of head-to-head comparison and a few preclinical studies, one could argue that the generalization that the sc route is more immunogenic than the iv route is not universally valid.A comparative immunogenicity study of three brands of insulin in type 1 diabetics showed an increase in incidence of anti-insulin titer development, across brands, in patients selfadministering via sc route as compared to iv administration in hospital in the same cohort (10). In the therapeutic use of erythropoietin-α, incidence of immunogenicity increased with the change from iv to sc. It is appropriate to mention here that elimination of human serum albumin from the formulation as well as stopper material change (11) coincided with changes in route of administration, and thus, the effect of the sc route of administration on immunogenicity is not unambiguous for erythropoietin. There are several examples from preclinical relative immunogenicity studies that show the sc route is more immunogenic than the iv route. The sc administration of FVIII showed significantly higher total antibody titers compared to hemophilia A mice that were given FVIII via the iv route (12). A similar ob...

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PEGylation of a Factor VIII–Phosphatidylinositol Complex: Pharmacokinetics and Immunogenicity in Hemophilia A Mice

Cited by 19 publications

References 60 publications

Enhanced blood–brain barrier transmigration using a novel transferrin embedded fluorescent magneto-liposome nanoformulation

Enhanced blood–brain barrier transmigration using a novel transferrin embedded fluorescent magneto-liposome nanoformulation

Clotting factor concentrate switching and inhibitor development in hemophilia A

Immunogenicity of Subcutaneously Administered Therapeutic Proteins—a Mechanistic Perspective

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