Patent Grant
11065378
The present invention relates to a method for extracorporeal removal of a pathogenic microbe, an inflammatory cell or an inflammatory protein from mammalian blood; use of a device comprising a carbohydrate immobilized on a solid substrate, said carbohydrate having a binding affinity for a pathogenic microbe, an inflammatory cell or an inflammatory protein, for extracorporeal removal of said pathogenic microbe, inflammatory cell or inflammatory protein from mammalian blood; use of a carbohydrate having a binding affinity for a pathogenic microbe, an inflammatory cell or an inflammatory protein, wherein said carbohydrate is immobilized on a solid substrate, in the preparation of a device for treatment of a condition caused or aggravated by said pathogenic microbe, inflammatory cell or inflammatory protein; and a method for treatment of a mammalian subject suffering from a condition caused or aggravated by a pathogenic microbe, an inflammatory cell or an inflammatory protein.
Biology
During a long evolution, many pathogenic microorganisms have learned to exploit eukaryotic cell surface glycoconjugates, i.e. glycolipids, glycoproteins and proteoglycans, as receptor molecules for cell attachment to facilitate tissue colonization and invasion processes. In brief, specific proteins called adhesins of the surface of bacteria, viruses, fungi and parasites interact with carbohydrate chains of glycoconjugates which enable microbes to colonize mucosal surfaces and tissue lesions.
The role of sialic acid in binding of pathogens to host cells has been reported over many years. Only recently proteoglycans with their carbohydrate chains (glycosaminoglycans) were shown to bind many different pathogens. By removing terminal carbohydrate moieties of these various glycoconjugates with sialidase and other exoglycosidases or with glycosaminoglycan (GAG) degrading enzymes on the cells in monolayers, these structures were proven to be receptor molecules for various sialoadhesins and heparan sulfate binding proteins (HeBPs).
These mechanisms are summarized in a review article by Siiri Hirmo, Meeme Utt and Torkel Wadström, Biology, Biochemistry, Clinical Biochemistry, Volume 12, including Proceedings from the 17th International Lectin Meeting in Würzburg, 1997, edited by Edilbert van Driessche, Sonia Beeckmans and Thorkild C. Bøg-Hansen, published by TEXTOP, Lemchesvej 11, DK-2900 Hellerup, Denmark, ISBN number 87-984583-0-2.
During microbial infections, inflammatory mediators are released and activated. These so-called “pro-inflammatory cytokines” include tumor necrosis factor alpha and beta (TNF-α and TNF-β), interleukin-1 (IL-1), and interleukin-6 (IL-6). These cytokines are part of the inflammatory response of sepsis. Multiple organ failure induced by sepsis is currently the leading cause of death in intensive care units.
In connection with microbial infections and cardiovascular surgery, for instance cardiopulmonary bypass, inflammatory responses are elicited and have a multitude of biological consequences, ranging from subclinical organ dysfunction to severe multiorgan failure. Cytokines are thought to be important mediators in this response.
The cytokines mentioned above have a capacity to bind selectively to a range of glycosaminoglycans, or GAGs, including heparan sulfate in tissues and on the surface of both endothelial cells and leucocytes.
Receptors
Heparan sulfate is a glycosaminoglycan that is present on the surface of almost all mammalian cells. It is built up by alternating D-glucosamine and uronic acid residues (L-iduronic and D-glucuronic). Heparan sulfates are highly charged (sulfated) heterogeneous polysaccharides and represent the carbohydrate portion of many glycoconjugates (syndecan, perlecan, glypican) on the cell surface.
Many microbes utilize heparan sulfates on the surface of the mammalian cell as receptors. This mechanism is general and valid for almost all bacteria, virus and parasites. Some microorganisms utilize more than one glycoconjugate receptor. Examples of other receptors that are used together with heparan sulfate are specific chondroitin sulfates and sialic acid containing glycoproteins.
Heparan sulfate/chondroitin sulfate binding microbes are exemplified by viruses like herpes simplex virus type 1 (HSV-1), causative agent of orolabial herpes; herpes simplex virus type 2 (HSV-2), causative agent of genital herpes; cytomegalovirus (CMV), the major complicating agent in immunosuppressed patients; dengue virus, which causes recurrent fevers; and human immunodeficiency virus (HIV); and by bacteria like Helicobacter pylori, Streptococcus sanguis, Streptococcus mutans, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Mycobacterium tuberculosis; and parasites like Plasmodium falciparum (which causes malaria), and Trypanosoma cruzi (which causes trypanosomiasis).
Further, cytokines, like TNF-β, also utilize heparan sulfate on cell surfaces for binding and activation.
Heparin as a Receptor
Heparin is a polysaccharide, which is isolated from mammalian tissue. Since its discovery in 1916 by the American scientist McLean, heparin has been recognized for its blood anticoagulant properties and heparin has, for more than 50 years, been used clinically as a blood anticoagulant and antithrombotic agent.
Whereas heparan sulfates are ubiquitous components of all tissue-organized animal life forms, heparin has a very particular distribution in mammalian tissue. Heparin is, in contrast to the heparan sulfates, present only in the basophilic granules of mast cells. However, today, in addition to its established place in prevention and therapy of thromboembolic disorders, heparin has demonstrated a broad spectrum of different activities independent of anticoagulation.
A large number of proteins in blood bind, with high affinity, to heparin and/or heparan sulfate. Examples are antithrombin (AT), fibronectin, vitronectin, growth factors (e.g. the fibroblast growth factors, the insulin like growth factors etc). Human serum albumin (HSA) also binds, but with a lower affinity. On the other hand, HSA is present in large amounts in blood.
To utilize these properties of heparin for hindering infections, introducing heparin fragments and/or sialic containing fragments into the vascular system has been contemplated. Thereby, it was thought, these fragments would bind to the lectins on the microbes, block them and thus hinder them from binding to the receptors on the mammalian cell surface. This concept has been tried by many scientists but with limited success, in most cases due to bleeding complications when large amounts of heparin are introduced into the vascular system.
U.S. Pat. No. 6,197,568 discloses methods for isolation and detection of flaviviruses and other hemorrhagic fever viruses, such as dengue virus, based on the sulfated polyanion-dependent interaction of flaviviruses and hemorrhagic fever viruses.
Extracorporeal devices are used in a variety of clinical situations including kidney dialysis, cardiopulmonary bypass and plasmapheresis. “Extracorporeal therapies” means procedures in which desired products like oxygen, blood-anticoagulants, anesthetics etc can be added to body fluids. Conversely, undesired products like toxins etc can be removed from body fluids outside the body. Examples are haemodialysis and haemofiltration which represent technologies whereby blood is rinsed from waste products.
An object of the present invention is to provide a method for treatment of a mammal suffering from diseases or conditions caused or aggravated by different pathogenic microbes, inflammatory cells or inflammatory proteins by removal of said pathogenic microbes, inflammatory cells or inflammatory proteins from the blood of said mammal.
Another object of the present invention is to provide a method for extracorporeal removal of pathogenic microbes, inflammatory cells or inflammatory proteins from mammalian blood.
The above mentioned objects, as well as further objects of the invention, which should be apparent to a person skilled in the art after having studied the description below, are accomplished by the different aspects of the present invention as described herein.
A first aspect of the present invention provides a method for extracorporeal removal of a pathogenic microbe, an inflammatory cell or an inflammatory protein from mammalian blood, comprising the steps:
The prior-art concept of introducing heparin fragments and/or sialic containing fragments into the vascular system of patients has shown limited success, in most cases due to bleeding complications when large amounts of heparin are introduced into the vascular system. The method according to the invention circumvents these problems by the carbohydrates being immobilized on a solid surface, as is inter alia described in Preparatory example 6.
Use of immobilized carbohydrates as defined by the method according to the invention also provides a further unexpected advantage. The inventors have found that the carbohydrate has to be immobilized onto a solid surface to have the capacity that is necessary for binding a significant amount of the compounds that are to be removed. This unexpected property is described in Comparative example 1 and Example 1 for HSV-1, showing that in solution, less than 3% of the virus binds to an excess of heparin (Comparative example 1) while more than 94% of the virus binds to immobilized heparin (Example 1).
The method of the present invention enables safe and efficient treatment of patients suffering from sepsis or septic shock by removing pathogens causative of the condition from the patient's blood stream. The method of the present invention allows removal of many different pathogenic microbes, inflammatory cells and inflammatory proteins. Examples of pathogenic microbes commonly associated with sepsis that may be removed using the method of the invention include staphylococci, such as Staphylococcus aureus, streptococci and E. coli.
As both heparin and heparan sulfates bind to a large number of components, as exemplified in the background section, it was expected that a heparin surface would be covered with many of these proteins, when brought into contact with blood, thus preventing the microbes from attaching. The present inventors have surprisingly found that highly efficient purification of serum and whole blood from mammals, including humans, can be achieved using a method and a device according to the present invention. It is disclosed herein that a column of moderate size managed to almost completely remove considerable amounts of viruses from blood serum and whole blood. See e.g. Examples 2, 3 and 4.
In an embodiment, said pathogenic microbe is selected from the group consisting of bacteria, viruses and parasites.
In an embodiment, said pathogenic microbe is a virus. In a more specific embodiment, said virus is selected from the group consisting of herpes simplex virus type 1, herpes simplex virus type 2, Influenza A virus, cytomegalovirus and human immunodeficiency virus. In another more specific embodiment, said virus is selected from the group consisting of herpes simplex virus type 1 or herpes simplex virus type 2.
In another embodiment, said pathogenic microbe is a bacterium. In a more specific embodiment, said bacterium is selected from the group consisting of Helicobacter pylori, Streptococcus sanguis, Streptococcus mutans, Staphylococcus aureus, Escherichia coli, Pseudomonas aureginosa and Mycobacterium tuberculosis. In a preferred embodiment, said pathogenic microbe is Helicobacter pylori or Staphylococcus aureus.
In yet another embodiment, said pathogenic microbe is a parasite. In a more specific embodiment, said parasite is selected from the group consisting of Plasmodium falciparum and Trypanosoma cruzi.
In a further embodiment, said inflammatory cell is selected from the group consisting of inflammatory lymphocytes and inflammatory macrophages.
In yet a further embodiment, said inflammatory protein is a pro-inflammatory cytokine. In a more specific embodiment, said pro-inflammatory cytokine is selected from the group consisting of tumor necrosis factor alpha (TNF-α), tumor necrosis factor beta (TNF-β) interleukin-1 (IL-1), and interleukin-6 (IL-6).
In an embodiment, said mammalian blood is human blood.
In an embodiment of the inventive method, said carbohydrate is selected from the group consisting of heparin, heparan sulfate, chondroitin sulfate, carbohydrates comprising sialic acid and carbohydrates comprising neuramic acid. In a more specific embodiment, said carbohydrate is heparin.
In yet another embodiment, said solid substrate comprises microparticles or hollow fibres. In certain embodiments of the invention, the material of said solid substrate is selected from the group consisting of glass, cellulose, cellulose acetate, chitin, chitosan, crosslinked dextran, crosslinked agarose, polypropylene, polyethylene, polysulfone, polyacrylonitrile, silicone, Teflon and polyurethanes.
In a further embodiment, said carbohydrate is covalently linked to said solid substrate. In a more specific embodiment, said carbohydrate is linked to said solid substrate by covalent end-point attachment. Covalent attachment of a carbohydrate to a solid substrate provides better control of parameters such as surface density and orientation of the immobilized molecules as compared to non-covalent attachment. These parameters have been shown by the inventors to be important in order to provide optimal pathogen binding to the immobilized carbohydrate molecules. The surface concentration of the carbohydrate on the solid substrate should preferably be in the range of 1-10 μg/cm2. Covalent end-point attachment means that the carbohydrate is covalently attached to the solid substrate via the terminal residue of the carbohydrate molecule. A second aspect of the present invention provides use of a device comprising a carbohydrate immobilized on a solid substrate, said carbohydrate having a binding affinity for a pathogenic microbe, an inflammatory cell or an inflammatory protein, for extracorporeal removal of a pathogenic microbe, inflammatory cell or inflammatory protein from mammalian blood.
Embodiments of a use according to the second aspect of the invention correspond to those specified above for the method according to the first aspect of the present invention regarding the pathogenic microbe, inflammatory cell, inflammatory protein, mammalian blood, carbohydrate, solid substrate and immobilization.
A third aspect of the invention provides use of a carbohydrate having a binding affinity for a pathogenic microbe, an inflammatory cell or an inflammatory protein, wherein said carbohydrate is immobilized on a solid substrate, in the preparation of a device for treatment of a condition caused or aggravated by a pathogenic microbe, inflammatory cell or inflammatory protein.
Embodiments of a use according to the third aspect of the invention correspond to those specified above for the method according to the first aspect of the present invention regarding the pathogenic microbe, inflammatory cell, inflammatory protein, mammalian blood, carbohydrate, solid substrate and immobilization.
A device as referred to in the use and method according to the invention may comprise a conventional device for extracorporeal treatment of blood and serum from patients, e.g. suffering from renal failure.
Local blood flow patterns in blood contacting medical devices for extracorporeal circulation are known to influence clot formation via shear activation and aggregation of platelets in stagnant zones. Consequently, a device as used in the second, third and fourth aspects of the invention should be designed in a fashion that does not create these problems.
A device as used in some embodiments of the invention may for example have the following properties:
A non-limiting example of such a device, which can be used in a use or a method according to the present invention, is a pediatric haemoflow dialyzer such as the Prisma M10 haemofilter/dialyzer from Gambro AB, Sweden. Other models or types of devices for extracorporeal treatment of blood or serum may also be used.
A fourth aspect of the present invention provides a method for treatment of a mammalian subject suffering from a condition caused or aggravated by a pathogenic microbe, an inflammatory cell or an inflammatory protein, comprising the steps:
In an embodiment of the treatment method according to the present invention, the extraction and reintroduction of blood is performed in a continuous loop, which loop comprises a part of the bloodstream of the subject.
Embodiments of a method for treatment according to the fourth aspect of the invention correspond to those specified above for the method according to the first aspect of the present invention regarding the pathogenic microbe, inflammatory cell, inflammatory protein, mammalian blood, carbohydrate, solid substrate and immobilization.
As used herein, the term “pathogenic microbe” means a microbe, which can cause disease in a living organism when introduced into said organism. Examples of “pathogenic microbes” include bacteria, viruses and parasites.
As used herein, the term “inflammatory cell” means a cell, which is involved in inflammatory response in a mammal. Examples of “inflammatory cells” include inflammatory lymphocytes and inflammatory macrophages.
As used herein, the term “inflammatory protein” means a protein, such as a cytokine, released for instance in connection with microbial infection or immunization.
As used herein, the term “cytokine” means a protein, released for instance in connection with microbial infection or immunization, selected from the group consisting of interleukins, interferons, chemokines and tumour necrosis factors.
Amination of Sephadex G 25
Sodium metaperiodate (NaIO4, 6.0 g) was dissolved in water (994 ml) and added to Sephadex G 25 (Pharmacia Biotech, Uppsala, Sweden) (50 g) in 1 l water. The mixture was kept in the dark under shaking for 24 h. After filtration and washing with water 5×1 l and finally 0.1 M phosphate buffer, pH 7.0, the resulting product was suspended in phosphate buffer, pH 7.0 (350 ml) and a solution of polyethylenimine (100 ml Lupasol (BASF, Germany), 5% in water) was added. The gel was stabilized by addition of an aqueous solution of NaBH3CN, sodium cyanoborohydride (0.5 g in 100 ml, phosphate buffer, 0.1 M, pH 7.0). The gel was filtered and washed as described above and finally washed with acetate buffer (500 ml, 0.1 M, pH 4.0), yielding aminated Sephadex G 25 (85 g).
Covalent End-Point Attachment of heparin onto a Chromatographic Gel
Aminated Sephadex G 25 (85 g) obtained as described in Preparatory example 1 was suspended in acetate buffer (800 ml, 0.1 M, pH 4.0) and 4.0 g nitrous acid degraded heparin (heparin from Pharmacia, Sweden) was added. After shaking for 0.5 h, NaBH3CN (0.4 g) was added. The reaction mixture was shaken for 24 h and then processed as above, yielding heparinized Sephadex G 25 (80 g).
The gel contains 2% heparin (w/w, sulfur analysis). The Sephadex G 25 beads have an average diameter of 50-150 μm. A rough calculation reveals that 1 cm3 contains 106 beads which gives a bead surface area of 0.03 m2/cm3. Further, if heparin is attached only to the surface of the beads, a heparinized Sephadex G 25 with 2% heparin w/w has about 0.003 μg heparin/cm2.
Covalent Attachment of heparin onto Aminated Glass Wool
A glass wool material is heparinized using the general procedure described below.
Glass wool is thoroughly cleaned with acid (HCl), rinsed with absolute ethanol, and dried in an oven at 100° C. for 4 hours.
Reactive amino functions are introduced on the glass wool surface by treatment with an aqueous solution of polyamine, polyethylenimine (PEI) or chitosan. For some purposes, the polyamines may be stabilized on the surface by crosslinking with bifunctional reagents, such as crotonaldehyde or glutaraldehyde.
The coating is further stabilized by ionic cross linking with a sulfated polysaccharide (dextran sulfate or heparin). If necessary, these steps are repeated and a sandwich structure is built up. Careful rinsing (water, suitable buffers) should be performed between each step. After a last addition of PEI or chitosan, end-point attachment (EPA) to the aminated surface of native heparin is done by reductive amination, utilizing the aldehyde function in the reducing terminal residue in native heparin. The coupling is performed in aqueous solution, by reductive amination (cyanoborohydride, CNBH3−) essentially as described in Preparatory example 2.
Surface analysis as described in Preparatory example 2 reveals that approximately 10 mg/cm2 of heparin is coupled to the glass surface.
Covalent Attachment of heparin onto Aminated Polymeric Surfaces
A polymeric surface was heparinized using the general procedure described below.
The polymeric surface is etched with a oxidizing agent (potassium permanganate, ammoniumperoxidisulfate) in order to introduce hydrophilic characteristics together with some reactive functional groups (—SO3H, —OH, —C═O, —C═C—). The surface can also be etched with plasma or corona.
Reactive amino functions are introduced by treatment with a polyamine, polyethylenimine (PEI) or chitosan. For some purposes the polyamines may be stabilized on the surface by cross linking with bifunctional reagents, such as crotonaldehyde or glutaraldehyde.
The coating is further stabilized by ionic cross linking with a sulfated polysaccharide (dextran sulfate or heparin). If necessary these steps are repeated and a sandwich structure is built up. Careful rinsing (water, suitable buffers) should be performed between each step. After a last addition of PEI or chitosan, end-point attachment (EPA) to the aminated surface of native heparin is done by reductive amination, utilizing the aldehyde function in the reducing terminal residue in native heparin. A more reactive aldehyde function in the reducing terminal residue can be achieved by partial, nitrous degradation of heparin. This shortens the reaction time, but the immobilized heparin will have a lower molecular weight. The coupling is performed in aqueous solution, by reductive amination (cyanoborohydride, CNBH3−) essentially as described in Preparatory example 2.
1-10 μg/cm2 of heparin can be coupled to all hydrophilic surfaces like glass, cellulose, chitin etc, and more or less all hydrophobic polymers like polyvinyl chloride, polyethylene, polycarbonate, polystyrene, PTFE etc.
Covalent Single- or Multipoint Attachment of heparin onto Polymeric Surfaces
Performed as described in Preparatory example 2, with the exception that the aldehyde functions were introduced in the heparin chain by oxidation with sodium periodate in aqueous solution.
Attachment of heparin onto the Inner Lumen of Hollow Fibers
In this preparatory example, a pediatric haemoflow dialyzer was used. The fibers of the dialyzer were made of polysulfone with an inner diameter of 200 microns and a wall thickness of 40 microns. The total surface area of the blood contacting material was 4000 cm2 and the priming volume was 28 ml.
The amination procedure was performed as generally described in Preparatory example 4 with the exception that the etching step was omitted. Polysulfone is hydrophilic and does not need etching. Immobilization of heparin was performed by pumping a solution containing nitrous acid degraded heparin (heparin from Pharmacia) together with NaBH3CN as described in Preparatory example 2. As measurement of the amount of heparin is a destructive procedure, a reference dialyzer that was heparinized under identical conditions was sacrificed and its fibers are subjected to sulfur analysis. The results revealed a heparin content of about 5 μg heparin/cm2, which corresponds to a content of 20 mg heparin in the device.
Covalent Attachment of Oligomers with Terminal sialic acid Residues onto the Inner Lumen of Hollow Fibers
In this preparatory example, the aldehyde group at the reducing terminal residue was used for coupling. Amination of the fibers was performed as described in Preparatory example 6 and coupling of the oligosaccharide of formula I, which contains terminal sialic acid residues, was performed by circulating the compound of formula I, dissolved in acetate buffer (800 ml, 0.1 M, pH 4.0) together with NaBH3CN (0.4 g), at room temperature for 24 h. The results revealed a sialic acid content of ca. 2 μg/cm2.
Binding of HSV-1 to heparin in Solution
A solution (10 μl) containing 101 plaque forming units of virus (Herpes simplex virus type 1 strain KOS321) was incubated with 20 μl of 3H-labelled heparan sulfate (HS) in a total volume of 400 μl of buffered NaCl for 30 min at 37° C. Thereafter, the solution was centrifuged through a Microsep 1 M filter, retaining virus and bound HS. 2.3% of HS was bound (479 CPM) to the virus, while 97.7% of the HS was unbound and passed through the filter.
Removal of HSV-1 and HSV-2 Virus Particles from Buffered saline by Binding to heparin Immobilized on sephadex Beads
Sephadex beads coated with heparin, as in Preparatory example 2, were soaked in buffered NaCl (PBS) and 0.8 ml was transferred to each of two small disposable columns, forming a gel layer of approximately 1 cm. After washing three times, 50 μl of 3H-thymidine radiolabelled viruses were suspended in 150 μl of PBS. 109 plaque forming units of HSV-1, corresponding to 1011 virus particles, were added to column 1, and 108 plaque forming units of HSV-2, corresponding to 1010 virus particles, were added to column 2. Virus was allowed to adsorb to the respective columns. Thereafter, 0.8 ml of PBS was added to each column and the pass-through fluid was collected for estimation of unabsorbed virus.
Subsequently, both columns were washed 4 times with 1 ml of PBS, and the washings were collected as fractions for quantification of washed out virus. These, and the following fractions, were transferred to scintillation vials and quantified with regard to amount of virus through determination of cpm in a beta counter. In the next step, the columns were subjected to elution of the respective heparin-bound viruses three times by 1 ml of 2 M NaCl, and the three fractions were collected from each column. Following that, elution was performed by twice adding 1 ml of 5% SDS in PBS (PBS-SDS), and the two fractions from each column were collected. Finally, the heparin-coated beads from the two columns were each suspended in 1 ml of PBS-SDS, and 200 μl aliquots were subjected to quantification of remaining bound virus particles by determination of radioactivity.
The results are shown in Table 1 below. As shown, only 5.5% of HSV-1 particles and 11.7% of HSV-2 particles did not adsorb to the column. Moreover, since the viral DNA and not their heparin-binding proteins are labeled with radioactivity, these non-adsorbed particles might represent non-infectious viruses with disrupted envelopes (i.e. the outer, fragile, parts of the virus that bind to heparin). The rest of the viruses (94.5% for HSV-1 and 88.3% of HSV-2) bind to the heparin-coated beads in the column. The binding appears to be strong, judging from the fact that only 0.5% of HSV-1 and 1.1% of HSV-2 was removed by 4 successive washings. The limited ability of 2 M NaCl at 3 successive attempts to elute the viruses underscores the high-affinity characteristic of the binding of both viruses to the heparin-coated beads. In contrast, substantial quantities of HSV-1 and HSV-2 were eluted by PBS-SDS.
A total of 48% of HSV-1 and 68.8% of HSV-2 were recovered from the columns. This can be attributed to the fact that 2 M NaCl spontaneously decreased the radioactivity of the samples by approximately 30% according to our past observations, and that SDS-PBS probably also has this effect.
Taken together, the results prove the principle that HSV-1 and HSV-2 virus particles can be removed from a fluid phase by passage through a short column containing heparin-coated Sephadex beads, and that extracted viruses bind with high affinity to the columns.
Removal of HSV-1 Virus Particles from Human Serum by Binding to heparin Immobilized on sephadex Beads
The experimental procedure as described in Example 1 was utilized with the difference that the radiolabelled HSV-1 virus particles at a quantity of 109 PFU equivalent to 1011 virus particles were mixed with 0.5 ml of human serum and then applied on heparin-coated beads in a disposable column. Thereafter, the procedure including elution and washing was followed as in Example 1. The results are shown in Table 2 below.
As shown, 97.6% of the HSV-1 particles suspended in human serum were bound to the column. By washing 4 times, only 3.8% of the virus particles were removed. Using 2 M NaCl, only 2.7% of the virus was eluted, and an additional 3.5% were eluted by SDS. The conclusion of these results is that suspending virus in serum, which is the real life situation during severe, disseminated infection, improved the performance of the virus-removing column as regards binding of radiolabelled virus, and that only 2.4% of the HSV-1 particles were unadsorbed. As a probable explanation, serum proteins helped to stabilize the virus particles and thereby improved the removal of HSV-1 by the heparinized Sephadex beads.
Removal of HSV-1 Virus Particles from Human Serum by Binding to heparin Immobilized on a Hollow Fiber Haemoflow Dialyzer
The experimental procedure as described in Example 1 was utilized with the difference that the radiolabelled HSV-1 virus particles at a quantity of 109 PFU equivalent to 1011 virus particles were mixed with 0.5 ml of human serum and then applied on the heparin-coated hollow fiber dialyzer of Preparatory example 6. Thereafter, the procedure including elution and washing was followed as in Example 1. The results are shown in Table 3 below.
As shown, 92.3% of the HSV-1 particles suspended in human serum were bound to the column. By washing 4 times, only 4.2% of the virus particles were removed. By 2 M NaCl, only 4.0% of the virus was eluted, and an additional 4.5% were eluted by SDS. The conclusion of these results is that the binding of virus particles suspended in human serum to heparinized fibers is comparable to that of similarly suspended virus binding to heparin-coated Sephadex beads, and that only 7.7% of the HSV-1 particles were unabsorbed.
Removal of HSV-1 and HSV-2 Virus Particles from Human Whole Blood by Binding to heparin Immobilized on ephadex Beads
The experimental procedure as described in Example 1 was utilized with the difference that the radiolabelled HSV-1 and HSV-2 virus particles at a quantity of equivalent to 1011 virus particles per ml were mixed with 1 ml of human blood and then applied to 1 ml heparin-coated beads in a disposable column. Thereafter, the procedure including elution and washing was followed as in Example 1.
The results are shown in Table 4 below. As shown, 99.1% of the HSV-1 particles and 99.8% of the HSV-2 particles suspended in human blood were bound to the column.
Removal of Influenza a Virus from Human Serum by Binding to Immobilized Oligosaccharides Containing sialic acid
Virus stocks of Influenza A H1N1 were replicated in MDCK cells grown at 35° C. under standard conditions for 3 days, after which the cells were homogenized and titrated to assess the number of focus-forming units (FFU)/ml. Virus particles were suspended in human serum to a final concentration of 106 FFU/ml. A 10 ml suspension was applied on a sialic acid-coated hollow fiber dialyzer, prepared using the method described in Preparatory example 7. After titrating the infectivity of the Influenza A-containing serum after passage through the dialyzer and comparing it with titers of an aliquot of the same virus-containing serum not passed through the device it was concluded that 87% of the Influenza A virus FFU remained bound to the fibers.
Removal of Helicobacter pylori and Staphylococcus aureus by Binding to Immobilized heparin
Four sterile pipettes were packed with glass wool (0.5 ml) that was heparinized as described in Preparatory example 3. The “columns” thus formed were washed with 3 ml of sterile phosphate saline buffer (PBS), pH 7.2. Two different strains of H. pylori and two different strains of S. aureus were tested. Each of the four different bacteria samples, suspended in PBS buffer, were applied to a separate “column”. The amounts of bacteria in the samples were measured before application to the column and after elution from the column by optical density (OD) at 560 nm and viable counts (CFU/ml). As is evident from the table below, roughly 90% of H. pylori and roughly 50% of S. aureus bacteria were immobilized on the columns.
H. Pylori
H. Pylori
S. aureus
S. aureus
The present application is a continuation application U.S. application Ser. No. 16/247,372, filed Jan. 14, 2019, now U.S. Pat. No. 10,688,239, which is a continuation of U.S. application Ser. No. 15/678,580, filed Aug. 16, 2017, now U.S. Pat. No. 10,188,783, which is a continuation application of U.S. application Ser. No. 14/873,133, filed Oct. 1, 2015, now U.S. Pat. No. 9,764,077, which is a continuation application of U.S. application Ser. No. 12/086,126, filed Sep. 10, 2008, now U.S. Pat. No. 9,173,989, which application is a 35 U.S.C. § 371 National Phase Application of PCT/SE2006/001421, filed Dec. 13, 2006, which application claims priority to SE 0502750-3, filed Dec. 13, 2005, the disclosures of which are hereby incorporated by reference in their entireties for all purposes.
| Number | Name | Date | Kind |
|---|---|---|---|
| 3782382 | Naftulin et al. | Jan 1974 | A |
| 4103685 | Lupien et al. | Aug 1978 | A |
| 4415665 | Mosbach et al. | Nov 1983 | A |
| 4430496 | Abbott | Feb 1984 | A |
| 4613665 | Larm | Sep 1986 | A |
| 4637994 | Tani et al. | Jan 1987 | A |
| 4820302 | Woodroof | Apr 1989 | A |
| 4955870 | Ridderheim et al. | Sep 1990 | A |
| 5116962 | Stueber et al. | May 1992 | A |
| 5211850 | Shettigar et al. | May 1993 | A |
| 5403917 | Boos et al. | Apr 1995 | A |
| 5437861 | Okarma et al. | Aug 1995 | A |
| 5447859 | Prussak | Sep 1995 | A |
| 5476509 | Keogh, Jr. et al. | Dec 1995 | A |
| 5753227 | Strahilevitz | May 1998 | A |
| 6037458 | Hirai et al. | Mar 2000 | A |
| 6159377 | Davankov et al. | Dec 2000 | A |
| 6197568 | Marks et al. | Mar 2001 | B1 |
| 6248127 | Shah et al. | Jun 2001 | B1 |
| 6312907 | Guo et al. | Nov 2001 | B1 |
| 6461665 | Scholander | Oct 2002 | B1 |
| 6544727 | Hei | Apr 2003 | B1 |
| 6559290 | Nakatani et al. | May 2003 | B1 |
| 6653457 | Larm et al. | Nov 2003 | B1 |
| 7179660 | Kirakossian | Feb 2007 | B1 |
| 7408045 | Maruyama et al. | Aug 2008 | B2 |
| 7695609 | Soundarrajan et al. | Apr 2010 | B2 |
| 8663148 | Larm et al. | Mar 2014 | B2 |
| 8758286 | Ward et al. | Jun 2014 | B2 |
| 9173989 | Larm et al. | Nov 2015 | B2 |
| 9408962 | Ward et al. | Aug 2016 | B2 |
| 9669150 | Larm et al. | Jun 2017 | B2 |
| 9764077 | Larm et al. | Sep 2017 | B2 |
| 10086126 | Ward et al. | Oct 2018 | B2 |
| 10188783 | Larm et al. | Jan 2019 | B2 |
| 10457974 | Ward et al. | Oct 2019 | B2 |
| 10487350 | Ward et al. | Nov 2019 | B2 |
| 10537280 | McCrea et al. | Jan 2020 | B2 |
| 10639413 | McCrea et al. | May 2020 | B2 |
| 10688239 | Larm et al. | Jun 2020 | B2 |
| 10786615 | Ward et al. | Sep 2020 | B2 |
| 20010005487 | Kamibayashi et al. | Jun 2001 | A1 |
| 20020018985 | Eible et al. | Feb 2002 | A1 |
| 20020058032 | Hirai et al. | May 2002 | A1 |
| 20020068183 | Huang et al. | Jun 2002 | A1 |
| 20020197249 | Brady et al. | Dec 2002 | A1 |
| 20020197252 | Brady et al. | Dec 2002 | A1 |
| 20030021780 | Smith et al. | Jan 2003 | A1 |
| 20030044769 | Ogino et al. | Mar 2003 | A1 |
| 20030148017 | Tuominen et al. | Aug 2003 | A1 |
| 20040084358 | O'Mahony et al. | May 2004 | A1 |
| 20040115278 | Putz et al. | Jun 2004 | A1 |
| 20040140265 | Lihme | Jul 2004 | A1 |
| 20040176672 | Silver et al. | Sep 2004 | A1 |
| 20040182783 | Walker et al. | Sep 2004 | A1 |
| 20040185553 | Hei | Sep 2004 | A9 |
| 20040202783 | Baumann et al. | Oct 2004 | A1 |
| 20050098500 | Collins et al. | May 2005 | A1 |
| 20050142542 | Hei et al. | Jun 2005 | A1 |
| 20050244371 | Lentz | Nov 2005 | A1 |
| 20050271653 | Strahilevitz | Dec 2005 | A1 |
| 20060093999 | Hei | May 2006 | A1 |
| 20060252054 | Lin et al. | Nov 2006 | A1 |
| 20070190050 | Davidner et al. | Aug 2007 | A1 |
| 20070218514 | Smith et al. | Sep 2007 | A1 |
| 20070231217 | Clinton et al. | Oct 2007 | A1 |
| 20080021365 | Kobayashi et al. | Jan 2008 | A1 |
| 20080138434 | Brady et al. | Jun 2008 | A1 |
| 20080268464 | Schumacher et al. | Oct 2008 | A1 |
| 20080314817 | Fujita et al. | Dec 2008 | A1 |
| 20090105194 | Flengsrud et al. | Apr 2009 | A1 |
| 20090136586 | Larm et al. | May 2009 | A1 |
| 20090173685 | Imai et al. | Jul 2009 | A1 |
| 20090206038 | Thomas | Aug 2009 | A1 |
| 20090246800 | Mattingly et al. | Oct 2009 | A1 |
| 20090325276 | Battrell | Dec 2009 | A1 |
| 20100069816 | Brady et al. | Mar 2010 | A1 |
| 20100079360 | McLaughlin et al. | Apr 2010 | A1 |
| 20100098666 | Wright | Apr 2010 | A1 |
| 20100112725 | Babu et al. | May 2010 | A1 |
| 20100145317 | Laster et al. | Jun 2010 | A1 |
| 20100216226 | Hyde et al. | Aug 2010 | A1 |
| 20100217173 | Hyde et al. | Aug 2010 | A1 |
| 20100239673 | Linhardt | Sep 2010 | A1 |
| 20100249689 | Larm et al. | Sep 2010 | A1 |
| 20100276359 | Ippommatsu et al. | Nov 2010 | A1 |
| 20100291588 | McDevitt | Nov 2010 | A1 |
| 20100326916 | Wrazel et al. | Dec 2010 | A1 |
| 20110150911 | Choo | Jun 2011 | A1 |
| 20110171713 | Bluchel et al. | Jul 2011 | A1 |
| 20110184377 | Ward et al. | Jul 2011 | A1 |
| 20110224645 | Winqvist et al. | Sep 2011 | A1 |
| 20120040429 | Federspiel et al. | Feb 2012 | A1 |
| 20120219561 | Alt et al. | Aug 2012 | A1 |
| 20120244557 | Yu et al. | Sep 2012 | A1 |
| 20120305482 | McCrea et al. | Dec 2012 | A1 |
| 20130102948 | Reich et al. | Apr 2013 | A1 |
| 20130131423 | Wang et al. | May 2013 | A1 |
| 20140012097 | McCrea et al. | Jan 2014 | A1 |
| 20140131276 | Larm et al. | May 2014 | A1 |
| 20140231357 | Ward et al. | Aug 2014 | A1 |
| 20150111849 | McCrea et al. | Apr 2015 | A1 |
| 20150260715 | Hu et al. | Sep 2015 | A1 |
| 20160003858 | McKendry et al. | Jan 2016 | A1 |
| 20160022898 | Larm et al. | Jan 2016 | A1 |
| 20160082177 | Ward et al. | Mar 2016 | A1 |
| 20160084835 | Ward et al. | Mar 2016 | A1 |
| 20160101229 | McCrea et al. | Apr 2016 | A1 |
| 20160214935 | Hutchinson et al. | Jul 2016 | A1 |
| 20160331886 | Ward et al. | Nov 2016 | A1 |
| 20170035956 | McCrea et al. | Feb 2017 | A1 |
| 20170073727 | Ward et al. | Mar 2017 | A1 |
| 20170340803 | Larm et al. | Nov 2017 | A1 |
| 20180361050 | Ward et al. | Dec 2018 | A1 |
| 20190038826 | McCrea et al. | Feb 2019 | A1 |
| 20190143027 | Larm et al. | May 2019 | A1 |
| 20200023001 | Ebong et al. | Jan 2020 | A1 |
| 20200056221 | Ward et al. | Feb 2020 | A1 |
| 20200171233 | McCrea et al. | Jun 2020 | A1 |
| Number | Date | Country |
|---|---|---|
| 1395620 | Feb 2003 | CN |
| 101370536 | Feb 2009 | CN |
| 101784294 | Jul 2010 | CN |
| 102740859 | Oct 2012 | CN |
| 102791307 | Nov 2012 | CN |
| 106255520 | Dec 2016 | CN |
| 4217917 | Dec 1993 | DE |
| 0306617 | Mar 1989 | EP |
| 0321703 | Jun 1989 | EP |
| 0533946 | Mar 1993 | EP |
| 0616845 | Sep 1994 | EP |
| 0810027 | Dec 1997 | EP |
| 1044696 | Oct 2000 | EP |
| 1057529 | Dec 2000 | EP |
| 1110602 | Jun 2001 | EP |
| 1219639 | Jul 2002 | EP |
| 2087916 | Aug 2009 | EP |
| 2556849 | Feb 2013 | EP |
| 2172812 | Oct 1986 | GB |
| 54-127493 | Sep 1979 | JP |
| 58-053757 | Mar 1983 | JP |
| 58-146354 | Aug 1983 | JP |
| 4-89500 | Mar 1992 | JP |
| 6040926 | Feb 1994 | JP |
| 6-505248 | Jun 1994 | JP |
| 7-178161 | Jul 1995 | JP |
| 96-510166 | Oct 1996 | JP |
| 11-502703 | Mar 1999 | JP |
| 2000-086688 | Mar 2000 | JP |
| 2000-217575 | Aug 2000 | JP |
| 2000-515543 | Nov 2000 | JP |
| 2011-509083 | Mar 2001 | JP |
| 2001-190273 | Jul 2001 | JP |
| 2002-505101 | Feb 2002 | JP |
| 2002-509518 | Mar 2002 | JP |
| 2003-128502 | May 2003 | JP |
| 2003-520048 | Jul 2003 | JP |
| 2005-514127 | May 2005 | JP |
| 2005-519744 | Jul 2005 | JP |
| 2005-532130 | Oct 2005 | JP |
| 2009-521413 | Jun 2009 | JP |
| 2010-518046 | May 2010 | JP |
| 2010-530288 | Sep 2010 | JP |
| 2012-501708 | Jan 2012 | JP |
| 2013-512078 | Apr 2013 | JP |
| 2014-500735 | Jan 2014 | JP |
| 2014-523914 | Sep 2014 | JP |
| 10-2008-0077405 | Aug 2008 | KR |
| 9104086 | Apr 1991 | WO |
| 9214361 | Sep 1992 | WO |
| 9426399 | Nov 1994 | WO |
| 9505400 | Feb 1995 | WO |
| 9629083 | Sep 1996 | WO |
| 9640857 | Dec 1996 | WO |
| 9735660 | Oct 1997 | WO |
| 9805341 | Feb 1998 | WO |
| 9829727 | Jul 1998 | WO |
| 9906086 | Feb 1999 | WO |
| 9945104 | Nov 1999 | WO |
| 0023792 | Apr 2000 | WO |
| 00038763 | Jul 2000 | WO |
| 0066260 | Nov 2000 | WO |
| 0118060 | Mar 2001 | WO |
| 0153525 | Jul 2001 | WO |
| 02060512 | Aug 2002 | WO |
| 03033143 | Apr 2003 | WO |
| 2003057356 | Jul 2003 | WO |
| 2003078023 | Sep 2003 | WO |
| 2004008138 | Jan 2004 | WO |
| 2004009798 | Jan 2004 | WO |
| 2005021799 | Mar 2005 | WO |
| 2007058592 | May 2007 | WO |
| 2007069983 | Jun 2007 | WO |
| 2007101064 | Sep 2007 | WO |
| 2007146162 | Dec 2007 | WO |
| 2008095905 | Aug 2008 | WO |
| 2008157570 | Dec 2008 | WO |
| 2009086343 | Jul 2009 | WO |
| 2009121959 | Oct 2009 | WO |
| 2010029317 | Mar 2010 | WO |
| 2011068897 | Jun 2011 | WO |
| 2011100354 | Aug 2011 | WO |
| 2012051595 | Apr 2012 | WO |
| 2012112724 | Aug 2012 | WO |
| 2012172341 | Dec 2012 | WO |
| 2013012924 | Jan 2013 | WO |
| 2013188073 | Dec 2013 | WO |
| 2014209782 | Dec 2014 | WO |
| 2015069942 | May 2015 | WO |
| 2015164198 | Oct 2015 | WO |
| Entry |
|---|
| Abdul-Razzak, K. et al., “Fetal and newborn calf thymus as a source of chromatin proteins: Purification of HMG-1 and HMG-2,” Preparative Biochemistry and Biotechnology, 17(1):51-61, 1987. |
| Alarabi, A. et al., “Treatment of pruritus in cholestatic jaundice by bilirubin- and bile acid-adsorbing resin column plasma perfusion,” Scandinavian Journal of Gastroenterology, 27(3):223-6, 1992. |
| Alfaro et al., “Interleukin-8 in cancer pathogenesis, treatment and follow-up,” Cancer Treat Rev., Nov. 2017, vol. 60:24-31 (abstract only). |
| Andrade-Gordon, P. et al., “Interaction of heparin with plasminogen activators and plasminogen: effects on the activation of plasminogen,” Biochemistry, 25(14):4033-4040, 1986. |
| Andreasen, P.A. et al., “The plasminogen activation system in tumor growth, invasion, and metastasis,” Cellular and Molecular Life Sciences, 57(1):25-40, 2000. |
| Ascencio, F. et al., “Affinity of the gastric pathogen Heficobacter py/ori for the N-sulphated glycosaminoglycan heparan sulphate,” J. Med. Microbiol., 38:240-244, 1993. |
| Axelsson, J. et al., “Cytokines in blood from septic patients interact with surface-immobilized heparin,” ASAIO Journal, 56:48-51, 2010. |
| Bartlett, A. and P. Park, “Proteoglycans in host-pathogen interactions: molecular mechanisms and therapeutic implications,” Expert Rev. Mol. Med., 12(e5):1-33, 2015. |
| Bhakdi, S. and Tranum-Jensen, J., “Alpha-toxin of Staphylococcus aureus,” Microbiological Reviews, 55(4):733-751, 1991. |
| Bindslev et al., “Treatment of acute respiratory failure by extracorporeal carbon dioxide elimination performed with a surface heparinized artificial lung,” Anesthesiology, 67(1):117-120, 1987. |
| Bjorklund et al., Abstract of “Synthesis of silica-based heparin-affinity adsorbents,” J. Chrom. A., 728(1-2):149-169, 1996. |
| Brat, D. et al., “The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis,” Neuro-oncology, 7(2):122-133, 2005. |
| Celik, T. et al., “Treatment of lyme neuroborreliosis with plasmapheresis,” J. Clinical Apheresis, 31:476-478, 2016. |
| Chase, H., “Affinity separations utilising immobilised monoclonal antibodies—a new tool for the biochemical engineer,” Chemical Engineering Science, 39(7-8):1099-1125, 1984. |
| Chen et al., “Microbial subversion of heparin sulfate proteoglycans,” Mol. Cells, 26:415-426, 2008. |
| Choong, P.F. et al., “Urokinase plasminogen activator system: a multifunctional role in tumor progression and metastasis,” Clinical Orthopaedics and Related Research, 415(Suppl):S46-58, 2003. |
| Dixon et al., “Anthrax,” New England Journal of Medicine, 341(11):815-826, 1999. |
| Dubreuil et al., “Effect of heparin binding on Helicobacter pylori resistance to serum,” J. Med. Micro., 53:9-12, 2004. |
| English translation of Chinese Office Action dated Mar. 23, 2011 for Application No. 200680052757.9. |
| English translation of Decision of Refusal dated Mar. 19, 2013 in Japanese Application No. 2008-545539. |
| English translation of Office Action dated Jul. 10, 2012 in Japanese Patent Application No. 2008-545539. |
| English translation of Russian Office Action dated Sep. 1, 2010 for Application No. 2008128416. |
| Era, K. et al., “Development of Systems for Passive and Active CAVH,” J. Japanese Society for Dialysis Therapy, 19(2):175-181, 1986. |
| Examination report dated Apr. 14, 2010 in New Zealand Application No. 568754. |
| Examination report dated Jul. 20, 2011 in New Zealand Application No. 568754. [our 110NZ]. |
| Frick, I. et al., “Interactions between M proteins of Streptococcus pyogenes and glycosaminoglycans promote bacterial adhesion to host cells,” Eur. J. Biochem, 270(10):2303-11, 2003. |
| Francy, D. et al., “Comparison of filters for concentrating microbial indicators and pathogens in lake water samples,” Applied and Environmental Microbiology, 79(4):1342-52, 2012. |
| Fujita, M. et al., “Adsorption of inflammatory cytokines using a heparin-coated extracorporeal circuit,” Artificial Organs, 26(12):1020-1025, 2002. |
| Garg, L. et al., “Isolation and separation of HMG proteins and histones H1 and H5 and core histones by column chromatography on phosphocellulose,” Protein Expression and Purification, 14(2):155-159, 1998. |
| Ge Healthcare, “Size exclusion chromatography columns and resins, Selection guide,” 2010, retreived online at <<https://cdn.gelifesciences.com/dmm3bwsv3/AssetStream.aspx?mediaformatid=10061&destinationid=10016&assetid=13947>> on Jun. 27, 2019, 10 pages. |
| Ghannoum, M. et al., “Extracorporeal treatment for carbamazepine poisoning: Systematic review and recommendations from the EXTRIP workgroup,” Clinical Toxicology, 52:993-1004, 2014. |
| Haase et al., “The effect of three different miniaturized blood purification devices on plasma cytokine concentration in an ex vivo model of endotoxinemia,” Int. J. Artif. Organs, 31(8):722-729, 2008. |
| Hirmo, S. et al., “Sialyglycoconjugate- and proteoglycan-binding microbial lectins,” Institute of Medical Microbiology, University of Lund, (Online). Retrieved Oct. 19, 1997 (Retrieved on Mar. 16, 2004). Retrieved from the Internet: <URL: http//www.plab.ku.dk/tcbh/Lectins12/Hirmo/paper.htm>. |
| International Preliminary Report on Patentability, dated Aug. 21, 2013, PCT Application No. PCT/US2012/025316; 8 pages. |
| International Search Report; PCT/SE2006/001421 dated Mar. 30, 2007. |
| International Search Report; PCT/US2010/058596 dated Mar. 29, 2011. |
| International Search Report; PCT/US2011/024229 dated May 30, 2011. |
| International Search Report; PCT/US2012/025316 dated May 23, 2012. |
| International Search Report; PCT/US2013/042377 dated Sep. 9, 2013. |
| International Search Report; PCT/US2014/043358 dated Dec. 1, 2014. |
| International Search Report; PCT/US2014/064419 dated Feb. 12, 2015. |
| International Search Report; PCT/US2015/026340 dated Jul. 28, 2015. |
| International Search Report; PCT/US2015/051239 dated Dec. 17, 2015. |
| International Search Report; PCT/US2016/057121 dated Dec. 30, 2016. |
| International Search Report; PCT/US2017/058536; dated Jan. 17, 2018. |
| International Search Report; PCT/US2020/032150; dated Jul. 24, 2020. |
| JP Interrogation for Appl. No. 2008-545539 dated Mar. 18, 2014. |
| Kenig, M. et al., “Identification of the heparin-binding domain of TNF-alpha and its use for efficient TNF-alpha purification by heparin-Sepharose affinity chromatography,” J. Chromatography B, 867:119-125, 2008. |
| Keuren et al., “Thrombogenecity of polysaccharide-coated surfaces,” Biomaterials, 24:1917-24, 2003. |
| Kim et al., “Role of the heparin in regulating a transcapillary exchange in far north conditions,” Bulletin of the Siberian Branch of the Russian Academy of Medical Sciences, 2(108), 2003. |
| Kishimoto, S. et al., “Human stem cell factor (SCF) is a heparin-binding cytokine,” J. Biochem., 145(3):275-278, 2009. |
| Kumari, N. et al., “Role of interleukin-6 in cancer progression and therapeutic resistance,” Tumour Biol., Sep. 2016, vol. 37(9), pp. 11553-11572 (abstract only). |
| Larm et al., “A new non-thrombogenic surface prepared by selective covalent binding of heparin via a modified reducing terminal residue,” Biomater Med Devices Artif Organs, 11(2&3):161-173, 1983. |
| Lemaire, M. et al., “Treatment of paediatric vancomycin intoxication: a case report and review of the literature,” NDT Plus, 3:260-264, 2010. |
| Lian, S. et al., “Elevated expression of growth-regulated oncogene-alpha in tumor and stromal cells predicts unfavorable prognosis in pancreatic cancer,” Medicine, Jul. 2016, 95(30), pp. 1-8. |
| Lopatkin et al., “Efferent methods in medicine, M.,” Medicine, pp. 266, 272-273, 276-279, 1989. |
| Low, R. et al., “Protein n, a primosomal DNA replication protein of Escherichia coli,” Journal of Biological Chemistry, 257(11):6242-6250, 1982. |
| Mandal, “Sialic acid binding lectins,” Experientia, 46:433-439, 1990. |
| Mariano et al, “Tailoring high-cut-off membranes and feasible application in sepsis-associated acute renal failure: in vitro studies,” Nephrol Dial Transplant, 20:1116-1126, 2005. |
| Mattsby-Baltzer, I. et al., “Affinity apheresis for treatment of bacteremia caused by Staphylococcus aureus and/or methicillin-resistant S. aureus (MRSA),” J. Microbiol. Biotechnol., 21(6):659-664, 2011. |
| Millen, H. et al., “Glass wool filters for concentrating waterborne viruses and agricultural zoonotic pathogens,” J. Vis. Exp., 61:e3930, 2012. |
| Murphy, J.W. et al., “Structural and functional basis of CXCL 12 (stromal cell-derived factor-1 a) binding to heparin,” Journal of Biological Chemistry, 282(13):10018-10027, 2007. |
| Nadkarni et al., Abstract of “Directional immobilization of heparin onto beaded supports,” Anal. Biochem., 222(1):59-67, 1994. |
| Ofek et al., “Mannose binding and epithelial cell adherence of Escherichia coli,” Infection and Immunity, 22(1):247-254, 1978. |
| Office Action dated Jun. 23, 2020 in Japanese Patent Application No. 2017-515161, with English translation, retrieved from <https://globaldossier.uspto.gov/#/details/JP/2017515161/A/129021> dated Aug. 13, 2020. |
| Park, P. et al., “Activation of Syndecan-1 ectodomain shedding by Staphylococcus aureus α-toxin and β-toxin,” J. Biol. Chem., 279(1):251-258, 2004. |
| Popova et al., “Acceleration of epithelial cell syndecan-1 shedding by anthrax hemolytic virulence factors,” BMC Microbiolgy, 6:8, pp. 1-16, 2006. |
| Rauvala, H. et al., “Isolation and some characteristics of an adhesive factor of brain that enhances neurite outgrowth in central neurons,” Journal of Biological Chemistry, 262(34):16625-16635, 1987. |
| Rauvala, H. et al., “The adhesive and neurite-promoting molecule p30: Analysis of the amino-terminal sequence and production of antipeptide antibodies that detect p30 at the surface of neuroblastoma cells and of brain neurons,” Journal of Cell Biology, 107(6,1):2293-2305, 1988. |
| Riesenfeld et al., “Quantitative analysis of N-sulfated, N-acetylated, and unsubstituted glucosamine amino groups in heparin and related polysaccharides,” Anal Biochem, 188:383-389, 1990. |
| Sagnella et al., “Chitosan based surfactant polymers designed to improve blood compatibility on biomaterials,” Colloids and Surfaces B: Biointerfaces, 42:147-155, 2005. |
| Salek-Ardakani, S. et al., “Heparin and heparan sulfate bind interleukin-10 and modulate its activity,” Blood, 96:1879-1888, 2000. |
| Salmivirta, M. et al., “Neurite growth-promoting protein (Amphoterin, p30) binds syndecan,” Experimental Cell Research, 200:444-451, 1992. |
| Sanaka, T. et al., “Continuous Arteriovenous Hemofiltration,” Artificial Organs, 14(5):1822-1830, 1985. |
| Sanchez, J. et al., “Control of contact activation on end-point immobilized heparin: The role of antithrombin and the specific antithrombin-binding sequence,” J. Bio. Mat. Res., 29:665-661, 1995. |
| Sasaki et al., Abstract: “Improved method for the immobilization of heparin,” J. Chrom., 400:123-32, 1987. |
| Sato, T. et al., “Experimental study of extracorporeal perfusion for septic shock,” Asaio Journal, 39(3):M790-M793, 1993. |
| Schefold et al., “A novel selective extracorporeal intervention in sepsis: immunoadsorption of endotoxin, interleukin 6, and complement-activating product 5A,” Shock, 28(4):418-425, 2007. |
| Sharon, “Bacterial lectins, cell-cell recognition and infectious disease,” FEBS letters, 217(2):145-157, 1987. |
| Smorenburg, S.M. et al., “The complex effects of heparins on cancer progression and metastasis in experimental studies,” Pharmacological Reviews, 53(1):93-106, 2001. |
| Supplementary European Search Report issued in European Application No. EP06835845 dated Mar. 26, 2013. |
| Swartz, “Recognition and management of anthrax—an update,” New Engl. J. Med., 345(22):1621-1626, 2001. |
| Thomas et al., “Common oligosaccharide moieties inhibit the adherence of typical and atypical respiratory pathogens,” Journal of Microbiology, 53:833-840, 2004. |
| Tonnaer, E. et al., “Involvement of glycosaminoglycans in the attachment of pneumococci to nasopharyngeal epithelial cells,” Microbes and Infection, 8:316-322, 2006, available online Sep. 16, 2005. |
| Utt, M. et al., “Identification of heparan sulphate binding surface proteins of Helicobacter pylori: inhibition of heparan sulphate binding with sulphated carbohydrate polymers,” J. Med. Microbiol., 46:541-546, 1997. |
| Wadstrom, T. and A. Ljungh, “Glycosaminoglycan-binding microbial proteins in tissue adhesion and invasion: key events in microbial pathogenicity,” J. Med. Microbiol., 48(3):223-233, 1999. |
| Wang, H. et al., “HMG-1 as a late mediator of endotoxin lethality in mice,” Science, 285:248-251, 1999. |
| Ward et al., “Specificity of adsorption in a prototype whole blood affinity therapy device for removal of Staphylococcus aureus,” Society for Biomaterials 2013 Annual Meeting and Exposition, Apr. 10, 2013, p. 1. |
| Waugh D. and Wilson, C., “The interleukin-8 pathway in cancer,” Clin. Cancer Res., 14(21):6735-41, 2008. |
| Webb, L. et al., “Binding to heparan sulfate or heparin enhances neutrophil responses to interleukin 8,” PNAS USA, 90:7158-62, 1993. |
| Weber et al., “Development of specific adsorbents for human tumor necrosis factor-α: influence of antibody immobilization on performance and biocompatibility,” Biomacromolecules, 6:1864-1870, 2005. |
| Weir, D., “Carbohydrates as recognition molecules in infection and immunity,” FEMS Microbiology Immunology, 47:331-340, 1989. |
| Wendel et al., “Coating-techniques to improve the hemocompatibility of artificial devices used for extracorporeal circulation,” European Journal of Cardio-thoracic Surgery, 16:342-350, 1999. |
| Yu, J. et al., “Adhesion of coagulase-negative staphylococci and adsorption of plasma proteins to heparinized polymer surfaces,” Biomaterials, 15(10):805-814, 1994. |
| Zhou et al., Abstract: “Heparin-agarose aqueous ethanol suspension,” J. Mol. Bio., 271(3):12, 1997. |
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