EP3700667A1 - Porous fibrous separation material - Google Patents
Porous fibrous separation materialInfo
- Publication number
- EP3700667A1 EP3700667A1 EP18803555.4A EP18803555A EP3700667A1 EP 3700667 A1 EP3700667 A1 EP 3700667A1 EP 18803555 A EP18803555 A EP 18803555A EP 3700667 A1 EP3700667 A1 EP 3700667A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- separation material
- separation
- nonwoven matrix
- blood
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
- B01J20/26—Synthetic macromolecular compounds
- B01J20/265—Synthetic macromolecular compounds modified or post-treated polymers
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
- B01J20/28023—Fibres or filaments
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/3085—Chemical treatments not covered by groups B01J20/3007 - B01J20/3078
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
- B01J20/3202—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the carrier, support or substrate used for impregnation or coating
- B01J20/3206—Organic carriers, supports or substrates
- B01J20/3208—Polymeric carriers, supports or substrates
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
- B01J20/3214—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the method for obtaining this coating or impregnating
- B01J20/3217—Resulting in a chemical bond between the coating or impregnating layer and the carrier, support or substrate, e.g. a covalent bond
- B01J20/3219—Resulting in a chemical bond between the coating or impregnating layer and the carrier, support or substrate, e.g. a covalent bond involving a particular spacer or linking group, e.g. for attaching an active group
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
- B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
- B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
- B01J20/3244—Non-macromolecular compounds
- B01J20/3246—Non-macromolecular compounds having a well defined chemical structure
- B01J20/3248—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such
- B01J20/3255—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such comprising a cyclic structure containing at least one of the heteroatoms nitrogen, oxygen or sulfur, e.g. heterocyclic or heteroaromatic structures
Definitions
- the present invention relates to porous fibrous separation materials, methods for the manufacture of such materials and to uses of such materials in separations and filtration, and in particular relates to separation materials comprising a porous fibrous nonwoven matrix, methods for their manufacture and use in the selective separation of components from and/or filtration of whole blood or blood plasma.
- ABO Blood groups are distinguished by the presence of blood group specific antigens found on the cell membrane surface.
- Groups A red blood cells contains the A antigen and Group B red cells contains the B antigen.
- Group AB cells contain both of these antigens.
- the body makes antibodies towards antigens that are not found on its red blood cells. For blood transfusions it is important that the correct blood is used. Currently, donated blood plasma can only be safely
- EP 1 165 159 B1 is directed to a column for the treatment of whole blood or blood plasma, to a method for extracorporeal removal of blood group A and blood group B antibodies from whole blood or blood plasma, to a saccharide-linker- O-matrix product and to the use thereof in a column during extracorporeal treatments.
- the saccharide disclosed is a blood group determinant A or a blood determinant B, while the matrix can be a polymeric material or a polysaccharide, especially agarose.
- the linker is an alkyl that can bear an aromatic moiety, a peptide, a protein or a polysaccharide.
- US 7,700,746 B2 discloses a filtration material comprising a saccharide which is coupled to a linker, which in turn is coupled to an agarose matrix, wherein the linker is an alkyldiamine or an anilyl alkyl alcohol derivative.
- EP2556848 relates to a separation material comprising a saccharide that is bound via a linker to a matrix for enabling the separation of substances from a liquid that selectively bind to saccharide moieties, to a method for preparing such material, to a method for separating substances from a liquid that selectively bind to saccharides, and to a device comprising a separation material for separating substances from a liquid that selectively bind to saccharides.
- the matrix can be either a flat sheet or a hollow fibre membrane.
- the separation material of the present invention may use an artificial antigen that mimics the structure of the naturally occurring antigens found on red blood cells. These artificial antigens are immobilised onto fibre surfaces within a fibrous nonwoven matrix, ideally a fabric, to produce a nonwoven immunoadsorption medium.
- fibrous nonwoven matrix ideally a fabric
- fibre refers to either continuous filaments, staple (discontinuous) fibres or a mixture thereof.
- the separation material of the present invention preferably comprises a tortuous interconnected pore network.
- the present invention provides a liquid permeable, fibre-based nonwoven immunoadsorption medium for the selective removal of proteins, specifically ABO antibodies, from blood or blood components, such as plasma or whole blood, in order to produce:
- the separation material of the present invention preferably has three key components.
- the first is a porous fibrous nonwoven matrix
- the second is a linker component
- the third is a separation specific active component.
- the separation specific active component is secured to fibres of the nonwoven separation material via the linker component. This can be represented by the following generic formula (A):
- the invention in a first aspect provides separation material comprising a porous fibrous nonwoven matrix covalently bonded to a separation specific active component.
- a separation specific active component covalently bonded to the constituent fibres of the nonwoven matrix and the linker also being covalently bonded to the separation specific active component.
- the separation specific active component comprises a saccharide. It is preferred that the saccharide is glycosidically coupled to the linker component. It is preferred that the nonwoven matrix is functionalized for a coupling reaction.
- the porous fibrous nonwoven matrix preferably comprises synthetic polymeric material.
- the separation material is structured to remove anti-A and/or anti-B antibodies from whole blood or blood plasma. Therefore, in a preferred embodiment the separation specific active component, preferably a saccharide, is a blood group determinant. In another embodiment of the invention, the separation specific active component, preferably a saccharide is a ligand for blood group antibodies. Such blood group antibodies are anti-A or anti-B antibodies.
- the invention provides, a method for selectively separating or removing substances from a liquid using a porous fibrous separation material according to the invention.
- the method is for the removing of substances from whole blood or blood plasma.
- the invention further provides a device for selectively separating, removing or isolating substances from a liquid, comprising a porous fibrous separation material according to the present invention.
- the device serves for removing from whole blood or plasma certain blood components.
- such blood components are blood group antibodies.
- the present invention provides a method for the manufacture of a porous fibrous separation material, which method comprises the following steps: a) providing a porous fibrous nonwoven matrix functionalized for a coupling reaction; and
- the method uses a fibrous nonwoven matrix prepared from fibres comprising polymers with inherent functionality for a coupling reaction.
- the method uses a fibrous nonwoven matrix prepared from fibres comprising polymers which require post synthesis
- the coupling functionality is provided to the polymer fibres when in the form of a porous fibrous nonwoven matrix.
- the method comprises an activation step (a1 ) after step (a) and before step (b).
- the activation step (a1 ) and step (b) are combined.
- the method of manufactures comprises a further sterilization step after the drying step.
- the separation specific active component comprises a linker component and a saccharide.
- a key component of the porous fibrous separation material of the present invention is the porous fibrous nonwoven matrix material.
- Synthetic nonwoven polymeric matrices may comprise hydrophilic and hydrophobic synthetic polymers and combinations thereof primarily in fibrous form or in combination with synthetic polymeric fibres.
- the polymers may be selected from the group comprising polyethylene (PE), polyoxymethylene (POM), polypropylene (PP), polyvinylchloride (PVC), polyvinyl acetate (PVA), polyvinylidene chloride (PVDC), polystyrene (PS), polytetrafluoroethylene (PTFE), polyacrylate, poly(methyl methacrylate) (PMMA), polyacrylamide, polyglycidyl methacrylate
- PGMA acrylonitrile butadiene styrene
- ABS polyacrylonitrile
- PET polycarbonate
- PET polyethylene terephthalate
- PEG polyamide
- PVP polyvinylpyrrolidone
- PS polysulfone
- polyethersulfone PES
- polyarylethersulfone PAES
- EVA ethylene vinyl acetate
- EVOH ethylene vinyl alcohol
- PCL polycaprolactone
- PEEK polyether ketone
- PEKK polyether imide
- PEI polyimide
- PLA polylactic acid
- PMP polymethyl pentene
- PPE poly(p-phenylene ether)
- PPE polyurethane
- SAN styrene acrylonitrile
- polybutenoic acid poly(4-allyl-benzoic acid
- poly(glycidyl acrylate) polyglycidyl methacrylate
- PGMA poly(allyl glycidyl ether)
- PV glycidyl ether polyvinyl glycidyl
- the synthetic polymeric material of the porous fibrous nonwoven matrix material must have the required functionality for subsequent activation with
- Fibre functionality may be present or introduced in the form of an amine, carboxylic acid, isocyanate, isothiocyanate, sulphonyl chloride, aldehyde, carbodiimide, acyl azide, anhydride, fluorobenzene, carbonate, NHS ester, imidoester, epoxide, fluorophenylester or other reactive functionality known in the art or combinations thereof. It is preferably an amine or carboxylic group functionality or both. The most preferred functionality is a carboxylic group.
- the required fibre functionality may be introduced by various means known in the art. These are broadly preparation of derivatised fibres during the fibre production process or post-production chemical or physical treatment of the fibres.
- the fibre post manufacture may inherently comprise specific functional groups (F 1 ), which are needed for further conversion of the porous fibrous nonwoven matrix material into the desired product.
- Derivatised fibres may be prepared during the fibre production process by use of pre-functionalised polymers containing the required fibre functionality. Protecting groups may be used to preserve the functionality during the fibre production stage and/or manufacture of the nonwoven matrix.
- the synthetic polymer material for the porous fibrous nonwoven matrix may lack any suitable functional groups (F 1 ), which are needed for further conversion of the porous fibrous nonwoven matrix material into the desired product and in this case require functionalization by modification to introduce functional groups.
- F 1 suitable functional groups
- required functionality may already be present in the as manufactured porous fibrous nonwoven matrix material or may be introduced via a further modification process or processes.
- the porous fibrous nonwoven matrix material used in the present invention comprises polymer fibres that require functionalization to enable further modification of the porous fibrous nonwoven matrix material.
- a synthetic fibre material made of an alkane chain e.g. polyethylene, or polybutylene terephthalate or polypropylene, does not comprise suitable functional groups for coupling a linker molecule thereto. Therefore, suitable functional groups have to be introduced chemically after polymer synthesis and/or after formation of the nonwoven matrix. It is preferred that the functional groups are introduced when the synthetic fibre is in the form of a nonwoven fabric matrix.
- the post functionalised matrix may then be represented by the following general formula (B):
- F 1 -NWmatrix (B) wherein F 1 : represents H 2 N-, N 3 -, HOOC-, OHC-, NH 2 -NH-, HC ⁇ C- or epoxy. It is most preferred that F 1 represents HOOC-.
- Examples of post-production chemical and physical processes can include any of the following, of combinations thereof: surface plasma treatment, irradiation to induce radical coupling, surface-initiated atom transfer radical polymerization (SI-ATRP), heat treatment, chemical treatments with combinations of reactive solvents and chemical reagents methods known to one skilled in the art.
- the preferred method is surface treatment.
- the method for the surface plasma treatment process can be varied by one skilled in the art in order to introduced different functionality to the fibre surface based on the desired immobilisation process.
- oxygen plasma treatment can introduce carboxylic acid functionality to the fibre surface (which can then be utilised for the immobilisation of receptor molecules).
- Mixtures of nitrogen and hydrogen can be introduced to introduce amine functionality (which can then be utilised for the immobilisation of receptor molecules).
- the functional groups that may be introduced by the precursor gas may be amino, carboxyl, aldehyde, ester, epoxy, hydroxyl or sulphonic acids groups.
- PBT and PP are the preferred polymers for the porous fibrous nonwoven matrix. These are hydrophobic polymers and must be made hydrophilic with sufficient wettability in order to filter aqueous media such as blood plasma. This may be achieved using a surface plasma treatment process. This process has been adapted to introduce functionality onto the surface of PBT or PP polymer surfaces at the same time as improving hydrophilic properties.
- the plasma treatment has two functions. The first is to introduce hydrophilic character to the polymeric porous fibrous matrix and the second is to provide required levels of functionality for coupling reactions.
- the level of fibre functionality can be of defined in terms of moles of functional groups / gram of fibre, ( ⁇ /g). This can be in the range of 0.1 ⁇ /g to 1000 ⁇ /g but preferably in the range of 50 - 500 ⁇ /g.
- the preferred polymers for use in the porous fibrous nonwoven matrix material are hydrophobic and are rendered hydrophilic when functionalized.
- the preferred polymers for use in the porous fibrous nonwoven matrix material are PBT or PP or mixtures thereof.
- the nonwoven matrix may be any form of nonwoven fibrous matrix and may be manufactured using any conventional method for the manufacture of fibrous nonwoven materials.
- One suitable nonwoven is a meltblown matrix used as a transfusion filter consisting of extruded synthetic fibres made from aliphatic polyester, polyolefin or aromatic polyester.
- the polyester is preferably either polybutylene terephthalate (PBT) or polyethylene terephthalate (PET), or the polyolefin is preferably polypropylene (PP).
- a suitable nonwoven matrix may consist of co-polymers or derivatives of PBT, PET, PP. Preferably, these are present as a meltblown porous fibrous nonwoven matrix material.
- the nonwoven matrix consists of filaments or fibres with an aspect ratio of >300:1 .
- the fibres/filaments are preferably in the range from 100 nm to 30 ⁇ in diameter, most preferably in the range 800 nm - 5 ⁇ .
- the fibres are preferably meltblown but may also be produced by methods known in the art to produce the nonwoven matrix including forcespinning, electrospinning or
- the nonwoven matrix consists of a nonwoven meltblown fibrous nonwoven matrix, which can be made from other nonwoven methods, such as electrospinning and forcespinning, however, meltblowing is preferred as it is more suitable for production of continuous sheets of nonwoven at low cost.
- the thickness of the nonwoven matrix is between 0.5 mm - 10 mm thick, but preferably is in the range from 0.1 mm to 1 mm.
- the nonwoven matrix is characterised by a substantially isotropic fibre orientation, wherein the machine direction (MD) to cross direction (CD) tensile strength is in the range 1 :1 to 3:1 .
- the specific permeability of the nonwoven matrix is between 1 - 1 ,000 Lnn ⁇ 2 s ⁇ 1 , but preferably in the range of 10 - 500 Lnn ⁇ 2 s ⁇ 1 .
- the porosity or void volume fraction
- the swelling ratio of the fibres in the nonwoven matrix is less than 5%.
- the moisture regain (@ 65% relative humidity and 20°C is less than 5%).
- the nonwoven matrix primarily consists of continuous filaments of one or more polymers, whose diameters vary both along their lengths and vary from filament to filament.
- a material comprising a biological receptor and preferably a synthetic antigen and most preferably a saccharide, which is bound via a linking group to fibres in a nonwoven material matrix.
- a saccharide as an example of a synthetic antigen and biological receptor; it should be understood that the term saccharide may be replaced with the terms synthetic antigen or biological receptor.
- This saccharide-linker-nonwoven matrix may be represented by general formula (I) saccharide-X-R 1 -(R 2 -R 1 )r -(R 3 -R 1 )n-E m -F-NWMatrix (I)
- the saccharide may be linked glycosidically to the adjacent linker group which links the saccharide to the nonwoven matrix.
- r, n and m are 1 , respectively. In another embodiment, r and m are 1 and n is 0. In yet another embodiment, r and m are 1 and n is 2. In yet another embodiment, r and m are 1 and n is 3.
- linker refers to the portion of formula (I) which is represented by the general formula (II)
- X represents O, S, Ch or NR', wherein R' represents H, methyl or a suitable protecting group.
- Suitable protecting groups for amines are acetyl (Ac), trifluoroacetyl (TFA), trichloroacetyl, benzoyl (Bz), benzyl (Bn),tert - butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (Moz), 9-fluorenylmethyloxycarbonyl (FMOC), vinyloxycarbonyl (Voc), allyloxycarbonyl (Alloc), p -methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMB),p -methoxyphenyl (PMP), triphenylmethyl (Tr), tosyl (Ts) or nosyl (Ns).
- R 1 represents, independently of one another, straight-chain or branched Ci -Cio alkyl such as methyl, ethyl, n- or iso-propyl, n-, iso-, sec- or tert-butyl, n- pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or n-decyl, preferably Ci -C6 alkyl, wherein the alkyl group can be unsubstituted, or substituted with at least one suitable substituent, selected from the group of substituents comprising halogen, alkyl, alkoxy, haloalkyl, cyano, nitro, amino, hydroxy, thiol,
- R 1 independently of one another represents straight-chain or branched unsubstituted alkyl of the formula
- the group of substituents of R 1 comprises amino, hydroxy, thiol, or chlorine.
- R 1 represents
- R 1 represents
- R2independently of one another represents - CO-NH- or -NH-CO-.
- r represents 0 or an integer from 1 -10.
- r is 0 or 1 .
- n represents 0 or an integer from 1 -600.
- n is 0 or an integer from 1 to 5. In another embodiment of the invention, n is 0. In yet another embodiment of the invention, n represents an integer from 500 to 600.
- F represents -NH-, -CO- or -CH2- C(OH)-.
- m represents 0 or 1 .
- m is 1 .
- E represents -CO- or -NH
- the separation material of formula (I) or (A) may be prepared, for example, by coupling a functionalized nonwoven matrix as depicted in formula (B) and/or a saccharide with a linker compound of the general formula (III)
- R 1 , R 3 and n are as defined before, and R 3A : represents HOOC-, H 2 N-, HC ⁇ C-, N 3 -, NH 2 -NH- or OH-.
- E 1 represents -COOH, -CHO, -NH 2 , -SH, -OH, -N 3 , -NH-NH 2 or -C ⁇ CH.
- R 3A represents HOOC- or H 2 N-
- E 1 represents -COOH or -NH 2
- n 0.
- E 1 represents -COOH, -CHO, or - NH 2 . In another embodiment of the invention, E 1 represents -NH 2 or -COOH.
- R 3A and E 1 may be the same or different.
- n is 0 and formula (III) becomes general formula (MIA)
- R 3A R 1. E 1 (IIIA), wherein R 3A R 1 and E 1 are as defined before.
- the compound of formula (IMA) may be coupled with at least one further compound of formula (IMA), which may be same or different, before reacting it with the Nonwoven matrix of formula (IV) or the saccharide of formula (V).
- the resulting compound may also be represented by the general formula (III), wherein R 3A R 1 , R 3 , n and E 1 are as described before.
- n is an integer from 2 to 10.
- the linker compound of formula (III) is first reacted with a functionalized nonwoven matrix of the general formula (IV) or (B),
- F 1 represents H 2 N-, N 3 -, HOOC-, OHC-, NH 2 -NH-, HC ⁇ C- or epoxy.
- F 1 is H2N-, HOOC- or epoxy.
- F 1 is H2N- or epoxy.
- F 1 is HOOC-, which reacts with H2N - functionality on the linker compound. This results in an nonwoven matrix that may now be coupled with a saccharide material.
- the linker compound of formula (III) may be reacted first with the saccharide of formula (V) and, in a second step, the linker modified saccharide is coupled to the functionalized matrix of formula (IV) or (B).
- the compounds of formula (III) are selected from the group of compounds comprising dicarboxylic acids of the general formula HOOC-R-COOH, diamines of the general formula F N-R-Nh and amino acids of the general formula H 2 N-CHR-COOH or H 2 N-(CH 2 ) n -COOH, wherein n is an integer from 1 to 10.
- the compound of formula (III) is selected from the group of compounds comprising 2-aminoethanol, 3- aminopropanol, 4-aminobutanol, 5-aminopentanol, 6-aminohexanol, 7- aminoheptanol, 8-aminooctanol, 9-aminononanol, 10-aminodecanol, 1 ,2- ethylenediamine, 1 ,3-propylenediamine, 1 ,4-butylenediamine, 1 ,5-pentylenediamine, 1 ,6-hexylenediamine, 1 ,7-heptylenediamine, 1 ,8-octylenediamine, 1 ,9- nonylenediamine, 1 ,10-decylenediamine, 2-aminoethanethiol, 3-aminopropanethiol, 4-aminobutanethiol, 5-aminopentanol, 6-amin
- the compound of formula (III) is selected from the group of compounds comprising 2-aminoethanoic acid, 3- aminopropanoic acid, 4-aminobutanoic acid, 5-aminopentanoic acid, 6- aminohexanoic acid, 7-aminoheptanoic acid, 8-aminononanoic acid and 9- aminodecanoic acid.
- the compound of formula (III) is 6-aminohexanoic acid.
- the compound of formula (III) is selected from the group of compounds comprising 1 ,2-ethylenediamine, 1 ,3- propylenediamine, 1 ,4-butylenediamine, 1 ,5-pentylenediamine, 1 ,6- hexylenediamine, 1 ,7-heptylenediamine, 1 ,8-octylenediamine, 1 ,9-nonylenediamine and 1 ,10-decylenediamine.
- (III) is selected from the group of compounds comprising propanedioic acid (malonic acid), butanedioic acid (succinic acid), pentanedioic acid (glutaric acid), hexanedioic acid (adipic acid), heptanedioic acid (pimelic acid), octanedioic acid (suberic acid), nonanedioic acid (azelaic acid), decanedioic acid (sebacic acid), glutathione or dicarboxy-PEG (DC-PEG).
- the compound of formula (III) is selected from glutaric acid or adipic acid.
- the compound of formula (III) is glutathione.
- the fibres in the nonwoven matrix of formula (IV) carry amino functions F 1 on their surface. If E 1 of the compound of formula (III) is carboxyl, E will be amide in the resulting material of formula (I).
- the amino function of the nonwoven matrix may react with a compound of formula (III) wherein E 1 is carbonyl and form a nonwoven matrix of formula (I) wherein E is an imine or a Schiff base.
- the amino function of the initial nonwoven matrix is transformed into F 1 being an azide function, the azide being suitable for a click chemistry reaction with a terminal alkyne E 1 of the compound of formula (III), leading to E being a triazolyl group.
- F 1 of the nonwoven matrix of formula (IV) represents a carboxyl group which is reacted with an amine function E 1 of the compound of formula (III), leading to E being an amide group. This is the most preferred combination for the present invention and most preferably when the compound of formula (III) is already secured to a saccharide.
- the nonwoven matrix of formula (IV) carries alkyne moieties on the constituent fibre surfaces.
- the alkyne groups on the nonwoven matrix surfaces are transformed into E being triazolyl groups via cycloaddition with an azide group E 1 of the compound of formula (III).
- the nonwoven matrix of formula (IV) carries hydrazine functions F 1 on its surface.
- a hydrazide linkage is then formed by reaction of the hydrazine with the carboxyl function E 1 of a compound of formula (III).
- the hydrazine group can be present as E 1 on a compound of formula (III), whereas the nonwoven matrix carries accessible carboxyl groups on its surface.
- the nonwoven matrix of formula (IV) carries hydrazine functions F 1 on its surface.
- a hydrazone linkage is then formed by reaction of the hydrazine with the carbonyl function E 1 of a compound of formula (III).
- the hydrazine group can be present as E 1 on a compound of formula
- the nonwoven matrix of formula (IV) carries an epoxy function F 1 on its surface.
- a secondary amine function is formed by the reaction of the epoxy function on the nonwoven matrix and a primary amino function E 1 of a compound of formula (III).
- (IV) may be reacted with a thiol function of E 1 leading to E being a thioether and F being -CH 2 -CH(OH)-.
- Compounds of the formula (III) may be formed by reacting at least two compounds of formula (IMA), wherein R 3A and E 1 are different and are chosen in a way which allows a reaction between R 3A of one compound of formula (IMA) with E 1 of another compound of formula (IMA).
- the compounds of formula (IMA) may be the same or different.
- a compound of formula (III) is formed and subsequently coupled to the nonwoven matrix of formula (IV) and the saccharide of formula (V) via a remaining group R 3A and a remaining group E 1 , respectively.
- a compound of formula (III) is, in a first step, coupled via R 3A to a saccharide of formula (IV) and a second compound of formula (III) is coupled to the nonwoven matrix via E 1 as described before.
- the linker is being formed by coupling the respective products via the remaining terminal functions R 3A and E 1 .
- the compound of formula (III) which is bound to the saccharide may be the same as the compound of formula (III) which is bound to the nonwoven matrix.
- the compound of formula (III) which is bound to the saccharide may be different from the compound of formula (III) which is bound to the nonwoven matrix.
- a compound of formula (III) may be used to directly synthesize the saccharide-linker-NWmatrix of formula (I) by coupling it, successively, first to the nonwoven matrix (IV) and then to the saccharide (V).
- a first compound of formula (III) is coupled to the saccharide, followed by reacting the attached compound having a free E 1 group to at least one additional compound of formula (III). The resulting molecule is then reacted with the nonwoven matrix of formula (IV).
- a first compound of formula (III) may be coupled to the saccharide, wherein the resulting compound has, at its free end, an amine function. This amine function can then be reacted with a dicarboxylic acid, followed by attaching the free carboxylic function of the coupled dicarboxylic acid to an amine group of a nonwoven matrix of formula (IV).
- the free amino group may directly be coupled to a nonwoven matrix of formula (IV) wherein F 1 is carboxy or epoxy.
- compounds of formula (III) are successively coupled to the nonwoven matrix of formula (IV), followed by coupling the resulting product to the saccharide.
- the at least two compounds of formula (III) may also be coupled to each other in a first step and then linked to the nonwoven matrix of formula (IV), followed by the coupling of the saccharide of formula (V).
- the product of formula (I) is formed by reacting a compound of formula (III) to a saccharide of formula (V), followed by reacting the resulting molecule to the nonwoven matrix of formula (IV).
- the product of formula (I) is formed by reacting a saccharide of formula (V) to the nonwoven matrix of formula
- the coupling is accomplished by reaction of the functional group Y of the saccharide (V) with the functional group F 1 of the nonwoven matrix (IV).
- F 1 is an amino function and Y a carboxy, leading to an amide as F.
- F 1 is an azide and Y an alkyne, F being a triazole.
- the linker group may therefore be selected from a group of linkers comprising: X(CH 2 )s-NH-CO-(CH 2 )s-CONH-,
- X represents O, N, S or CH 2 ;
- s represents, independently of one another, an integer from 1 -10, and
- 1 represents an integer from 1 -600.
- X is O or N. In another embodiment of the invention X is O.
- a separation material of formula (I) is provided, wherein the saccharide is linked to the nonwoven matrix via the linker
- a separation material of formula (I) is provided, wherein the saccharide is linked to the nonwoven matrix via the linker
- a separation material of formula (I) is provided, wherein the saccharide is linked to the nonwoven matrix via the linker
- a separation material of formula (I) is provided, wherein the saccharide is linked to the nonwoven matrix via the linker
- a separation material of formula (I) is provided, wherein the saccharide is linked to the nonwoven matrix via the linker
- a separation material of formula (I) is provided, wherein the saccharide is linked to the nonwoven matrix via the linker
- the linker is preferably 10 to 1 ,000 Angstroms in length, but most preferably 20 - 100 Angstroms in length.
- saccharide refers to monosaccharides, disaccharides, oligosaccharides, or polysaccharides. In the context of the present invention, the term may further be defined as a carbohydrate containing molecule or derivative thereof that has biological or any other sort of affinity to another molecule, protein or cell. In one embodiment of the invention, the term “saccharide” refers to a disaccharide, trisaccharide, tetrasaccharide, pentasaccharide or hexasaccharide.
- Saccharides according to the invention may also comprise saccharides which are otherwise linked to proteins in glycoproteins, to lipids in glycolipids.
- the saccharides according to the invention may have been produced by enzymatic synthesis, by chemical synthesis, recombinant techniques, isolation from natural sources or may comprise a mixture made by any combination of these methods.
- the saccharide may be a monosaccharide such as, for example, arabinose, lyxose, ribose, ribulose, xylose, xylulose, allose, altrose, glucose, Mannose, gulose, idose, galactose, talose, psicose, fructose, sorbose, tagatose, their respective uronic acids, N- acetylgalactosamine, N-acetylglucosamine, fucose, fuculose, deoxyribose, rhamnose or combinations or modified versions thereof.
- Modifications may be present on one or more of the saccharides' hydroxyl groups or n-acetyl groups. Further, the di-, tri-, tetra- and pentasaccharides as well as higher oligosaccharides may be formed by a combination of the above listed monosaccharides, wherein the saccharide - which is glycosidically coupled to the linker - has a a- or ⁇ -configuration to the linker moiety.
- saccharide as used herein alone or within formula (V) is a disaccharide such as, for example, sucrose, lactulose, lactose, maltose, trehalose, isomaltose, or cellobiose.
- the term "saccharide” as used herein alone or within formula (V) is a trisaccharide.
- Trisaccharides are oligosaccharides consisting of three monosaccharides which are connected by two glycosidic bonds. Analogous to disaccharides, each glycosidic bond can be formed between any hydroxyl group of the underlying monosaccharides. Different bond combinations (regiochemistry) and stereochemistry (alpha- or beta-) are possible, also between the same monosaccharide moieties, which results in triaccharides that are diastereoisomers with different chemical and physical properties.
- the saccharide is a Gala1 -3Gal type of saccharide.
- the saccharide is a blood group determinant.
- Examples for such saccharides are Gala1 -3Gal types of saccharides, comprising, inter alia, blood group determinants A (a-L-Fuc-(1 ⁇ 2)-[a- D-GalNAc-(1 ⁇ 3)]-D-Gal) and B (a-1 -Fuc-(1 ⁇ 2)-[a-D-Gal-(1 ⁇ 3)]-D-Gal).
- saccharides can be employed for binding the respective blood group antibodies, for example before or after transplantation, thus reducing the antibody concentration in the patient's blood or plasma, or for isolating said antibodies from blood.
- saccharides as such or within formula (V) means carbohydrate structures which are specific for toxins, viruses, bacteria and/or cells and may be used for the preparation of separation material for the removal or isolation of any such materials.
- saccharides specific for pathogens, toxins, viruses, bacteria and cells have been described before in literature and may in accordance with the present invention be effectively coupled to a nonwoven matrix via functionalization and activation. The resultant separation material may then be used to purify, isolate or eliminate proteins, peptides, toxins, viruses, cells and/or bacteria from whole blood, plasma, culture media, food products, water or other materials.
- the separation material is manufactured from a porous fibrous nonwoven matrix that has been coupled with a linker modified saccharide having the general formula (V) saccharide-X-R 1 -(R 2 -R 1 )rY (V) , wherein
- X, r, R 1 and R 2 are defined as before, and
- Y represents -COOH, -NH 2 , -C ⁇ CH, -N 3 , -NH-NH 2 or -OH.
- Y represents -COOH or -IMH2. It is most preferred that it represents -IMH2.
- the linker component may be referred to as a scaffold spacer.
- the preferred saccharides are oligosaccharides and in particular antigenic oligosaccharides that are capable of binding antibodies and preferably anti- A and/or anti-B antibodies.
- the antigenic oligosaccharides have been modified with a linker or spacer molecule that has the required
- oligosaccharide components are trisaccharide, tetrasaccharide, pentasaccharide or hexasaccharide, more preferably trisaccharide, tetrasaccharide or hexasaccharide, and most preferably tetrasaccharide or hexasaccharide.
- the oligosaccharide component may be manufactured using traditional synthetic chemistry techniques or they may be prepared using microbiological synthetic routes such bio-fermentation synthetic routes using genetically modified E.coli and in particular those prepared by the methods disclosed in US Pat. No. 7521212 and International Publication No. WO0104341 .
- the antigenic oligosaccharide for use in the present invention is derived from bio-fermentation.
- the most preferred are those antigenic oligosaccharides that may be modified to provide linker/spacer functionality and most preferably that have been modified to provide linker/spacer functionality.
- Suitable antigenic oligosaccharides of group A include:
- GalNAcat -3 (Fucat -2) Gal t -3GlcNAc t -3Gal,
- GalNAcat -3 (Fucat -2) Gal t -3GlcNAc t -3-Lac,
- GalNAcat -3 (Fucat -2) Gal t -4GlcNAc t -3Gal,
- GalNAcat -3 (Fucat -2) Gal t -3GalNAc 1 -3Gal;and
- Suitable antigenic oligosaccharides of group B include:
- Suitable antigenic oligosaccharides are those prepared using conventional chemical synthetic techniques such as the oligosaccharide based antigens manufactured by Carbosynth, Newbury, United Kingdom; these are manufactured with linker/spacer functionality.
- Suitable antigenic oligosaccharides derived via bio- fermentation with scaffold spacers or linkers include those manufactured and supplied by Elicityl SA - 746 avenue Ambroise Croizat - F-38920 Crolles - France under the brand OligoTech ® Glycan Oligosaccharides.
- Another suitable source are those manufactured using bio-fermentation and supplied by GlycoBAR, 38240 Meylan, France.
- Specific preferred examples are hexasaccharide based antigenic oligosaccharides with linker chemistry:
- Blood group A antigen hexarose type 1 -N-acytal-spacer1 -NH2 also designated as:
- Blood group B antigen hexarose type 1 -N-acytal-spacer1 -NH2 also designated as:
- Galcd -3 (Fuca1 -2) ⁇ 3 ⁇ 1 -3 ⁇ 1 -3 ⁇ 3 ⁇ 1 -4 ⁇ - ⁇ spacer"! -NH2 (6GrB1 -Nac-sp1 - NH2) (hexa B)
- Galcd -3 (Fuccd -2) Ga ⁇ 1 -4G ⁇ -NAc-Spacer1 -NH2 (GLY038-3-NAc-sp1 -NH2) (Tetra B)
- the separation specific active component of the separation material of the present invention comprises one or more saccharides that have been manufactured via bio-fermentation, most preferably oligosaccharides that have been manufactured via bio-fermentation, and most preferably hexasaccharide that has been manufactured via bio-fermentation.
- the separation material of the present invention is provided when the functionalized porous fibrous nonwoven material is coupled with the saccharide component preferably via a linker component. This coupling is achieved through a chemical reaction between the functional groups on the fibres in the nonwoven matrix and an appropriate group on the saccharide or linker.
- a linker component preferably via a linker component.
- this is a reaction between carboxylic acid functional groups on the fibres of the nonwoven matrix and amine functionality either on the saccharide or more preferably provided by the linker component.
- the resultant covalent boding is therefore provided by the resultant amide group.
- the formation of such amide bonds can be carried out according to any procedure known to the person skilled in the art. It is preferred however that in the process of the present invention that the carboxylic acid functionality of the nonwoven fibre matrix is initially activated. This activation assists in the reaction with the antigenic saccharide/linker and ensures effective use of these expensive components.
- a preferred method of activation comprises the activation of the carboxylic acid with a carbodiimide, thus facilitating the coupling to an amine.
- an amide using a carbodiimide is straightforward, but with several side reactions complicating the subject.
- the carboxylic acid reacts with the carbodiimide to produce the key intermediate, an O-acylurea, which can be referred to as a carboxylic ester with an activated leaving group.
- the O-acylurea then reacts with amines to give the desired amide and urea as byproduct. It is preferred therefore that the process utilizes a controlling additive which assists in increasing the yields of the desired component and decreases such side reactions.
- These additive substances can react with the O-acylurea to form an active ester which is less reactive and less in danger of racemization.
- Examples of suitable carbodiimides include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC) .
- DCC dicyclohexylcarbodiimide
- DIC diisopropylcarbodiimide
- EDC 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide
- EDC is the preferred activating agent for use in the process of the present invention in both aqueous reaction conditions and non-aqueous solvent reaction conditions.
- Suitable controlling additives include N- hydroxybenzotriazole (HOBt), 1 -Hydroxy-7-azabenzotriazole (HOAt), N- hydroxysuccinimide (NHS), N-hydroxysulfosuccinimide (Sulfo-NHS) and 4- (Dimethylamino) pyridine (DMAP).
- HOBt N- hydroxybenzotriazole
- HOAt N- hydroxysuccinimide
- Sulfo-NHS N-hydroxysulfosuccinimide
- DMAP 4- (Dimethylamino) pyridine
- An alternative to HOBt and HOAt is ethyl 2- cyano-2-(hydroxyimino)acetate (trade name Oxyma Pure), which is not explosive and has a reactivity of that in between HOBt and HOAt.
- the preferred controlling additives are hydroxysuccinimide (NHS), N-hydroxysulfosuccinimide (Sulfo-NHS) and 4-(Dimethylamino) pyridine (DMAP). It is preferred that hydroxysuccinimide (NHS) is used in both aqueous reaction conditions and non-aqueous solvent reaction conditions, most preferably non-aqueous solvent reaction conditions.
- the reaction solvent for each reaction step may be a single solvent or a mixture of two or more solvents selected from the group comprising water, alcohols, DMSO, DMF, tBuOH, acetone, 1 ,4-dioxane or mixtures thereof.
- Preferred solvents for the reactions are water, aqueous reaction solvents and non-aqueous solvents; most preferably water or alcohols.
- steps (a1 ) and/or (b) or the combined (a1 ) and (b) may be undertaken in a single solvent or a mixture of two or more solvents selected from the group comprising water, alcohols, DMSO, DMF, tBuOH, acetone, 1 ,4-dioxane or mixtures thereof, preferably a single alcohol or mixture of alcohols.
- steps (a1 ) and/or (b) or the combined (a1 ) and (b) may be carried out in water or an aqueous solvent mixture or a non-aqueous solvent environment and step (b) is followed by a further step (c) of a water or aqueous water or non-aqueous solvent washing step to remove unreacted activation or coupling components and/or to remove the waste products of the activation and/or coupling reactions. It is preferred that the washing step is undertaken with a non-aqueous solvent and most preferably a solvent that is also able to remove residual water or moisture from the product of step (c).
- Preferred solvents for washing are alcohols or mixtures thereof and in particular ethanol alone or in admixture with other alcohols or non-aqueous solvents. There may be low levels of water included with the washing solvents and preferably less than 5% by weight of water is present.
- the washing step is preferably followed by a drying step (d) to remove and residual solvents.
- Most medical devices, including blood filters typically must be sterilised at the end of the manufacturing process. This is typically performed using either steam, gamma irradiation, or beta irradiation. In the present invention it is important to select a sterilisation protocol that does not adversely or significantly adversely impact the efficacy of the separation material. It has surprisingly been found that the use of beta irradiation may be used as an effective sterilisation method with minimum impact on separation medium efficacy. The preferred sterilisation method is beta irradiation.
- Another aspect of the invention is a separation and/or filtration device comprising the separation material according to the invention. Most preferably a separation and/or filtration device comprising an immunoadsoprtion medium according to the present invention.
- the separation material of the present invention is used in a device in the form of a packaged filter and/or immunoadsorbent separation device. These may consist of multiple layers of the separation material, positioned one above the other in layers to form a stratified stack, referred to as a mattress. It may be a single layer of the separation material or may be multiple layers of the same separation material or may be multiple layers consisting of different separation materials.
- the mattress may be either horizontally or vertically oriented with respect to the blood/plasma fluid.
- the stratified stack may further comprise other layer materials such as non-active porous fibrous nonwoven matrix materials or other forms of porous materials. These materials may have different porosity, permeabilities and other properties compared to the separation material layer of the present invention.
- the separation material of the present invention is physically sandwiched between two or more non-active porous layers, preferably nonwoven material based or is interleaved with the same.
- This construct has a number of benefits for operation of the device of the present invention incorporating the separation material of the present invention.
- the presence of the outer layers in the stack with different porosity and flow properties helps to partition the flow of blood into the device more evenly and effectively over the antigenic surfaces in the separation material. They also assist in modulating the overall flow rate through the device, and therefore the rate of antibody presentation to the antigenic surfaces.
- These layers also protects the separation material and antigenic sites from inadvertent damage due the flow pressure or materials handling during manufacture and/or packaging. In addition they may act as physical support for the antigenic separation material.
- a further advantage is that the use of these layers in maximizing the effectiveness of the separation layer means that less antigenic material may be required to treat a given sample; this construction therefore maximizes the efficiency of the separation material, which is the most expensive component of the device.
- the number of layers of all types may be between 1 and 1000, but preferably is between 10 - 1000, preferably in the range 20 - 100 and more preferably 20 to 50 depending on the individual nonwoven matrix thickness.
- each layer may be functionalised with a different antigenic or biologically active
- the separation materials of the present invention may be integrated into the production of other types of fibrous blood filter, e.g. leukodepletion filters.
- This adaption of the present invention reduces the time of treatment for the two processes.
- the cross sectional area of the layers in the device are preferably between 1 - 500 cm 2 , most preferably in the region of 25 - 150 cm 2 .
- the stack of fibre webs (the mattress) is preferably housed inside a casing which can either be a low Tg polymer material such as polyvinyl chloride or a high Tg polymer material, such as polycarbonate.
- the liquid flow into the device may be directed transversely through the mattress or parallel with the individual layers therein, or can be a combination thereof.
- the purpose is to ensure all the constituent fibre surfaces within the mattress are contacted by the permeating fluid.
- the device contains entrance and exit ports that direct the flow of fluid into and out of the filter. Various arrangements are possible to ensure fluid is directed to the fibre surfaces within the mattress. [00126]
- the device is connected to a blood bag containing blood or blood products via a tube connected to the entrance port on the filter.
- the blood bag is positioned above the filter.
- the tubing is between 1 - 100 cm in length, preferably between 20 - 60 cm in length.
- the device is connected to a collect bag via a separate piece of tubing connected to the exit port on the filter.
- the tubing is between 1 and 100 cm in length, preferably between 20 to 60 cm in length.
- the present invention also provides for a method of treatment of whole blood to remove one or more components using a separation material of the present invention.
- the flux of blood or whole blood through the separation material may be between 0.05 to 100 mm min ⁇ 1 , but is preferably in the region of 1 to 10 mm min -1 .
- the ratio of mass of separation material or total nonwoven matrix material in the device to volume of blood (or blood product) is in the region of 5 to 500 grams of nonwoven matrix per litre of blood or blood product, but preferably in the range of 10 to 100 grams.
- Processing times for a typical unit of plasma (250 ml) are in the range of 20 seconds to 60 minutes, but preferably in the region of 5 to 20 minutes.
- the present invention also provides for a process where the porous and fibrous nonwoven matrix is functionalised either before or after it has formed into a mattress and welded into a filter housing.
- This production method has utility in that it reduces production costs as only the required nonwoven matrix functionalised - i.e. no nonwoven matrix is wasted from cutting to size.
- the advantage of this approach is that it can significantly reduce wastage and costs when using expensive receptor species.
- An advantage of this approach is that simplifies the manufacturing process.
- the filters can be produced as normal (meltblown fabric is cut, treated and welded as usual). Once welded, the filters are functionalised in situ within the filter housing by passing a solution of the reagents through the filter. This process is performed with multiple filters simultaneously connected in series or in parallel as required.
- the separation materials of the present invention have the ability to simultaneously achieve a high solid surface area per unit volume, whilst still maintaining an overall porosity of >60% and therefore a high liquid permeability.
- the amount of the artificial antigen on the fibre of the matrix is referred to as Antigen Loading and defined in terms of moles / gram of fibre.
- the Antigen Loading is between 0.000001 ⁇ to 1000 ⁇ / gram of fibre, preferably, 1 to 50 ⁇ per gram.
- the average spacing between the artificial antigen molecules on the surface of the fibre is also between 1 nm to 10,000 nm, but preferably in the range of 50 - 1000 nm.
- the antigen loading level and average spacing can be controlled as desired by controlling one or more of the processes described herein. For example, these may include: The level of functionality on the fibre, amount of artificial antigenic species used in the immobilisation process, and the reaction conditions used to immobilise the artificial antigen species.
- the receptor loading can be controlled by limiting the functionality introduced to the fibre surface by the plasma treatment.
- a process where the receptor species loading level can be controlled by limiting the amount of receptor species in the immobilisation or coupling process.
- a process where the loading of artificial antigen species can also be controlled by the reaction conditions; these may include any parameter that affects the rate or yield of reaction. These include, but are not limited to; time, temperature, concentration and pH, etc.
- the loading level can be controlled by controlling the residence time of the reaction.
- the separation material of the present invention has many other potential applications.
- any target species can be removed from a fluid if a suitable receptor species exists.
- This functionality on the fibre surface allows almost any receptor species to be immobilised onto the surface providing the receptor species can be functionalised with either an amine or carboxylic acid group.
- a saccharide-linker-NWmatrix of formula (A) comprises carbohydrate structures which are derived from cell surface glycolipids and glycoproteins, generally referred to as tumor or cancer-antigens, may be produced according to the present invention.
- Such antigens may be recognized by antibodies, for example in connection with prostate-, breast-, intestine- or skin- cancer.
- Such material may then be used, for example, for isolating such tumor antigen binding antibodies from whole blood, blood plasma, from cell culture media or any other medium the antibodies need to be isolated from. After elution from the separation material, the antibodies can be used for treating said cancer diseases, for example in immunotherapy treatment of cancer.
- the separation material may be used in the course of different types of organ transplantations as a part of the treatment of the recipient before, during, and eventually after the transplantation.
- the removal of blood group A and/or blood group B antibodies is needed to minimize the problem of blood group incompatibility between donor and recipient.
- Either whole blood or blood plasma of the patient who is awaiting, undergoing or has gone through a transplantation procedure may be passed trough the separation material.
- the separation material may also be used for blood group compatible transplantations, wherein problems in connection with donor and recipient of the same blood group, but of different blood group subgroups are addressed.
- the separation material is used for purifying, isolating or eliminating glycoproteins, glycopeptides, viruses and/or bacteria in whole or in part from whole blood, plasma, blood products, cell culture media, food products, water or other materials.
- the separation material is used for isolating antibodies from whole blood or blood plasma, wherein said antibodies bind to tumor- or cancer-antigens, for example in connection with prostate-, breast-, intestine- or skin-cancer. After elution from the separation material, the antibodies may be used for treating said cancer diseases, for example by producing pharmaceutically active reagents.
- the separation material may also be used for removing an excess of antibodies from whole blood or blood plasma during immunotherapy of cancer.
- the separation material of the invention is used in plasmapheresis type applications. In a further embodiment of the invention, the separation material is used in hemodialysis, hemodiafiltration or hemofiltration type applications.
- the separation material of the invention can be used for these purposes instead of conventional membranes, but in a similar manner.
- Another aspect of the invention is the use of the separation material of the invention in bioprocessing applications, plasma fractionation and the preparation of protein solutions.
- the membrane of the invention can be used for these purposes instead of membranes conventionally used for these purposes.
- FIG. 1 shows the shape and dimensions of the nonwoven material used in Example 1 .
- FIG. 2 shows a representation of the separation material or the present invention as prepared in Example 2,
- FIG. 3 (a) and (b) is a graphical representation of the data presented in Table 4 of Example 4, and
- FIG. 4 is a graph showing the impact of exposure time on antibody Titre of blood treated with a separation medium of the present invention in Example 9.
- Untreated PBT meltbown was cut into small sheets with dimensions as required for an LXT format filter ( Figure 1 ) the dimensions selected were slightly larger than needed to allow for shrinkage during the functionalisation process and to make it easier to fit the compression lines during subsequent welding).
- the sheets were functional ised using PICO low temperature low pressure plasma coater (40 kHz; Diener GmbH, Ebhausen Germany).
- the PBT meltblown were treated for 20 minutes on each side using the conditions in Table 1 .
- the chamber was allowed to equilibrate for 5 minutes prior to the plasma treatment.
- the two meltbown sheets (representing 1 mol eq. of acid groups) were gently rolled up into loose rolls and inserted into the vials, containing an aqueous solution of EDC (5 mol eq.) and DMAP (0.8 mol eq.) and left for 1 minute to absorb into the meltblown.
- the volume of water used to dissolve the EDC and DMAP was selected so as to be that which fully wetted the meltblown, but with no excess fluid remaining. This reaction activated the fucntionalised nonwoven substrate.
- This is typically performed using either steam, ethylene oxide, gamma irradiation, or beta irradiation.
- NB The A+B filters only contain half of each of the antigens compared to the other filters in
- a second round of efficacy testing was performed on further examples using high titre plasma.
- High titre plasma units were pooled and split into 250 ml portions.
- the objective of this example was to confirm if the filters were capable of neutralising high titre plasma as well and also to determine the total neutralisation capacity of the filters.
- a filter comprising PBT meltbown functionalised with artificial antigen was assembled and tested for immunoadsorption properties.
- PBT meltblown was exposed to an oxygen surface plasma treatment to introduce functionality onto the fibre surface.
- the meltbown was cut into 32 rectangular sheets.
- a commercially available blood Group B trisaccharide antigen was immobilised onto the surface of the fibre using an amide coupling reaction with EDC/DAMP to give an antigen loading level of 50 mg per gram of fibre.
- the sheets were stacked to form a mattress which was welded into a polycarbonate casing.
- the IgG titre was reduced from 1 : 16 to 1 :1 and the IgM titre level was reduced from 4:1 to 1 :1 .
- Example 7 [00173] A filter was made and tested in the same way as described in 6, but with the use of a hexarose Blood Group B antigen.
- the IgG titre was reduced from 1 :32 to 1 :1 and the IgM titre level was reduced from 1 :16 to 0.
- a filter was made as described in Example , but with the use of a hexarose Blood Group A antigen.
- the IgG titre was reduced from 1 :64 to 0 and the IgM titre level was reduced from 1 :4 to 0.
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Abstract
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GBGB1717555.5A GB201717555D0 (en) | 2017-10-25 | 2017-10-25 | Blood filter |
PCT/EP2018/079358 WO2019081688A1 (en) | 2017-10-25 | 2018-10-25 | Porous fibrous separation material |
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CN113797900B (en) * | 2021-09-29 | 2023-11-10 | 广州康盛生物科技股份有限公司 | Adsorption material for blood purification, preparation method and application thereof, adsorption column and blood adsorption device |
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CA1204667A (en) * | 1982-10-04 | 1986-05-20 | Masashi Kodama | Blood treating material |
ATE233100T1 (en) * | 1989-08-02 | 2003-03-15 | Mitra Medical Technology Ab | SYSTEM FOR USE IN A PROCESS OF THERAPEUTIC AND DIAGNOSTIC TREATMENT |
US6686457B1 (en) | 1996-12-23 | 2004-02-03 | Kurt Nilsson | Material |
FR2796082B1 (en) | 1999-07-07 | 2003-06-27 | Centre Nat Rech Scient | PROCESS FOR PRODUCING OLIGOSACCHARIDES |
US20040022784A1 (en) | 2000-02-08 | 2004-02-05 | Kurt Nilsson | Oligosaccharide supports for e.g. removal of antibodies from blood |
SE526038C2 (en) * | 2002-07-08 | 2005-06-21 | Gambro Lundia Ab | Polymer affinity matrix, process for its preparation and use thereof |
EP2556848A1 (en) | 2011-08-08 | 2013-02-13 | Gambro Lundia AB | Separation material comprising saccharide ligands |
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