FR3008097A1 - AFFINITY CHROMATOGRAPHY MATRIX - Google Patents

Abstract

The invention relates to an affinity chromatography matrix, comprising polymer particles on which at least one oligosaccharide corresponding to a blood group A and / or group B epitope is grafted, said oligosaccharide being grafted via a spacer. The invention also relates to the uses of this matrix for preparing immunoglobulin concentrates for therapeutic use.

Description

The present invention relates to a matrix for carrying out an affinity chromatography for retaining and removing antibodies to blood group A and / or blood group B antigens.

BACKGROUND ART: Many pathologies are currently treated with immunoglobulin (Ig) compositions. Examples include primitive immune deficiencies with defective antibody production, Kawasaki disease, immunologic thrombocytopenic purpura in children and adults, secondary immune deficiencies with defective antibody production, in particular chronic lymphocytic leukemia or myeloma associated with recurrent infections, childhood HIV infection associated with bacterial infections, multifocal motor neuropathies, Guillain-Barré syndrome, severe acute or chronic parvovirus B19 infections , acquired or constitutional immunodeficiency, corticosteroid dermatomyositis, acute myasthenia, idiopathic chronic polyradiculoneuropathy, immune thrombocytopenic purpura, for example associated with HIV infection, stiff man syndrome (Stiffman syndrome) , autoimmune neutropenia, resistant autoimmune erythroblastopenia, anticoagula syndrome acquired by autoantibodies, rheumatoid arthritis, uveitis, etc.

The increasing use of Ig-enriched human plasma fractions in therapy requires the large-scale production, from, for example, human plasma, of highly purified, intravenous (IVIg), or subcutaneous ( GSCI). However, this production faces numerous constraints, particularly in terms of the safety of the Ig concentrates obtained. According to the European Pharmacopoeia, in order to reduce the risk of haemolysis, these concentrates must have a reduced level of antibodies directed against the blood group A and / or blood group B antigens (referred to in the description, abbreviated as "antibodies"). anti-blood group A "and" anti-blood group B ", or" anti-A "and" anti-B "antibodies, or" anti-A isoagglutinins "and" anti-B isoagglutinins ").

As the need for Ig is constantly increasing, it is necessary to have increasingly large pools of donors, which will be statistically all the richer in blood group O. It has therefore become essential to have methods allowing to eliminate anti-A and anti-B antibodies from blood products, during the industrial production of Ig concentrates from blood plasma pools. WO2007 / 077365 discloses a process for preparing Ig concentrates, comprising an immunoaffinity chromatography step for depleting them of anti-A and anti-B antibodies.

SUMMARY OF THE INVENTION: The Applicant has now developed a carrier, particularly useful for retaining, and removing, anti-A and / or anti-B antibodies from a blood product, by scale affinity chromatography. industrial. The invention thus provides an affinity chromatography matrix, comprising polymer particles on which at least one oligosaccharide corresponding to a blood group A and / or group B epitope is grafted, said oligosaccharide being grafted to said particles via a spacer. characterized in that said spacer has the formula (I) -NH-R1-CO-NH-R2-, wherein R1 is a C4-C6 alkyl group, R2 is a C3-C8 alkyl group, and said spacer is bound by its amine function to the particle. A diagram of these grafted particles is presented in Figure 1.

In a particular embodiment, the matrix comprises (i) polymer particles on which at least one oligosaccharide corresponding to a blood group A epitope is grafted, and / or (ii) polymer particles on which at least one oligosaccharide corresponding to a blood group epitope B is grafted.

In a preferred embodiment, the matrix comprises (i) polymer particles on which at least one oligosaccharide corresponding to a blood group A epitope is grafted, and (ii) polymer particles on which at least one oligosaccharide corresponding to an epitope of blood group B is grafted. This embodiment is illustrated in Figure 4A. In another embodiment, the matrix comprises polymer particles on which both at least one oligosaccharide corresponding to a blood group A epitope, and less an oligosaccharide corresponding to a blood group B epitope, are grafted. This embodiment is illustrated in Figure 4B. In a particular embodiment, the matrix comprises a mixture of (i) polymer particles on which at least one oligosaccharide corresponding to a blood group A epitope is grafted, (ii) polymer particles on which at least one oligosaccharide corresponding to a blood group B epitope is grafted, and (iii) polymer particles on which both at least one oligosaccharide corresponding to a blood group A epitope, and less an oligosaccharide corresponding to a blood group B epitope, are grafted. embodiment is illustrated in Figure 4C. In all embodiments, the spacer that binds the ligand corresponding to a blood group A epitope to the particle, and the spacer that binds the ligand corresponding to a blood group B epitope to the particle may be the same or different but always of formula (I). Preferably the spacers are identical. In a preferred embodiment, crosslinked cellulose beads are mixed on which are grafted ligands which are trisaccharides corresponding to a blood group A epitope (N-acetylgalactosamine (GalNAc) -Galactose (Gal) -Fucose), as shown in FIG. Figure 2, and crosslinked cellulose beads on which are grafted ligands which are trisaccharides corresponding to a blood group B epitope (Galactose-Galactose-Fucose), as shown in Figure 3. The trisaccharides are grafted to the beads by a spacer of formula: (bead) -NH-C5Hio-CO-NH-C3H6- (ligand) The invention also relates to the use of this matrix, or support, in an affinity chromatography binding anti-A and / or or anti-B. The invention also provides a method for preparing an immunoglobulin (Ig) concentrate for therapeutic use, comprising obtaining an Ig composition from blood plasma, ethanolic fractionation and / or caprylic fractionation and / or or chromatographic separation, and the removal of the anti-A and / or anti-B antibodies possibly present in the composition, by means of an affinity chromatography using the matrix as defined herein.

One advantage of this matrix is its high selectivity and specificity with respect to anti-A and anti-B antibodies, and its high binding capacity thereto. As a result, it becomes possible to reduce the processing time of the products on an industrial scale, by passing a larger amount of product per column volume.

Legends of the Figures: Figure 1 is a schematic diagram of a polymer particle on which an oligosaccharide corresponding to a blood group A or B epitope is grafted, according to the invention. Figure 2 is a schematic diagram of a particular embodiment of the invention, showing a polymer particle on which a trisaccharide corresponding to a blood group A epitope is grafted. Figure 3 is a schematic diagram of a particular embodiment of the invention showing a polymer particle on which a trisaccharide corresponding to a blood group B epitope is grafted. Figure 4A is a schematic diagram of a particular embodiment of the invention, of a matrix comprising a mixture of particles bearing an oligosaccharide corresponding to a blood group A epitope, and particles carrying an oligosaccharide corresponding to a Figure 4B is a simplified schematic of a particular embodiment of the invention, a matrix comprising particles carrying both an oligosaccharide corresponding to a blood group A epitope, and an oligosaccharide. corresponding to a blood group epitope B. FIG. 4C represents a simplified diagram of a particular embodiment of the invention, of a matrix comprising a mixture of particles carrying an oligosaccharide corresponding to a blood group A epitope, particles carrying an oligosaccharide corresponding to a blood group B epitope, and particles bearing both an oligosaccharid e corresponding to a blood group A epitope, and an oligosaccharide corresponding to a blood group B epitope.

DETAILED DESCRIPTION OF THE INVENTION The support: The matrix of the invention comprises a support based on polymer particles, and is preferably in the form of a gel or a resin.

These polymer particles are preferably of spherical or oblong shape, it may be in particular beads. These particles generally have an average size of about 0.1 μm to about 1000 μm, preferably about 20 to about 500 μm, more preferably about 50 to about 2001 μm, more preferably about 70 μm. at about 1201.1m in diameter.

Preferably these particles are porous. The polymer may be natural or non-natural, organic or inorganic, crosslinked or uncrosslinked. The polymer is preferably an organic polymer, preferably crosslinked. In a preferred embodiment, the polymer is cellulose, and the particles are preferably porous cellulose beads. More preferably, it is crosslinked cellulose. Other types of possible polymers include agarose, dextran, polyacrylates, polystyrene, polyacrylamide, polymethacrylamide, copolymers of styrene and divinylbenzene, or mixtures of these polymers.

The particles can provide a chromatography medium that can be used to fill a column, for example.

The ligands: The ligands carried by the support according to the invention are oligosaccharides representing the blood group A or B antigens, which are naturally monosaccharides. More specifically, the oligosaccharide corresponding to a blood group A epitope and / or the oligosaccharide corresponding to a blood group B epitope carried by the matrix according to the invention are typically trisaccharides. The term "blood group epitope corresponding oligosaccharides" refers to antigenically identical or similar motifs to the antigenic determinants recognized by the anti-A and anti-B antibodies, respectively. The ligands carried by the support according to the invention are therefore specific for anti-A or anti-B antibodies. Preferably, the oligosaccharide corresponding to a blood group A epitope, used as ligand in the invention, is a trisaccharide N-acetylgalactosamine (GalNAc) -Galactose (Gal) -Fucose, specifically N-acetylGalcc 1-3 (Fuc a1- 2) Gal, the spacer is bonded by the oxygen atom preferably bonded to the carbon at the 1-position of galactose: ## STR5 ## The oligosaccharide corresponding to a blood group epitope B, used as ligand in the invention is preferably a Galactose-GalactoseFucose oligosaccharide, more specifically Gal a1-3 ((Fuc a1-2) Gal, the spacer is bonded by the oxygen atom preferably bonded to the carbon in position 1 The spacer, represented in FIG. 1, has the formula (I) -NH-R 1 -CO-NH-R 2 -, said spacer being linked by its amine function (in bold above particle can carry one or more spacers The spacer makes it possible to reduce the steric hindrance e t to increase the accessibility of the ligand to anti-A and anti-B antibodies to bind. The spacer serves to immobilize, on a particle, either an oligosaccharide corresponding to a blood group A epitope, which is preferably an N-acetyl Glala 1-3 (Fuc al-2) Gal trisaccharide as described above, or an oligosaccharide corresponding to a blood group epitope B, which is preferably a Gal al-3 ((Fuc al-2) Gal trisaccharide as described above.R1 is a linear or branched C4-C6 alkyl group R 1 is preferably C 1 -C 8 alkyl, linear or branched, preferably linear, and preferably R 2 is C 3 -C 8 alkyl. In a preferred embodiment, the ligands (which are preferably trisaccharides as described above) are grafted to the particles by a spacer of the formula: (particle) -NH-OH-CO-NH-C3H6- (ligand). the matrix: The ligands are immobilized chemically by covalent bonds between the particles and the spacer, and between the spacer and the ligand.

This immobilization can be carried out in a conventional manner by those skilled in the art. In a preferred embodiment, the particle carries an -NH-R1-COOH arm. Preferably it is s-aminocaproic acid (where R 1 is a pentyl group). Typically, the particle can be activated using bifunctional reagents such as epichlorohydrin, epibromohydrin, dibromo-and dichloropropanol, dibromobutane, ethylene glycol diglycidyl ether, butanediol diglycidylether, divinylsulfone, allylglycidylether, and the like. allyl bromide. The bifunctional reagent is capable of reacting with both the particles and the -NH-R1-COOH arm. The heterofunctional allyl compounds, such as allyl bromide, are preferred bifunctional reagents and make it possible to obtain an activated matrix. For certain solid supports, such as cellulose, hydrogel-containing composites, or other materials having hydroxyl groups, it is advantageous to deprotonate the hydroxyl groups with a hydroxide source, for example, before the reaction with a bifunctional reagent. .

The ligands representing the blood group A and / or B antigens are then immobilized on the activated particle carrying the -NH-R1-COOH arm via a linker group - NH-R2-, where R2 is a C3-C8 alkyl group, linear or branched, preferably linear. For this, the COOH function of the -NH-R 1 -COOH arm carried by the particle is reacted with the NH 2 function of the NH 2 -R 2 -rigosaccharide ligand, by the use of an N-ethoxycarbonyl type condensation agent. -2-ethoxy-1,2-dihydroquinoline (EEDQ). Those skilled in the art can graft either a ligand representing a group A antigen or a group B antigen ligand, or both, on the same particle. Preferably, the spacer used is identical. This is particularly advantageous for ensuring an equivalent grafting of ligands representing a group A antigen relative to the ligands representing a group B antigen. The person skilled in the art can also be placed under appropriate conditions, depending on the reactivity of the ligands. with respect to the particles, to obtain particles bearing a determined proportion of ligands representing a group A antigen relative to the ligands representing a group B antigen.

The gel matrix is prepared by conventional addition of a buffer to the ligand-carrying polymer particles, as known to those skilled in the art, so as to obtain a gel matrix suitable for chromatography. affinity.

Advantageously, the ligand density, that is to say the amount of ligands (i.e., oligosaccharides corresponding to a blood group epitope A or B) grafted, per volume of template in gel form, can be from about 0.2 to about 0.7 mg / ml of matrix, more preferably from about 0.3 to about 0.4 mg / ml of template. Preferably the density of oligosaccharides is about 0.3 mg / ml of matrix. According to the invention, this density makes it possible to drastically reduce the purification time by affinity chromatography, compared with a density of 1 mg / ml (for example on GLYCOSORB ABO® gel from Glycorex Transplantation AB (Sweden), mentioned in application WO2007 / 077365). The volume of matrix can be increased and the flow rate through the chromatography column can be increased. Thus, with a ligand density of 0.3 mg / ml of matrix (compared to a density of 1 mg / ml), the duration of the process was divided by 2, which, on an industrial scale, represents a remarkable gain .

In a preferred embodiment, the polymer particles on which at least one oligosaccharide corresponding to a blood group A epitope is grafted, and the polymer particles on which at least one oligosaccharide corresponding to a blood group B epitope is grafted, can then be mixed, for example in a proportion of 25/75 to 75/25 (v / v), preferably about 50/50 (v / v).

The polymer particles on which at least one oligosaccharide corresponding to a blood group A epitope is grafted, and the polymer particles on which at least one oligosaccharide corresponding to a blood group B epitope is grafted, may also, if appropriate, to be mixed with polymer particles bearing both at least one oligosaccharide corresponding to a blood group A epitope, and at least one oligosaccharide corresponding to a blood group epitope B.

Affinity Chromatography: The matrix as defined herein is useful in an affinity chromatography binding anti-A and / or anti-B antibodies. For this, the matrix can be introduced into a chromatography column. On an industrial scale, the column can contain from 1 to 150 liters. In the case of implementation on a pilot scale, columns of 1 to 50 cm in height can be used, the diameter is then adapted to the column height used. The volume of matrix used in the column is adjusted according to the desired residual level of anti-A and / or anti-B antibodies relative to the initial level of anti-A and / or anti-B antibodies of the solution.

The anti-A and / or anti-B antibodies present in the immunoglobulin liquid preparation (or the blood product derivative) bind to the matrix, and the non-adsorbed product is recovered, depleted of anti-A antibodies and / or anti-B. The liquid immunoglobulin preparation or blood product derivative is poured through the matrix at a rate and under conditions that allow binding of the antibodies to the ligands carried by the matrix. The matrices can be re-used repeatedly, without degradation. Their regeneration can be carried out by procedures known to those skilled in the art, for example by treatment with sodium hydroxide (NaOH), for example 1M.

Purification of immunoglobulin products: An affinity chromatography using the matrix of the invention is particularly advantageous for purifying immunoglobulin preparations or compositions, by eliminating the undesirable anti-A and / or anti-B antibodies possibly present in these immunoglobulin preparations. preparations or compositions, and thus prepare immunoglobulin concentrates for therapeutic use. By "elimination" is meant a substantial reduction in the amount of anti-A and / or anti-B antibodies present, preferably at least 25%, more preferably at least 50%, more preferably at least 50%. at least 80 or 90%. The Ig concentrate of the invention obtained after affinity chromatography has respective contents of anti-A and anti-B antibodies conforming (at the 1/64 dilution) to a negative result with the direct Coombs test carried out with an initial concentration of IgG at 30g / l. Preferably, the Ig concentrate of the invention obtained after affinity chromatography comprises an anti-A antibody content of not greater than 23 ng / mg IgG, and an anti-B antibody content of not more than 20 ng. mg of IgG. Methods for assaying the residual anti-A and anti-B antibodies are described in particular in application WO2007 / 077365. Preferably, a method for assaying the anti-A and anti-B antibodies is carried out by flow cytometry, the principle of which is based on the use of human A or B group red blood cells, depending on the specific determination of the titer of the antibodies. anti-A and anti-B desired, implementing the detection of a fluorescence signal proportional to the content of these antibodies. The flow cytometry assay method generally uses a standard sample, for example a positive control of immunoglobulins (such as EDQM 1:32, ref # 07/306, Thorpe et al., 2009, Vox Sang. , 160-168), or a monoclonal anti-D antibody concentrate or other suitable reference product. The immunoglobulin products essentially contain IgG. Typically, these IgGs are polyclonal IgG obtained from blood plasma or an already enriched Ig blood plasma fraction. Ig concentrates for therapeutic use are at concentrations of between 50 and 100 g / l. These concentrates are intended for clinical use and may in particular be injected intravenously. For this purpose, they must be safe and, where appropriate, contain excipients, such as stabilizers, compatible with this clinical use. Ig concentrates for therapeutic use may also be administered subcutaneously. In this case, the concentration of the products is greater than or equal to 100 g / l, advantageously greater than or equal to 150 g / l.

Ig concentrates for therapeutic use may also be administered intramuscularly. These Ig concentrates can be obtained as follows: a) preparation of an Ig composition, for example by ethanolic fractionation and / or by caprylic fractionation and / or by chromatographic separation, b) percolation immunoaffinity chromatography of the composition of Ig on a matrix of the invention, and c) step of biological securing, preferably nanofiltration so as to eliminate viruses and / or contaminating particles. The Ig composition can be obtained by ethanolic fractionation originally developed by Cohn et al (Cohn et al, 1946. J. Am Chem Soc 68, 459, Uncley et al, 1949, J. Am. Chem Soc 71, 541), or by chromatographic separation, as described for example in EP 0 703 922 and WO 99/64462, or by caprylic fractionation as described by Steinbuch et al 1969, Arch Biochem Biophys. . 134 (2): 279-84). Particularly preferred methods developed by the Applicant in the patent applications WO 94/29334 and WO 02/092632, and particularly that described in WO 02/092632. In this case, a blood plasma, or an IgG-enriched blood plasma fraction, is subjected to caprylic fractionation (prepurification by precipitation of non-immunoglobulin contaminants), a single chromatography on an anion exchange resin carrier carried out at alkaline pH selective elution of the IgGs in one step with an appropriate buffer at a pH of between 4 and 7. A viral inactivation treatment can be carried out, preferably carried out by solvent-detergent, as described by Horowitz in US Pat. No. 4,764,369. The IgG fraction thus harvested is already concentrated, but can then undergo additional concentration steps by ultrafiltration, and sterilizing filtration.

This concentrate is then subjected to an immunoaffinity chromatographic step on the matrix of the invention. Preferably, the pH of the immunoglobulin preparation is adjusted to a pH of about 6 to about 7, preferably about 6, prior to chromatography. The charge of the column is adapted to the desired residual level of anti-A and / or anti-B antibodies. The specificity of such a matrix does not require prior conditioning of the IgG fraction, ie any fraction or IgG concentrate obtained by plasma fractionation techniques may be suitable. Percolation of the concentrate does not involve an elution mechanism. Therefore, regardless of how the IgG concentrate is obtained, it is drilled through the column, possibly through a pump. This percolation allows the retention of anti-A and anti-B antibodies. The contact time between the ligands and the Ig preparation is greater than or equal to one minute, advantageously of the order of 2 minutes. The column can then be washed with water to recover IgG still present in the dead volume of the column.

After percolation of the IgG concentrate, an IgG fraction depleted of anti-A and anti-B antibodies is obtained. The method may further include ultrafiltration and sterilizing filtration steps. The chromatographic column and the matrix can then be washed and eluted, to desorb the anti-A and anti-B antibodies retained. The following example illustrates the present invention without limiting its scope. Example: Affinity Chromatography (Industrial Scale) Chromatographic Conditions: An immunoglobulin preparation, obtained by fractionation according to the process described in application WO2002 / 092632, comprising 10 ± 2 g / l of IgG, is subjected to industrial scale, at a step of anti-A / anti-B affinity chromatography carried out on a column comprising a 50/50 (v / v) mixture of crosslinked cellulose beads on which are grafted trisaccharides corresponding to an epitope of the group blood A (N-acetylgalactosamine (Ga1NAc) -Galactose (Gal) -Fucose), as shown in Figure 2 (gel designated "Iso A HyperCel"), and crosslinked cellulose beads on which are grafted trisaccharides corresponding to an epitope blood group B (Galactose-Galactose-Fucose), as shown in Figure 3 (gel designated "Iso B HyperCel"). The trisaccharides are grafted onto the beads by a spacer of formula: (bead) -NH-OH-CO-NH-C3H6- (ligand) The density of grafted trisaccharides is 0.3 mg per ml of matrix gel.

To verify the residual anti-A and anti-B activity, the immunoglobulin preparation designated Eluat (fraction obtained after anion-exchange chromatography), whose pH was adjusted to 6 (± 0.05) was passed on a column. of 1 ml (comprising 0.5 ml of HyperCel Iso A gel + 0.5 ml of HyperCel Iso B gel) Column format: D = 0.5 cm x 5.1 cm (column volume (VC) = 1 m1). Contact time: 2 min Charge: 6 g of Eluat preparations / mg of A + B ligands, ie 180 ml of product per column. Before the test, the gel is washed with water (10 VC minimum). The conditions of the various process steps are summarized in the table below: Table of the steps: Step Solution Volume Sanitization 1M NaOH (30min) 6VC 1M Phosphate pH 8.0 4VC Balancing PPI Water 10VC (Return to neutral pH 5 to 7) Fixation Eluat ± 180m1 Unfractionated collection of FNA Wash 150mM NaCl + Phosphate 10VC 15mM pH 6.2 Elution acid Glycine 0.1M pH 3 6VC Basic elution Glycine 0.1M pH 11 6VC VC: column volume; ANF: Non-adsorbed fraction A single non-adsorbed Fraction (ANF) was collected. Assay Tests: The yield was determined by assaying IgG in the unadsorbed fraction, after washing and percolation. The residual anti-A and anti-B activity, corresponding to the percentage of anti-A and anti-B isoagglutinins present in the final preparation relative to their concentration before the affinity chromatography step, was measured by cytometry. in flow (technique more sensitive and precise than that of the dilutions required by the European Pharmacopoeia), according to the technique described below. Red blood cells of groups A- and B- were collected on EDTA and washed twice in 0.9% NaCl solution (centrifugation at 1730 g for 5 min between the two washes). 2.106 RBCs were distributed on a microtiter plate and 50 μL of standard positive control (1:32 EDQM, ref # 07/306, Thorpe et al., 2009) or diluted samples at a working concentration (PBS) were added. pH 7.4, 1% BSA). The plates were incubated for 2h at 37 ° C with shaking. After washing, an anti-human IgG F (ab ') 2 antibody (Fc specific) (Beckman Coulter) labeled with phycoerythrin (PE) was used diluted 1/20 in PBS-BSA. The plates were incubated for 30 min at room temperature and protected from light. After washing, each pellet was resuspended in 200 μl of PBS-BSA, and read by flow cytometer (Beckman Coulter Cytomics FC 500). The mean fluorescence intensity (MFI) of the positive control was reported as a function of the IgG concentration (standard curve) for concentrations ranging from 0.23 g / L to 30 g / L. The results are expressed as the ratio between the slope of the sample and the slope of the positive standard. The equation of the standard curve is y = ax + b; where "a" is the value of the slope of the standard curve and "b" is the zero point corresponding to the background noise of the test. Since the sample equation is y '= a'x + b, and using the known MFI values of the sample (y') and the IgG concentration (x '), the slope ratio was calculated as [(IMF-b) / [IgG concentration]] / a. Results: The yield of IgG and the residual anti-A and anti-B activity obtained are presented in the table below: Table of results: Vol Conc. Amount (g) Charge g / mg Cytometer Cytometer (mL) (g / L) IgG ligands Calculation IgG Calculation IgG IgG Gel A + B Anti-A Anti-B Act.resid Act.resid Start FNA 180.0 11.60 2 , 1 6,8 5,14 3,44 Wash + E + R 183,8 11,10 2,0 0,60 0,29 18,8 1,20 0,0 12% 8% The results in this table show a 98% IgG yield in the unadsorbed fraction, which proves that the affinity support has a good specificity with respect to anti-A and anti-B isoagglutinins.

The results in this table also show a significant reduction in the residual anti-A and anti-B activity, which are respectively 12% and 8%. The product thus obtained is then in conformity (at 1/64 dilution) with a negative result in the direct Coombs test carried out with an initial IgG concentration of 30 g / l. 10

Claims (16)

REVENDICATIONS1. An affinity chromatography matrix, comprising polymer particles on which at least one oligosaccharide corresponding to a blood group A and / or group B epitope is grafted, said oligosaccharide being grafted to said particles via a spacer, characterized in that said spacer has the formula (I) -NH-R1-CO-NH-R2-, wherein R1 is a C4-C6 alkyl group, R2 is a C3-C8 alkyl group, and said spacer is bonded by its amine function to the particle. 2. Matrix according to claim 1, comprising (i) polymer particles on which at least one oligosaccharide corresponding to a blood group A epitope is grafted, and / or (ii) polymer particles on which at least one corresponding oligosaccharide to an epitope of blood group B is grafted. 3. Matrix according to claim 2, comprising (i) polymer particles on which at least one oligosaccharide corresponding to a blood group A epitope is grafted, and (ii) polymer particles on which at least one oligosaccharide corresponding to one blood group epitope B is grafted. 4. Matrix according to claim 1, comprising polymer particles on which both at least one oligosaccharide corresponding to a blood group A epitope, and at least one oligosaccharide corresponding to a blood group B epitope, are grafted. 5. Matrix according to claim 1, comprising a mixture of (i) polymer particles on which at least one oligosaccharide corresponding to a blood group A epitope is grafted, (ii) polymer particles on which at least one oligosaccharide corresponding to an epitope blood group B is grafted, and (iii) polymer particles on which at least one oligosaccharide corresponding to a blood group A epitope, and at least one oligosaccharide corresponding to a blood group B epitope, are grafted. 6. Matrix according to one of claims 1 to 5, wherein the oligosaccharide corresponding to a blood group epitope A and / or the oligosaccharide corresponding to a blood group epitope B is a trisaccharide. The matrix of claim 6 wherein the oligosaccharide corresponding to a blood group A epitope is a N-acetylgalactosamine (Ga1NAc) -Galactose (Gal) -Fucose trisaccharide. The matrix of claim 6, wherein the oligosaccharide corresponding to a blood group epitope B is a Galactose-Galactose-Fucose oligosaccharide. 9. Matrix according to one of claims 1 to 8, wherein R1 is a C5 alkyl group. 10. Matrix according to one of claims 1 to 9, wherein R2 is a C3 alkyl group. 11. Matrix according to claim 3, in which the polymer particles on which at least one oligosaccharide corresponding to a blood group A epitope is grafted, and the polymer particles on which at least one oligosaccharide corresponding to a blood group B epitope. are grafted, are mixed in a proportion of 25/75 to 75/25 (v / v), preferably about 50/50 (v / v). 12. Matrix according to one of claims 1 to 11, wherein the polymer is a crosslinked polymer. The matrix of claim 12, wherein the polymer is cellulose, and the particles are preferably porous cellulose beads. 14. Use of the matrix according to one of claims 1 to 13, in an affinity chromatography binding anti-A and / or anti-B antibodies. 15. Use of the matrix according to claim 14, for the production on an industrial scale of immunoglobulin G (IgG) for therapeutic use. A process for the preparation of an immunoglobulin (Ig) concentrate for therapeutic use, comprising obtaining an Ig composition from blood plasma, by ethanolic fractionation and / or caprylic fractionation and / or chromatographic separation, and removing the anti-A and / or antiB antibodies possibly present in the composition, by means of an affinity chromatography using the matrix according to one of claims 1 to 13.20.