Interaction of Polysorbate 80 with Erythropoietin: A Case Study in Protein–Surfactant Interactions

Villalobos, Alexander; Gunturi, Srinivas R.; Heavner, George A.

doi:10.1007/s11095-005-5356-7

Cited by 49 publications

(27 citation statements)

References 20 publications

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“…Previous reports by other researchers on protein-surfactant interactions have suggested an estimated stoichiometry of binding. 60,62 In order to calculate stoichiometric binding of rhGH to surfactants, Bam et al made an assumption that surfactants preferentially bound to protein rather than micelles, and that surfactant binding to protein was saturable. The binding stoichiometry determination of Epoetin alfa-PS-80 by Villalobos et al implicitly suggested that similar assumptions were made.…”

Section: Discussionmentioning

confidence: 99%

Physical and biophysical effects of polysorbate 20 and 80 on darbepoetin alfa

Deechongkit

Wen

Narhi

et al. 2009

Journal of Pharmaceutical Sciences

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Section: Discussionmentioning

confidence: 99%

Physical and biophysical effects of polysorbate 20 and 80 on darbepoetin alfa

Deechongkit

Wen

Narhi

et al. 2009

Journal of Pharmaceutical Sciences

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“…Historically, excipients were considered inert substances that could be used mainly in the manufacture of drug products as diluents, fillers, binders, lubricants, coatings, solvents, and dyes (7). However, with the advances in pharmaceutical science, some "active" excipients have been found to be capable of influencing drug absorption or bioavailability through a variety of mechanisms, such as modification in solubility/dissolution, change in intestinal permeability (including transporters), and modulation of gastrointestinal (GI) motility (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). To further investigate the effects of "active" excipients on the absorption of BCS class III drugs, this paper examines those that may modulate GI motility and affect the transit time of drugs in the gut.…”

Section: Introductionmentioning

confidence: 99%

Impact of Osmotically Active Excipients on Bioavailability and Bioequivalence of BCS Class III Drugs

Chen

Sadrieh

2013

AAPS J

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“…2 The factors that underlie immunogenicity of biomedical products can be related to the structure of protein, such as the presence of promiscuous T-cell epitopes 3 or posttranslational modifications, 4 but also to the formulation of the biomolecule. 5 Treatment-related parameters such as dosage, frequency, route of administration, and concomitant infections may also contribute to the induction of antidrug immune responses. 2 In patients with protein deficiencies administered therapeutics may be recognized by the immune system as non-self, thereby greatly increasing the risk of Ab development.…”

Section: Introductionmentioning

confidence: 99%

Modification of an exposed loop in the C1 domain reduces immune responses to factor VIII in hemophilia A mice

Wroblewska

Haren

Herczenik

et al. 2012

Blood

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Development of neutralizing IntroductionOver the past decades protein therapeutics such as hormones, enzymes, blood coagulation factors, or Abs have provided effective treatment for numerous diseases. 1 Treatment commonly requires frequent high-dose administration of protein therapeutics and, although generally considered safe, they often induce immune responses. 2 The factors that underlie immunogenicity of biomedical products can be related to the structure of protein, such as the presence of promiscuous T-cell epitopes 3 or posttranslational modifications, 4 but also to the formulation of the biomolecule. 5 Treatment-related parameters such as dosage, frequency, route of administration, and concomitant infections may also contribute to the induction of antidrug immune responses. 2 In patients with protein deficiencies administered therapeutics may be recognized by the immune system as non-self, thereby greatly increasing the risk of Ab development. 2 Hemophilia A is an X-linked bleeding disorder that is caused by a deficiency in blood coagulation factor VIII (FVIII). Conventional treatment comprising frequent administration of FVIII often results in formation of neutralizing Abs, which inhibit FVIII activity. 6,7 Both treatment-related factors, such as intensive treatment episodes, 8 and genetic risk factors can contribute to the development of inhibitors. Polymorphic sites in genes involved in the adaptive immune response have been associated with anti-FVIII Ab formation. 9-11 Development of high-affinity IgG Abs directed against FVIII is a CD4 ϩ T cell-dependent process. 12,13 Endocytosis of FVIII by professional APCs comprises the initial step leading to activation of helper T cells. Uptake and transfer of Ags through the lyso-endosomal pathway results in intracellular processing and presentation of FVIII-derived peptides on MHC II molecules to CD4 ϩ helper T cells. 14 Here, we hypothesized that prevention of FVIII uptake by APCs will lead to diminished T-and B-cell responses. Previously, we have shown that endocytosis of FVIII by APCs is mediated via its C1 domain, because administration of a mAb directed toward an antigenic surface in the C1 domain reduced inhibitor titers in FVIII-deficient mice. 15 With the use of an Ab-guided mutagenesis strategy we designed a C1 domain variant of FVIII which displayed a strongly reduced internalization by APCs. In vivo studies revealed that this C1 domain variant showed decreased immunogenicity in a murine model for inhibitor development in hemophilia A. Our findings provide a novel paradigm for the reduction of the intrinsic immunogenicity of FVIII by modulating its uptake by APCs. Methods MaterialsFicoll-Paque Plus (GE Healthcare), CD14 microbeads (Miltenyi Biotech), and human recombinant GM-CSF and IL-4 (both Cellgenix Technology Transfer) were used for generation of human monocyte-derived dendritic cells (MDDCs); M-CSF (PeproTech) was used to generate human monocytederived macrophages (MDM⌽s). For culturing murine BM-derived DCs (BMDCs), mouse recombinant GM-CSF ...

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Interaction of Polysorbate 80 with Erythropoietin: A Case Study in Protein–Surfactant Interactions

Abstract: Based on controlled studies, previous results suggesting that EPREX contains micelle-associated erythropoietin were incorrect. As with other surfactants and proteins, polysorbate 80 associates with erythropoietin in a defined stoichiometric ratio.

Cited by 49 publications

References 20 publications

Physical and biophysical effects of polysorbate 20 and 80 on darbepoetin alfa

Physical and biophysical effects of polysorbate 20 and 80 on darbepoetin alfa

Impact of Osmotically Active Excipients on Bioavailability and Bioequivalence of BCS Class III Drugs

Modification of an exposed loop in the C1 domain reduces immune responses to factor VIII in hemophilia A mice

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