EP4225329A2

EP4225329A2 - Method and device for preparing universal plasma

Info

Publication number: EP4225329A2
Application number: EP21786928.8A
Authority: EP
Inventors: Andreas Greinacher; Konstanze Aurich
Original assignee: Universitaet Greifswald; Universitaetsmedizin Greifswald UMG
Current assignee: Universitaet Greifswald; Universitaetsmedizin Greifswald UMG
Priority date: 2020-10-06
Filing date: 2021-10-05
Publication date: 2023-08-16
Also published as: US20240318138A1; CA3197820A1; WO2022073966A3; DE102020212609B3; WO2022073966A2

Abstract

A first aspect of the present invention relates to a method for preparing blood plasma depleted of anti-A antibodies and/or anti-B antibodies. Furthermore, a second aspect of the invention relates to a blood plasma depleted of anti-A antibodies and/or anti-B antibodies that is obtained or obtainable by the method of the first aspect of the invention. A third aspect of the invention relates to the use of a blood plasma depleted of anti-A antibodies and/or anti-B antibodies that is obtained or obtainable by the method of the first aspect of the invention or of a blood plasma depleted of anti-A antibodies and/or anti-B antibodies of the second aspect of the invention. Furthermore, the invention relates to a blood plasma depleted of anti-A antibodies and/or anti-B antibodies or a blood plasma depleted of anti-A antibodies and/or anti-B antibodies of the second aspect of the invention for use in a therapeutic method or an in-vivo diagnostic method or a surgical method. A fourth aspect of the invention relates to a device for preparing blood plasma depleted of anti-A antibodies and/or anti-B antibodies.

Description

Process and device for the production of universal plasma

In a first aspect, the present invention relates to a method for producing blood plasma which is depleted in anti-A antibodies and/or anti-B antibodies, comprising the steps: (a) providing blood plasma of blood group A, B or zero or a mixture of two or more blood plasmas of blood group A, B and zero; (b) providing erythrocytes of blood group A and/or erythrocytes of blood group B and/or erythrocytes of blood group AB; (c) combining the blood plasma according to (a) and the erythrocytes according to (b) to obtain a blood plasma which is depleted in anti-A antibodies and/or anti-B antibodies compared to the blood plasma according to (a) and a cell sediment; (d) Separation of the blood plasma obtained according to (c) and depleted in anti-A antibodies and/or anti-B antibodies from the cell sediment. In a second aspect, the invention further relates to a blood plasma depleted in anti-A antibodies and/or anti-B antibodies, obtained or obtainable by the method of the first aspect. According to a third aspect, the invention relates to the use of a blood plasma depleted in anti-A antibodies and/or anti-B antibodies obtained or obtainable by the method of the first aspect or a blood plasma depleted in anti-A antibodies and/or anti-B antibodies Antibodies-depleted blood plasma according to the second aspect for the production of a transfusion solution, for the production of a coagulation factor concentrate, for the production of albumin, for the production of immunoglobulin, for the production of tissue adhesive, for the production of a prothrombin complex concentrate (PPSB), for the production of a cell culture The invention also relates a blood plasma depleted in anti-A antibodies and/or anti-B antibodies, in particular a blood plasma free of anti-A antibodies and/or anti-B antibodies, obtained or obtainable by the method of the first aspect described above, or a blood plasma depleted of anti-A antibodies and/or anti-B antibodies, in particular A blood plasma free of anti-A antibodies and/or anti-B antibodies according to the second aspect for use in a therapeutic or an in vivo diagnostic or a surgical method. A fourth aspect of the invention relates to a device for the production of blood plasma which is depleted in anti-A antibodies and/or anti-B antibodies, comprising: at least one collection container, a connecting device for connecting at least a first container, wherein the first container comprises blood plasma of blood group A, B or zero or a mixture of two or more blood plasmas of blood group A, B and zero, and at least one second container, wherein the second container comprises blood group A erythrocytes, erythrocytes of blood group B and/or or has erythrocytes of blood group AB, with the collection container such that the blood plasma of the first container can be combined with the erythrocytes in the collection container.

Blood plasma must be transfused in an ABO blood group-compatible manner because the anti-A and anti-B antibodies in the plasma harm the patient if the corresponding antigen is present on his blood cells. Only plasma of blood group AB can be universally transfused to every recipient, as this contains neither A nor B antibodies. However, in the European population only 4% of donors have AB blood type. A A procedure that removes the antibodies present from plasmas of blood groups A, B and O is therefore of great importance.

Antibody-depleted plasma is already available on the market (Noddeland, H. et al. Universal solvent/detergent-treated fresh frozen plasma (Uniplas-rationale and clinical properties. Thrombosis research 107 Suppl 1, S33-37 (2002); Solheim, B.G. , Chetty, R. & Flesland, O. Indications for use and cost-effectiveness of pathogen-reduced ABO-universal plasma Current opinion in hematology 15, 612-617 (2008) However, this market is dominated by very few suppliers worldwide These suppliers use artificially produced antigens or antigen fragments from erythrocytes for antibody adsorption For example, WO 2007/100294 A1 describes a method in which a binding molecule is used which is bound to a solid phase (matrix), optionally via a spacer molecule. Polymers, polysaccharides or crosslinked polysaccharides are described as matrix materials, the matrix being used in the form of small balls or in the form of a filter lekul is selected from glycoproteins, saccharides and mucins. The antibody-depleted plasmas produced in this way, so-called "universal plasmas", are very expensive, and the production methods are also time-consuming and material-intensive.

The object of the invention was therefore to provide a method and a device with which universal plasmas can be generated quickly, easily and inexpensively.

The object was achieved with a method for producing blood plasma which is depleted in anti-A antibodies and/or anti-B antibodies, preferably free of anti-A antibodies and anti-B antibodies, comprising the steps:

(a) providing blood plasma of blood group A, B or zero or a mixture of two or more blood plasmas of blood group A, B and zero;

(b) providing erythrocytes of blood group A and/or erythrocytes of blood group B and/or erythrocytes of blood group AB;

(c) combining the blood plasma according to (a) and the erythrocytes according to (b) to obtain a blood plasma which is depleted in anti-A antibodies and/or anti-B antibodies compared to the blood plasma according to (a) (depleted blood plasma) , wherein the depleted blood plasma is preferably free of anti-A antibodies and/or anti-B antibodies, and a cell sediment;

(d) separating the blood plasma obtained according to (c) and depleted in anti-A antibodies and/or anti-B antibodies, preferably the blood plasma free of anti-A antibodies and/or anti-B antibodies, from the cell sediment.

The advantage of this method is that a simple device, as described in detail below for the fourth aspect of the invention, can be used. With this device, erythrocytes of blood group B, for example, can be added to plasma of blood group A, for example, in a closed system. As a result, the anti-B antibody is adsorbed and the plasma can be given to the patient regardless of blood group. For this purpose, erythrocytes from an erythrocyte concentrate of the blood group B can be used. Experience has shown that these erythrocyte concentrates are rarely in demand, since the proportion of patients with blood group B is rather low at 9%.

An advantage of the method and the device is that this method can be used by any blood donation service at any time with the means available to it. In this way, universal plasmas can be produced if required. Another advantage is the manageable costs.

“Anti-A antibodies” means antibodies against blood group A, in particular against erythrocytes of blood group A, “anti-B antibodies” means antibodies against blood group B, in particular against erythrocytes of blood group B. Anti-A antibodies preferably include at least Anti-A immunoglobulin M (IgM) and/or anti-A immunoglobulin G (IgG), anti-B antibodies preferably include at least anti-B immunoglobulin M (IgM) and/or anti-B immunoglobulin G (IgG). "Free of anti-A antibodies and/or anti-B antibodies means that the blood plasma contains only low levels of anti-A antibodies and/or anti-B antibodies, where "low levels" has a maximum titer of 1 :4 means anti-A and/or anti-B antibodies. Those skilled in the art know that antibody levels are not given in absolute units because there is no standard for this. In addition, the reaction of antibodies differs greatly depending on how strong their binding strength is. For this reason, antibody titer levels, i.e. dilution levels, are specified, since these indicate the dilution in which the antibodies still trigger agglutination of erythrocytes, regardless of the amount and binding strength of the antibodies. Dilution takes place with isotonic saline solution (0.9% by weight aqueous NaCl solution). The titer is the dilution level at which the regular antibodies against erythrocyte A and B antigens contained in the plasma just react with the same amount of test erythrocytes. The reciprocal value of the last plasma dilution in which agglutinates are still visible is given as the titer of an antibody. 1:4 means that the plasma only had to be diluted 1:4 in order to still be able to visually recognize agglutinates; in the next dilution (1:8) these can no longer be seen. The dilution is volume-based, i.e. a titre of 1:4 means that one volume unit of plasma is mixed with three times the volume of the diluent, in particular isotonic saline solution. The presence of agglutinates is determined using methods known to those skilled in the art, such as the tube test or using a gel card (plastic card with microtiter columns, principle of size exclusion chromatography), the latter being preferred because of the higher sensitivity. The visual determination is based on the possibly agglutinated erythrocytes which lie on the gel surface after centrifugation (positive result) or the non-agglutinated erythrocytes which have migrated through the gel to the bottom of the tube (negative result).

"Cell sediment" means erythrocytes that have bound anti-A and/or anti-B antibodies, i.e. a reaction product of antibody and erythrocyte that is insoluble in blood plasma and carries the corresponding antigen and the antibodies bound to it.

Blood plasma which is depleted in anti-A antibodies and/or anti-B antibodies, preferably blood plasma which is free of anti-A antibodies and anti-B antibodies, ie which can be universally transfused to any recipient is also referred to as "universal plasma".

In one embodiment of the method, in (a) blood plasma of blood group A is provided; in (b) blood group B erythrocytes are provided; and in (c) a blood plasma is obtained which is depleted in anti-B antibodies. In an alternative embodiment of the method, blood plasma of blood group B is provided in (a); in (b) erythrocytes of blood group A are provided; and in (c) a blood plasma depleted in anti-A antibodies is obtained. In an alternative embodiment of the method in (a) blood plasma of blood group zero is provided; in (b) blood group A erythrocytes, blood group B erythrocytes and/or blood group AB erythrocytes are provided; and in (c) a blood plasma depleted in anti-A antibodies and anti-B antibodies is obtained. In an alternative embodiment of the method in (a) blood plasma of blood group A, B or zero is provided; in (b) erythrocytes of blood group AB are provided; and in (c) a blood plasma depleted in anti-A antibodies and anti-B antibodies is obtained.

Blood plasma is the liquid and almost cell-free part of the blood obtained or obtainable by separating the blood cells (erythrocytes, thrombocytes and leukocytes) from a non-coagulable whole blood sample by suitable measures, for example by plasmapheresis, sedimentation, centrifugation and/or size exclusion filtration. Due to the separation, blood plasma contains a very small proportion of residual cells, for example only leukocytes in a concentration of < 0.1 x 10 ⁹ /l, thrombocytes in a concentration of < 50 x 10 ⁹ /l, erythrocytes in a concentration of < 6 x 10 ⁹ /l (hemotherapy guideline, complete amendment 2017), but - in contrast to blood serum - still all coagulation factors. The whole blood sample is made "non-coagulable" by adding anticoagulants, preferably selected from the group consisting of sodium citrate, EDTA (ethylenediaminetetraacetate), heparin and mixtures of two or more of these substances. After at least the erythrocytes have been separated from the whole blood sample, the blood plasma obtained is optionally treated further. The blood plasma is preferably not enriched when the blood cells are separated from the whole blood, ie the blood plasma has at least 90% the same concentration of anti-A antibodies or anti-B antibodies as the whole blood on which it is based.

In a preferred embodiment of the method, the blood plasma according to (a) is selected from the group consisting of fresh plasma, frozen fresh plasma, quarantine plasma, apheresis (plasmapheresis) plasma, irradiated plasma, filtered plasma, leukocyte-depleted plasma, pathogen-reduced, preferably pathogen-inactivated plasma and mixed forms of these plasma types. Mixed forms of these plasma types are known to the person skilled in the art and mean, for example, fresh apheresis plasma which is leucocyte-depleted and is or was frozen. An example to be mentioned here is frozen leukocyte-depleted aphresis fresh plasma, which is available for example under the approval/reg no. (AMG76): PEI.H.01187.01 .1 is registered Pathogen reduction or pathogen inactivation of blood products serves the purpose of eliminating a large part of the clinically relevant viruses, Effectively reduce or inactivate bacteria and protozoa. With the help of pathogen reduction or pathogen inactivation, any leukocytes that may have remained in the blood plasma are also reduced or inactivated. Processes for pathogen reduction or pathogen inactivation are known to the person skilled in the art, examples which may be mentioned are the Intercept process, the Mirasol process, the Theraflex MB and the Theraflex UVC process.

In a preferred embodiment of the method, the blood plasma according to (a) contains one or more substances selected from the group consisting of (DNA, RNA) intercalating substances, preferably amotosalen (UVA irradiation), riboflavin (UVB irradiation), and methylene blue ( irradiation with visible light). Alternatively or additionally, the blood plasma according to (a) can be irradiated with UVC light or has been irradiated without any of the substances mentioned above having been added. In a preferred embodiment of the method, the blood plasma according to (a) contains one or more anticoagulants, preferably selected from the group consisting of sodium citrate, EDTA, heparin and mixtures of two or more of these substances.

Erythrocytes, in particular erythrocyte concentrates (RBC) are obtained or obtainable from whole blood, as already described above for blood plasma. An erythrocyte concentrate is preferably enriched when it is separated from the whole blood, i.e. the erythrocyte concentrate has a higher concentration of erythrocytes than the whole blood on which it is based, the specification of the erythrocyte concentrate according to the hemotherapy guideline means a hematocrit in the range of 0.5-0.7 liters /liter (whole blood 0.3-0.5 liters/liter) and hemoglobin > 40 g/unit (unit: approx. 250 ml) (whole blood approx. 35 g/250 ml). The separation of the erythrocytes from the whole blood is usually carried out gravimetrically, preferably by centrifugation, with the residue containing the erythrocytes being taken up again in additive solution, as a result of which the erythrocyte concentrate is obtained.

Due to the replacement of most of the plasma in the erythrocyte concentrate with the additive solution, the plasma content of the erythrocyte concentrate is reduced to approx. 15 ml in approx. 300 ml. An "additive solution" is, as known to those skilled in the art, a nutrient solution such as SAG-M (sodium adenine glucose mannitol lcfc//?/i//ösr//7ß), PAGGS-M (phosphates, adenine, guanosine, glucose, sodium (sodium), mannitol) or ADSOL (adenine, dextrose, sodium (sodium), mannitol). Accordingly, 15 ml erythrocyte concentrate still contain approx. 0.75 ml plasma. If these 15 ml of red cell concentrate are added to 1 liter of plasma to adsorb the isoagglutinins, the amount of 0.75 ml of plasma is negligible.

In a preferred embodiment of the method, the erythrocytes of blood group A, erythrocytes of blood group B and/or erythrocytes of blood group AB according to (b) are provided in the form of an erythrocyte concentrate which has been obtained from whole blood, in particular by means of centrifugation and/or erythrocyte apheresis, the Erythrocyte concentrate preferably has a cell count in the range from 10 ¹⁰ to 10 ¹⁴ erythrocyte cells/liter, more preferably in the range from 10 ¹¹ to 10 ¹³ erythrocyte cells/liter, more preferably in the range from 1×10 ¹² to 1×10 ¹³ erythrocyte cells/liter, more preferably in the range from 3×10 ¹² to 9×10 ¹² erythrocyte cells/liter, more preferably in the range from 4×10 ¹² to 8.5×10 ¹² erythrocyte cells /liter, more preferably in the range from 5 x 10 ¹² to 8.2 x 10 ¹² erythrocyte cells/liter, more preferably in the range from 5.5 x 10 ¹² to 8 x 10 ¹² erythrocyte cells/liter, more preferably in the range of 5, 96 x 10 ¹² to 7.76 x 10 ¹² erythrocyte cells/liter.

In a preferred embodiment of the method, the erythrocytes, preferably the erythrocyte concentrate, are selected from the group consisting of apheresis erythrocyte concentrate, irradiated erythrocyte concentrate, filtered erythrocyte concentrate, leukocyte-depleted erythrocyte concentrate, pathogen-reduced, preferably pathogen-inactivated erythrocyte concentrate, washed erythrocyte concentrate and mixed forms of these erythrocyte concentrates. Mixed forms of these erythrocyte concentrates are known to the person skilled in the art, for example leukocyte-depleted, irradiated erythrocyte concentrate, as is available, for example, under the approval/reg. no. (AMG76): PEI.H.02806.01.1 is registered.

In a preferred embodiment of the method, the erythrocytes, preferably the erythrocyte concentrate, contain one or more anticoagulants, preferably selected from the group consisting of sodium citrate, EDTA, heparin, ACD-A solution and mixtures of two or more of these substances. In a preferred embodiment of the method, the erythrocytes, preferably the erythrocyte concentrate, contain one or more additives selected from the group consisting of citric acid, sodium citrate, glucose, dextrose, sodium dihydrogen phosphate, sodium monohydrogen phosphate, sodium phosphate, mannitol, adenine, guanosine, inosine, sodium chloride, and Mixtures of two or more of these additives.

Preference is given to the erythrocytes according to (b), in particular erythrocyte concentrate, and blood plasma according to (a) in a volume ratio of erythrocyte concentrate: blood plasma in the range from 1:100 to 30:100, preferably in the range from 2:100 to 25:100, more preferably im Range from 3:100 to 20:100, more preferably in the range from 4:100 to 19:100, provided or brought together according to (c). If erythrocyte suspensions or plasma are concentrated or diluted, the ratio between erythrocytes and plasma is adjusted in such a way that more antigens (A and/or B antigens) are present on the erythrocytes than soluble corresponding antibodies in the plasma.

In a preferred embodiment of the method, the erythrocytes of blood group B according to (b), in particular erythrocyte concentrate of blood group B and blood plasma of blood group A according to (a) in a volume ratio of erythrocyte concentrate: blood plasma in the range from 2:100 to 6:100, are preferred in the range from 3:100 to 5:100, more preferably in the range from 3.5:100 to 4.5:100, more preferably in the ratio of 4:100, provided or combined according to (c). In a preferred embodiment of the method, erythrocytes of blood group A according to (b), in particular erythrocyte concentrate of blood group A, and blood plasma of blood group B according to (a) in a volume ratio of erythrocyte concentrate: blood plasma in the range from 2:100 to 6:100 are preferred in the range from 3:100 to 5:100, more preferably in the range from 3.5:100 to 4.5:100, more preferably in the ratio of 4:100, provided or combined according to (c).

In a preferred embodiment of the method, erythrocytes of blood group A and/or erythrocytes of blood group B according to (b), preferably erythrocytes of blood group A and erythrocytes of blood group B, in particular erythrocyte concentrate of blood group A and erythrocyte concentrate of blood group B, and blood plasma of Blood group zero according to (a) in a volume ratio of erythrocyte concentrate (A, B and/or AB): blood plasma in the range from 10:100 to 30:100, preferably in the range from 12:100 to 25:100, more preferably in the range of 14 : 100 to 20:100, more preferably in the range from 17:100 to 19:100, provided or combined according to (c).

In a preferred embodiment of the method, erythrocytes of blood group AB according to (b), in particular erythrocyte concentrate of blood group AB, and blood plasma of blood group A, B or zero according to (a) in a volume ratio of erythrocyte concentrate (AB): blood plasma in the range of 10:100 to 30:100, preferably in the range from 12:100 to 25:100, more preferably in the range from 14:100 to 20:100, more preferably in the range from 17:100 to 19:100, provided or according to (c) merged.

In a preferred embodiment of the method, step (c) comprises:

(c.1) combining the blood plasma according to (a) and the erythrocytes according to (b) to obtain a mixture comprising blood plasma and erythrocytes;

(c.2) Incubation of the mixture obtained according to (c.1.) for at least 10 minutes, preferably for a period of time in the range from 10 minutes to 48 hours, more preferably in the range from 30 minutes to 24 hours, more preferably in the range of 1 hour to 5 hours, more preferably in the range from 1.5 hours to 3 hours;

(c.3) Separation of blood plasma and cell sediment depleted in anti-A antibodies and/or anti-B antibodies.

(c.2) preferably takes place at a temperature in the range from 2 to 40.degree. C., preferably in the range from 15 to 30.degree. C., more preferably in the range from 20 to 25.degree. Steps (c.1) and/or (c.2) preferably take place with active mixing, preferably by a method selected from the group consisting of pivoting, rotating, shaking, stirring and mixed forms of two or more of these methods, of blood plasma and erythrocytes. Without active mixing, there is already a sufficient reaction of anti-A antibodies and/or anti-B antibodies with the erythrocytes, in particular the erythrocytes and the anti-A antibodies and/or anti-B antibodies already react for the most part, ie preferentially more than 50%, more preferably 50 to 100%, more preferably 60 to 100%, more preferably 80 to 100%, more preferably 90 to 100%, with each other, so that an anti-A antibodies and /or anti B antibodies depleted blood plasma and a reaction product of erythrocytes and anti-A antibodies and/or anti-B antibodies (cell sediment) is formed.

In a preferred embodiment of the method, the separation according to (d) takes place by means of a method selected from the group consisting of centrifugation, decanting, filtration, sedimentation and mixtures of two or more of these methods.

In a preferred embodiment, the method further comprises:

Examination of the blood plasma obtained according to (d) and depleted in anti-A antibodies and/or anti-B antibodies for agglutination, preferably by adding erythrocytes of blood groups A, B or AB and optionally anti-human globulin serum (Coombs- serum) to a sample of the blood plasma obtained according to (d) and depleted in anti-A antibodies and/or anti-B antibodies, with an absence of an agglutinate, preferably determined visually, indicating that the blood plasma is free of anti-A antibodies and/or anti-B antibodies.

The method for producing blood plasma which is depleted in anti-A antibodies and/or anti-B antibodies, preferably free of anti-A antibodies and anti-B antibodies, is preferably an in vitro method. The blood plasma or the whole blood sample preferably originates from a mammal, more preferably from a human.

Second aspect - blood plasma depleted in anti-A antibodies and/or anti-B antibodies

In a second aspect, the invention relates to a blood plasma depleted in anti-A antibodies and/or anti-B antibodies, in particular blood plasma free of anti-A antibodies and/or anti-B antibodies, obtained or obtainable by the method of the first aspects as described above.

Third aspect - use

A third aspect of the invention relates to the use of a blood plasma depleted in anti-A antibodies and/or anti-B antibodies, in particular a blood plasma free of anti-A antibodies and/or anti-B antibodies, obtained or obtainable according to Method of the first aspect described above, or a blood plasma depleted in anti-A antibodies and/or anti-B antibodies, in particular a blood plasma free of anti-A antibodies and/or anti-B antibodies, according to the second Aspect for producing a transfusion solution, for producing a coagulation factor concentrate, for producing albumin, for producing immunoglobulin, for producing tissue adhesive, for producing a prothrombin complex concentrate (PPSB), for producing a cell culture, preferably a stem cell culture, with all the productions mentioned preferably ex i//i/o or in vitro. The invention also relates to a blood plasma depleted in anti-A antibodies and/or anti-B antibodies, in particular a blood plasma free of anti-A antibodies and/or anti-B antibodies, obtained or obtainable by the process described above first aspect, or a blood plasma depleted in anti-A antibodies and/or anti-B antibodies, in particular a blood plasma free of anti-A antibodies and/or anti-B antibodies according to the second aspect for use in a therapeutic or an in vivo diagnostic or a surgical method, preferably for use in transfusion medicine for transfusion or prior to ABO dissimilar organ transplantation or stem cell transplantation. In the case of an ABO unequal organ transplantation, anti-A antibodies or anti-B antibodies can damage a transplanted organ, in particular an organ selected from the group consisting of kidney, liver, heart and stem cell, if the transplanted organ comes from a donor of the blood group A or blood group B and the recipient has anti-A antibodies and/or anti-B antibodies in his blood. Before an organ transplant, anti-A antibodies and/or anti-B antibodies are already removed from the blood of a transplant recipient using various methods.

Fourth Aspect - Device

According to a fourth aspect, the invention relates to a device for producing blood plasma which is depleted in anti-A antibodies and/or anti-B antibodies, preferably free of anti-A antibodies and anti-B antibodies, comprising: at least one collection container, a connecting device designed to connect at least one first container, the first container having blood plasma of blood group A, B or zero or a mixture of two or more blood plasmas of blood group A, B and zero, and at least one second Container, wherein the second container has erythrocytes of blood group A, erythrocytes of blood group B and/or erythrocytes of blood group AB, with the collection container such that the blood plasma of the first container can be combined with the erythrocytes of the second container in the collection container.

The device is suitable for depleting the blood plasma of anti-A antibodies and/or anti-B antibodies in such a way that the blood plasma essentially contains no anti-A antibodies and no anti-B antibodies. The expression "essentially none" refers to a technical realization in which anti-A antibodies and no anti-B antibodies are only present in the finished blood plasma in technically unavoidable quantities. "Free of anti-A antibodies and/or anti-B antibodies means that the blood plasma contains only low levels of anti-A antibodies and/or anti-B antibodies, where "low levels" has a maximum titer of 1 :4 means anti-A and/or anti-B antibodies. Details in this regard are described above for the first aspect; these apply accordingly to the device of the fourth aspect. As already described above for the first aspect, the erythrocytes of the second container are preferably present as erythrocyte concentrates (ERC). Details in this regard are described above for the first aspect; these apply accordingly to the device of the fourth aspect. In a preferred embodiment of the device, the collection container is designed for mixing the blood plasma from the first container with the erythrocytes from the second container.

In a preferred embodiment of the device, it comprises a mixing device, the mixing device being designed for actively mixing the blood plasma from the first container with the erythrocytes from the second container in the collection container.

In a preferred embodiment of the device, the mixing device is designed to mix the blood plasma of the first container with the erythrocytes of the second container in the collection container by stirring, rotating, pivoting and/or moving the collection container.

In a preferred embodiment of the device, the connecting device has at least one channel, one pipe and/or one hose. The channel, tube and/or hose is preferably made of a material that is approved for medical-technical purposes.

In a preferred embodiment of the device, it comprises a plurality of channels, tubes and/or hoses, the channels, tubes and/or hoses being at least partially connectable or connected to one another.

In a preferred embodiment of the device, it further comprises a separating device, wherein the separating device is designed for separating blood plasma depleted in anti-A antibodies and/or anti-B antibodies from cell sediment. The separating device is preferably at least one separating device selected from the group consisting of: separator, centrifuge, decanter, filter and settling tank.

In a preferred embodiment of the device, the connection device is designed to feed the blood plasma from the first container and the erythrocytes from the second container into the collection container by means of gravity or by means of a pump device.

In a preferred embodiment of the device, the connecting device is designed to connect the first container and the second container to the collection container by means of a screw connection, a clamped connection, a welded connection (sterile docking) or a plug-in connection.

In a preferred embodiment of the device, the connection device is also designed to supply the depleted blood plasma to the first container and/or the second container.

In a preferred embodiment, the device further comprises a pump device, wherein the connection device for supplying the depleted blood plasma to the first container and/or the second container is formed by means of the pump device. The pumping device is preferably a manually operable pumping device or an electric pumping device.

In a preferred embodiment of the device, the first container, the second container and/or the collection container is at least partially made of plastic. In a preferred embodiment of the device, the first container, the second container and/or the collection container are each independently a bag or a bottle.

The present invention is illustrated in more detail by the following embodiments and combinations of embodiments, which result from the corresponding back references and references. It should be noted here that in all cases where a range of embodiments is mentioned, for example in the context of an expression such as "method according to any one of embodiments (1) to (4)", each embodiment in this range is explicitly disclosed to the person skilled in the art is to be considered, i.e. this expression is to be understood by the person skilled in the art as synonymous with 'process according to one (each) of embodiments (1), (2), (3) and (4)'. Furthermore, it is explicitly noted that the following set of embodiments is not the set of claims, which determines the scope, but rather represents an appropriate structured part of the description, which is directed to general and preferred aspects of the invention.

In one embodiment (1), the invention relates to a method for producing blood plasma which is depleted in anti-A antibodies and/or anti-B antibodies, preferably free of anti-A antibodies and anti-B antibodies, including the steps:

A preferred embodiment (2), which substantiates embodiment (1), relates to the method in which (a) blood plasma of blood group A is provided; in (b) blood group B erythrocytes are provided; and in (c) obtaining a blood plasma depleted in anti-B antibodies; or wherein in (a) blood plasma of blood group B is provided; in (b) erythrocytes of blood group A are provided; and in (c) obtaining a blood plasma which is depleted in anti-A antibodies, or wherein in (a) blood plasma of blood group zero is provided; in (b) blood group A erythrocytes, blood group B erythrocytes and/or blood group AB erythrocytes are provided; and in (c) obtaining a blood plasma which is depleted in anti-A antibodies and in anti-B antibodies, or wherein in (a) blood plasma of blood group A, B or zero is provided; in (b) erythrocytes of blood group AB are provided; and in (c) a blood plasma is obtained which is depleted in anti-A antibodies and in anti-B antibodies.

A preferred embodiment (3), which specifies embodiment (1) or (2), relates to the method, wherein the blood plasma according to (a) is selected from the group consisting of fresh plasma, frozen fresh plasma, quarantine plasma, apheresis (plasmapheresis)- Plasma, irradiated plasma, filtered plasma, leukocyte-depleted plasma, pathogen-reduced, preferably pathogen-inactivated, plasma and mixed forms of these plasma types.

A preferred embodiment (4), which specifies one of the embodiments (1) to (3), relates to the method in which the blood plasma according to (a) contains one or more substances selected from the group consisting of (DNA, RNA) intercalating substances , preferably amotosalen (UVA irradiation), riboflavin (UVB irradiation), and methylene blue (irradiation with visible light) and/or with UVC light.

A preferred embodiment (5), which specifies one of the embodiments (1) to (4), relates to the method, wherein the blood plasma according to (a) contains one or more anticoagulants, preferably selected from the group consisting of sodium citrate, EDTA, heparin and Mixtures of two or more of these substances.

A preferred embodiment (6), which specifies one of the embodiments (1) to (5), relates to the method, wherein the erythrocytes of blood group A, erythrocytes of blood group B and/or erythrocytes of blood group AB according to (b) in the form of an erythrocyte concentrate be provided, which was obtained from whole blood, in particular by means of centrifugation and/or erythrocyte apheresis, the erythrocyte concentrate preferably having a cell count in the range from 10 ¹⁰ to 10 ¹⁴ erythrocyte cells/liter, more preferably in the range from 10 ¹¹ to 10 ¹³ erythrocyte cells/liter preferably in the range from 1×10 ¹² to 1×10 ¹³ erythrocyte cells/liter, more preferably in the range from 3×10 ¹² to 9×10 ¹² erythrocyte cells/liter, more preferably in the range from 4×10 ¹² to 8.5×10 ¹² erythrocyte cells/ liters, more preferably in the range from 5 x 10 ¹² to 8.2 x 10 ¹² erythrocyte cells/liter, more preferably in the range from 5.5 x 10 ¹² to 8 x 10 ¹² erythrocyte cells/litre, more preferably in the range of 5.96 x 10 ¹² to 7.76 x 10 ¹² erythrocyte cells/litre.

A preferred embodiment (7), which specifies one of the embodiments (1) to (6), relates to the method in which the erythrocytes, preferably the erythrocyte concentrate, is selected from the group consisting of apheresis erythrocyte concentrate, irradiated erythrocyte concentrate, filtered erythrocyte concentrate, leukocytes -depleted erythrocyte concentrate, pathogen-reduced, preferably pathogen-inactivated erythrocyte concentrate, washed erythrocyte concentrate and mixed forms of these erythrocyte concentrates.

A preferred embodiment (8), which specifies one of the embodiments (1) to (7), relates to the method in which the erythrocytes, preferably the erythrocyte concentrate, contain one or more anticoagulants, preferably selected from the group consisting of sodium citrate, EDTA, heparin , ACD-A solution and mixtures of two or more of these substances.

A preferred embodiment (9), which specifies one of the embodiments (1) to (8), relates to the method in which i the erythrocytes, preferably the erythrocyte concentrate, one or more additives selected from the group consisting of citric acid, sodium citrate, glucose, dextrose , sodium dihydrogen phosphate, disodium phosphate, sodium phosphate, mannitol, adenine, guanosine, inosine, sodium chloride, and mixtures of two or more of these additives.

A preferred embodiment (10), which specifies one of the embodiments (1) to (9), relates to the method, wherein erythrocytes according to (b), in particular erythrocyte concentrate, and blood plasma according to (a) in a volume ratio of erythrocyte concentrate: blood plasma in the range of 1 : 100 to 30:100, preferably in the range from 2:100 to 25:100, more preferably in the range from 3:100 to 20:100, more preferably in the range from 4:100 to 19:100, provided or according to ( c) be merged.

A preferred embodiment (11), which specifies one of the embodiments (1) to (10), relates to the method, wherein erythrocytes of blood group B according to (b), in particular erythrocyte concentrate of blood group B and blood plasma of blood group A according to (a) in one Volume ratio of erythrocyte concentrate: blood plasma in the range from 2:100 to 6:100, preferably in the range from 3:100 to 5:100, more preferably in the range from 3.5:100 to 4.5:100, more preferably in the ratio of 4 : 100, are provided or merged according to (c).

A preferred embodiment (12), which specifies one of the embodiments (1) to (11), relates to the method, wherein erythrocytes of blood group A according to (b), in particular erythrocyte concentrate of blood group A, and blood plasma of blood group B according to (a) in a volume ratio of erythrocyte concentrate : blood plasma in the range of 2 : 100 to 6:100, preferably in the range of 3:100 to 5:100, more preferably in the range of

3.5:100 to 4.5:100, more preferably in a ratio of 4:100, provided or brought together according to (c).

A preferred embodiment (13), which specifies one of the embodiments (1) to (12), relates to the method, wherein erythrocytes of blood group A and / or erythrocytes of blood group B according to (b), preferably erythrocytes of blood group A and erythrocytes of blood group B, in particular erythrocyte concentrate of blood group A and erythrocyte concentrate of blood group B, and blood plasma of blood group zero according to (a) in a volume ratio of erythrocyte concentrate: blood plasma in the range from 10:100 to 30:100, preferably in the range from 12:100 to 25:100 , more preferably in the range from 14:100 to 20:100, more preferably in the range from 17:100 to 19:100, provided or brought together according to (c).

A preferred embodiment (14), which specifies one of the embodiments (1) to (13), relates to the method in which erythrocytes of blood group AB according to (b), in particular erythrocyte concentrate of blood group AB, and blood plasma of blood group A, B or zero according to (a) in a volume ratio of erythrocyte concentrate (AB): blood plasma in the range from 10:100 to 30:100, preferably in the range from 12:100 to 25:100, more preferably in the range from 14:100 to 20:100, more preferably in the range from 17:100 to 19:100, or combined according to (c).

A preferred embodiment (15), which specifies one of the embodiments (1) to (14), relates to the method, wherein step (c) comprises:

A preferred embodiment (16), which specifies embodiment (15), relates to the process in which (c.2) is carried out at a temperature in the range from 2 to 40° C., preferably in the range from 15 to 30° C., more preferably in the range from 20 to 25 °C.

A preferred embodiment (17), which specifies embodiment (15) or (16), relates to the process in which (c.1) and/or (c.2) is carried out with active mixing, preferably by a process selected from the group consisting of Pivoting, rotating, shaking, stirring and mixed forms of two or more of these methods, of blood plasma and erythrocytes. A preferred embodiment (18), which specifies one of the embodiments (1) to (17), relates to the process in which the separation according to (d) takes place by means of a method selected from the group consisting of centrifugation, decantation, filtration, sedimentation and Mixtures of two or more of these methods.

A preferred embodiment (19), which specifies one of the embodiments (1) to (18), relates to the method, which is an in vitro method.

A preferred embodiment (20), which specifies one of the embodiments (1) to (19), relates to the method in which the blood plasma or the whole blood sample originates from a mammal, preferably from a human.

A preferred embodiment (21), which specifies one of the embodiments (1) to (20), relates to the method, further comprising:

One embodiment (22) of the invention relates to a blood plasma depleted in anti-A antibodies and/or anti-B antibodies, in particular blood plasma free of anti-A antibodies and/or anti-B antibodies, obtained or obtainable by the method according to any of the embodiments (1) to (21).

An embodiment (23) of the invention relates to the use of a blood plasma depleted in anti-A antibodies and/or anti-B antibodies, in particular a blood plasma free of anti-A antibodies and/or anti-B antibodies, obtained or obtainable according to the method according to one of embodiments (1) to (21) or a blood plasma depleted in anti-A antibodies and/or anti-B antibodies, in particular one free of anti-A antibodies and/or anti-B antibodies Blood plasma, according to embodiment (22) for the production of a transfusion solution, for the production of a coagulation factor concentrate, for the production of albumin, for the production of immunoglobulin, for the production of tissue adhesive, for the production of a prothrombin complex concentrate (PPSB), for the production of a cell culture, preferably one stem cell culture.

One embodiment (24) of the invention relates to a blood plasma depleted in anti-A antibodies and/or anti-B antibodies, in particular blood plasma free of anti-A antibodies and/or anti-B antibodies, obtained or obtainable by the method according to one of embodiments (1) to (21), or blood plasma depleted in anti-A antibodies and/or anti-B antibodies, in particular anti-A antibodies and/or anti-B antibodies Free blood plasma according to embodiment (22) for use in a therapeutic or an in vivo diagnostic or a surgical method, preferably for use in transfusion medicine for transfusion or before an ABO dissimilar organ transplantation or stem cell transplantation.

An embodiment (25) of the invention relates to a device for the production of blood plasma which is depleted in anti-A antibodies and/or anti-B antibodies, preferably free of anti-A antibodies and anti-B antibodies, comprising: at least one collection container, a connecting device designed to connect at least one first container, the first container having blood plasma of blood group A, B or zero or a mixture of two or more blood plasmas of blood group A, B and zero, and at least a second container, the second container having erythrocytes of blood group A, erythrocytes of blood group B and/or erythrocytes of blood group AB, with the collection container such that the blood plasma of the first container can be combined with the erythrocytes of the second container in the collection container.

A preferred embodiment (26), which substantiates embodiment (25), relates to the device, wherein the collection container is designed for mixing the blood plasma of the first container with the erythrocytes of the second container.

A preferred embodiment (27), which specifies embodiment (25) or (26), relates to the device, further comprising a mixing device, wherein the mixing device is designed to actively mix the blood plasma of the first container with the erythrocytes of the second container in the collection container.

A preferred embodiment (28), which specifies embodiment (27), relates to the device, wherein the mixing device is designed to mix the blood plasma of the first container with the erythrocytes of the second container in the collection container by stirring, rotating, pivoting and/or moving the collection container is.

A preferred embodiment (29), which specifies one of the embodiments (25) to (28), relates to the device, wherein the connecting device has at least one channel, one tube and/or one hose.

A preferred embodiment (30), which substantiates embodiment (29), relates to the device, wherein the channel, the pipe and/or hose is made of a material that is approved for medical-technical purposes.

A preferred embodiment (31), which specifies embodiment (29) or (30), relates to the device further comprising a plurality of channels, tubes and/or hoses, the channels, tubes and/or hoses being at least partially connectable or connected to one another. A preferred embodiment (32), which specifies one of the embodiments (25) to (31), relates to the device, further comprising a separation device, the separation device for separating anti-A antibodies and/or anti-B antibodies being depleted Blood plasma is formed from cell sediment.

A preferred embodiment (33), which specifies embodiment (32), relates to the device, wherein the separating device is at least one separating device selected from the group consisting of: separator, centrifuge, decanter, filter and settling tank.

A preferred embodiment (34), which substantiates one of the embodiments (25) to (33), relates to the device, wherein the connecting device for feeding the blood plasma of the first container and the erythrocytes of the second container into the collection container is designed by gravity or by means of a pump device is.

A preferred embodiment (35), which specifies one of the embodiments (25) to (34), relates to the device, wherein the connecting device for connecting the first container and the second container to the collection container by means of a screw connection, clamp connection, welded connection (sterile docking) or Connector is formed.

A preferred embodiment (36), which substantiates one of the embodiments (25) to (35), relates to the device, wherein the connection device is also designed to supply the depleted blood plasma to the first container and/or the second container.

A preferred embodiment (37), which specifies embodiment (36), relates to the device, further comprising a pump device, wherein the connection device is designed to supply the depleted blood plasma to the first container and/or the second container by means of the pump device.

A preferred embodiment (38), which substantiates embodiment (39), relates to the device, wherein the pumping device is a manually operable pumping device or an electric pumping device.

A preferred embodiment (39), which specifies one of the embodiments (25) to (38), relates to the device, wherein the first container, the second container and/or the collecting container is at least partially made of plastic.

A preferred embodiment (40), which specifies one of the embodiments (25) to (39), relates to the device, wherein the first container, the second container and/or the collection container are each independently a bag or a bottle. Furthermore, it is explicitly noted that the preceding set of embodiments is not the set of claims that determine the scope, but rather constitutes a suitable structured part of the description directed to general and preferred aspects of the invention.

Description of the illustrations

Fig. 1 shows a graphic plot of the volume of red blood cell concentrate of blood group B necessary for the complete depletion of anti-B antibodies in plasma of blood group A (n=15), with the volume used in each case being indicated on the Y-axis erythrocyte concentrate in milliliters and the isoagglutin specificities IgM or IgG are shown on the X-axis.

Fig. 2 shows a graph of the volume of blood group B red cell concentrate required for the complete depletion of anti-B IgG antibodies in blood group A plasma at various incubation times (n=5), with on the Y-axis the volume of erythrocyte concentrate used in each case is shown in milliliters and the incubation time in hours is shown on the X-axis.

Fig. 3 shows an embodiment of the device for the production of blood plasma which is depleted in anti-A antibodies and/or anti-B antibodies.

Figure 4 shows a photograph of an embodiment of the device with plasma bags containing plasma, bag containing packed red blood cells and empty collection bags

The invention is explained below using examples, without being restricted thereto.

examples

Plasma unit: fresh frozen plasma from whole blood of blood group A

Red blood cell concentrate: blood group B, cell count in the range from 5.96 x 10 ¹² to 7.76 x 10 ¹²

RBC cells/liter (standard deviation 0.55 x10 ¹² RBC cells/liter, n=17)

Example 1 Determination of the volume of erythrocyte concentrate

First, it was determined how much volume of erythrocyte concentrate of blood group B is required for the adsorption of anti-B antibodies of a plasma unit of blood group A. A plasma unit (300 ml) of blood group A was treated with different volumes between zero ml (reference sample) and 40 ml of erythrocyte concentrate of blood group B at room temperature (20-24° C.) for 1-5 hours. Thereafter, the agglutinates formed from erythrocytes and isoagglutinins were removed by means of centrifugation (e.g. 4000 g, 10 min) and subsequent separation manually by pressing.

The antibody titer for anti-B-IgM and anti-B-IgG was then determined as follows:

1. Preparation of a volume-based dilution series (1:1, 1:2, 1:4, 1:8, 1:16, 1:32) of the plasma, diluted with 0.9% by weight aqueous NaCl solution (isotonic saline solution )

2. Preparation of test erythrocyte suspensions A1, B and 0: 10 μl erythrocyte sediment + 1 ml ID Diluent 2 (Biorad)

3. 50 μl each of the appropriate erythrocyte suspension were placed in the reaction chambers of a gel card (neutral and AH card for the determination of IgM or IgG antibodies; Biorad).

4. 50 μl each of plasma and plasma were added

5. 15 min incubation at room temperature

6. Centrifugation in a gel card centrifuge (85 g, 10 min)

7. Visually assess and document the reaction

The results are shown graphically in Figure 1. As can be seen from Figure 1, an average of 12 ml of red blood cell concentrate was required to remove anti-B antibodies, in particular anti-B IgM and anti-B IgG, from blood group A plasma.

Example 2 Determination of the incubation time

Furthermore, the incubation time was determined, which is necessary to adsorb the anti-B antibodies to the added erythrocytes.

For this purpose, a plasma unit (300 ml) of blood group A was mixed with different volumes between zero ml (comparative sample) and 30 ml of erythrocyte concentrate of blood group B. The samples were then left to stand at room temperature (20-24°C) for a period of 1 to 5 hours.

The antibody titer with regard to anti-B-IgG was then determined as indicated in example 1.

The results are shown graphically in Figure 2. Based on the results, 2 hours was determined as the optimal incubation time.

Example 3 Configuration of an apparatus for preparing blood plasma

A device for the production of blood plasma has been developed with which anti-B antibodies are removed or can be removed from plasma of blood group A. The device comprises at least one collection container S, a connecting device W, a first container B1 and at least one second container B2. The first and second containers B1, B2 are connected to the collection container S via the connecting device W in such a way that blood plasma in the first container B1 can be brought together in the collection container S with the erythrocytes in the second container B2. The collection container S is designed to mix the blood plasma from the first container B1 with the erythrocytes from the second container B2.

An embodiment of the device is shown schematically in FIG. 3, in which an antibody depletion could be carried out simultaneously for 3 plasma units. The first container B1, second container B2 and collection container S were designed as bags, the connecting device W was designed as a tube system with a suitable number of connection points, 4 in this case. This device was also referred to as a blood bag system.

The two empty collection containers were two empty 500 ml bags S1, S2. These were welded to the connection points of the tube system via sterile docking and 3 bags with plasma B1-1, B1-2, B1-3, each with 300 ml blood plasma of blood group A, and a bag B2, which contained 40 ml erythrocyte concentrate of blood group B , connected Fig. 4 shows a photograph of the structure with plasma-containing plasma bags B1-1, B1-2, B1-3, bag B2 containing erythrocyte concentrate and empty collection bags S1, S2.

Example 4 Use of the device for the production of antibody-depleted blood plasma

The device in the embodiment shown in Fig. 3 was used. Plasma from bags B1-1, B1-2, B1-3 and the packed red blood cells from bag B2 were transferred to the collection bags S1, S2 by gravity. The two filled collection bags S1 and S2 were then incubated for 2 hours at room temperature (23 °C), possibly after disconnection from the tubing system, then centrifuged and the supernatant was removed, if necessary after docking to the tubing system again and after disconnecting the bag B2, pressed back into the original plasma bags B1-1, B1-2, B1-3, for example by applying a corresponding pressure to the collection bags S1 and S2. The plasma bags B1-1, B1-2, B1-3, which contained the antibody-depleted plasma (universal plasma), were sterilely separated.

It was then checked whether antibodies were still present in the universal plasma produced, i.e. the antibody titer with regard to anti-B-IgM and anti-B-IgG was determined as described in example 1.

In all tested dilution levels 1:1, 1:2, 1:4, 1:8. 1:16, 1:32 no agglutination could be determined by adding erythrocytes of blood group B to the universal plasma. That is, the anti-B antibodies were completely eliminated from the plasma. The device described can be modified as follows. The device can have a mixing device which is designed to actively mix the blood plasma in the first container B1 with the erythrocytes in the second container B2 in the collection container S. In principle, the active mixing can take place by stirring, rotating, pivoting and/or moving the collecting container S. As an alternative or in addition to the hoses described, the connecting device VV can comprise at least one channel or one tube. The hoses described and, if applicable, the optional channels or tubes are made of a material that is approved for medical-technical purposes. The device can have a separating device which is designed to separate blood plasma depleted in anti-A antibodies and/or anti-B antibodies from cell sediment. The separating device can be at least one separator, centrifuge, decanter, filter and/or settling tank. The blood plasma from the first container B1 and the erythrocytes from the second container B2 can be fed into the collection container S by means of a pump device. The connection device can also be designed to supply the depleted blood plasma to the first container B1 and/or the second container B2. For example, the pump device can be used to supply the depleted blood plasma to the first container B1 and/or the second container B2. The pumping device can be a manually operable pumping device or an electric pumping device. The connecting device can be designed to connect the first container B1 and the second container B2 to the collection container S by means of a screw connection, clamp connection or plug connection.

Cited Literature

Noddeland, H. et al. Universal solvent/detergent-treated fresh frozen plasma (Uniplas- rationale and clinical properties. Thrombosis research 107 Suppl 1 , S33-37 (2002). Solheim, BG, Chetty, R & Flesland, O. Indications for use and cost-effectiveness of pathogen-reduced ABO-universal plasma Current opinion in hematology 15, 612-617 (2008).

WO 2007/100294 A1

Claims

patent claims

1 . Method for producing blood plasma which is depleted in anti-A antibodies and/or anti-B antibodies, comprising the steps:

(b) providing erythrocytes of blood group A and/or erythrocytes of blood group Bund/or erythrocytes of blood group AB;

(c) combining the blood plasma according to (a) and the erythrocytes according to (b) to obtain a blood plasma which is depleted in anti-A antibodies and/or anti-B antibodies compared to the blood plasma according to (a), and a cell sediment , wherein the depleted blood plasma is free of anti-A antibodies and/or anti-B antibodies, wherein free of anti-A antibodies and/or anti-B antibodies means that the depleted blood plasma has a maximum titer of 1: 4 anti-A and/or anti-B antibodies;

(d) Separation of the blood plasma obtained according to (c) and depleted in anti-A antibodies and/or anti-B antibodies from the cell sediment.

2. The method of claim 1, wherein step (c) comprises:

(c.2) incubating the mixture obtained according to (c.1.) for at least 10 minutes;

3. The method according to claim 1 or 2, which is an in vitro method.

4. The method according to any one of claims 1 to 3, wherein the blood plasma or the whole blood sample originates from a mammal.

5. Blood plasma depleted in anti-A antibodies and/or anti-B antibodies obtained or obtainable by the method according to any one of claims 1 to 4.

6. Use of a blood plasma depleted in anti-A antibodies and/or anti-B antibodies obtained or obtainable by the method according to any one of claims 1 to 4 or one depleted in anti-A antibodies and/or anti-B antibodies Blood plasma according to claim 5 for the production of a transfusion solution, for the production of a coagulation factor concentrate, for the production of albumin, for the production of immunoglobulin, for the production of tissue adhesive, for the production of a prothrombin complex concentrate (PPSB), for the production of a cell culture.

7. Blood plasma depleted in anti-A antibodies and/or anti-B antibodies obtained or obtainable by the method according to any one of claims 1 to 4, or in anti-A

- 22 - Blood plasma depleted in antibodies and/or anti-B antibodies according to claim 5 for use in a therapeutic or an in vivo diagnostic or a surgical method. Device for the production of blood plasma which is depleted in anti-A antibodies and/or anti-B antibodies, comprising: at least one collection container, a connecting device which is designed to connect at least one first container, the first container containing blood plasma of the blood group A, B or zero or a mixture of two or more blood plasmas of blood group A, B and zero, and at least one second container, wherein the second container contains erythrocytes of blood group A, erythrocytes of blood group B and/or erythrocytes of blood group AB, with the collection container in such a way that the blood plasma of the first container can be brought together with the erythrocytes in the collection container. Device according to claim 8, wherein the collection container is designed for mixing the blood plasma of the first container with the erythrocytes of the second container. Apparatus according to claim 8 or 9, wherein the connecting device comprises at least one channel, pipe and/or hose. Device according to one of Claims 8 to 10, in which the connection device is designed to feed the blood plasma of the first container and the erythrocytes of the second container into the collection container by means of gravity or by means of a pump device.