WO2014194931A1 - Traitement de réduction d'agent pathogène - Google Patents

Traitement de réduction d'agent pathogène Download PDF

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Publication number
WO2014194931A1
WO2014194931A1 PCT/EP2013/061399 EP2013061399W WO2014194931A1 WO 2014194931 A1 WO2014194931 A1 WO 2014194931A1 EP 2013061399 W EP2013061399 W EP 2013061399W WO 2014194931 A1 WO2014194931 A1 WO 2014194931A1
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Prior art keywords
substrate
oxygen
pathogen
blood
plasma
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PCT/EP2013/061399
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English (en)
Inventor
Hendrik B. FEYS
Philippe VANDEKERCKHOVE
Veerle Compernolle
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Onderzoeks- En Ontwikkelingsfonds Rode Kruis-Vlaanderen
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Priority to PCT/EP2013/061399 priority Critical patent/WO2014194931A1/fr
Publication of WO2014194931A1 publication Critical patent/WO2014194931A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
    • A61L2/0029—Radiation
    • A61L2/0047—Ultraviolet radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/10—Inactivation or decontamination of a medicinal preparation prior to administration to an animal or a person
    • A61K41/17—Inactivation or decontamination of a medicinal preparation prior to administration to an animal or a person by ultraviolet [UV] or infrared [IR] light, X-rays or gamma rays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
    • A61L2/0029—Radiation
    • A61L2/0035—Gamma radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
    • A61L2/0029—Radiation
    • A61L2/0041—X-rays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
    • A61L2/0029—Radiation
    • A61L2/0052—Visible light
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
    • A61L2/0029—Radiation
    • A61L2/0058—Infrared radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
    • A61L2/0029—Radiation
    • A61L2/0076—Radiation using a photocatalyst or photosensitiser

Definitions

  • the present invention relates to a method for reducing a risk to the occurrence of unwanted side reactions in a substrate that is subjected to a pathogen reduction treatment, wherein a sensitizing compound capable of targeting said pathogen is added to the substrate and the sensitizing compound is activated for targeting of the pathogen, according to the preamble of the first claim.
  • the present invention in particular relates to a method for reducing a risk to the formation of toxic substances during pathogen reduction treatment of blood, blood components or blood products.
  • blood products or blood components such as blood plasma, platelets, red cells, Factor VIII, plasminogen, fibronectin, anti- thrombin, human plasma protein fraction, albumin, immune serum globulin, prothrombin complex plasma growth hormones and other components that may
  • transfusion products Inherently carry a risk of pathogen transfer, methods have been developed for reducing the concentration or viability of such pathogens in the transfusion product.
  • An example thereof is the addition to the transfusion product of a chemical radiation sensitizer which is capable of targeting said viral, bacterial and/or parasitic contaminants, and exposing the transfusion product containing such chemical radiation sensitizer to electromagnetic radiation of a wavelength and intensity and for a period of time sufficient to activate the sensitizer.
  • blood components have been supplemented with photosensitive compounds, which when irradiated with light of the appropriate wavelength, get activated and interact with the pathogen to destroy the ability of the pathogen to cause infection.
  • the electromagnetic energy that is absorbed by the photosensitizing compound mediates a transition of the sensitizer molecules to an excited molecular state.
  • the excited sensitizer molecules readily react with the surrounding environment, thereby altering the latter's composition.
  • Many bio-molecules or solutes present in the transfusion product are able to directly react with the excited sensitizing compounds, and the bio-molecules and other solutes all compete for chemistry.
  • pathogen reduction treatment of blood components inhibition of pathogen replication results from cross- linking or damage caused to the nucleic acids of the pathogen.
  • the sensitizers are believed to bind the nucleic acids of the pathogen.
  • the short-lived triplet state of the sensitizer derivatives react to induce strand breakage or cross-linking, thereby irreversibly preventing replication of the pathogen*! ) .
  • a frequently used sensitizer is methylene blue (Macopharma, Duluth, GA or Baxter International Inc Deerfield and Fenwal, Illinois, US). Methylene blue treatment is common practice in some European countries. Methylene blue treatment is often carried out either after freezing of the blood component to release cytoplasm-borne pathogens, since it is believed that methylene blue difficultly penetrates cell walls®, or requires additional filtering steps to ensure that the presence of cellular components is reduced to an absolute minimum.
  • Another type of frequently used sensitizer, amotosalen or S-59 made available by Cerus Corporation, Concord, Canada, does not necessarily require a freezing or additional filtering step®.
  • Riboflavin or vitamin B2 Terumo BCT, Lakewood CO, is a vitamin and therefore does not require cumbersome removal following treatment. Both amotosalen and riboflavin have been reported to be useful for the reduction of pathogens in platelet concentrates and have since also been validated for treatment of single plasma units ⁇ 5, 6) .
  • Sensitization in general and photo-sensitization in particular further finds applications in a.o. oncology, ophthalmology, atherosclerosis and transfusion® as a technique which is at the basis of cellular proliferation preventing procedures.
  • Photo-sensitization utilizes reactive oxygen species which are generated upon irradiation of the substrate to be treated, with locally directed light of sensitizers, to kill off cancer cells.
  • Sensitizer mediated oxidative stress can be an effective down-regulator of cell proliferation, it is currently employed in photodynamic therapy for treatment of malignancy®.
  • the present inventors have unfortunately observed that upon irradiation of whole blood and blood plasma in photo-sensitizer mediated pathogen reduction treatments, besides pathogens, also benign bio-molecules or essential constituents of the blood which are ultimately required upon transfusion, downstream of blood processing, risk to be affected. Thus, pathogen inactivation risks going at the sacrifice of the viability of the desired cells and functional bio- molecules.
  • EP-A-633.786 discloses a process for reducing viral, bacterial and/or parasitic contaminants in a substrate such as whole blood, blood components or cell culture, by mixing the substrate in a liquid state with a chemical radiation sensitizer capable of targeting the contaminant, and exposing the composition in the lyophilized state to electromagnetic radiation to activate the sensitizer. It is believed that in this manner damage may be localized on the targeted viral or bacterial particle due to the inability of the sensitizer to migrate in the frozen suspension and the inability of the hydroxy radicals to form and migrate through the frozen suspension.
  • the process disclosed in EP-A- 633.786 however presents the disadvantage that the substrate is lyophilized to a dry state, and as a consequence needs to be reconstituted before it is suitable for use.
  • Lyophilization however often has a detrimental effect on platelet quality, and the percentage of recovery upon reconstitution and transfusion is expected to be low, as shown in a xenographic rabbit mode 24) .
  • preclinical research in a porcine model of thrombocytopenia indicated thrombotic complications ⁇ 25) .
  • sensitizer mediated pathogen reduction method which permits to reduce the risk to the occurrence of unwanted side reactions in a liquid or solid substrate, that would adversely affect the substrate and/or involve the formation of unwanted, potentially toxic side products.
  • a method which permits to reduce the risk to the occurrence of unwanted side reactions in liquid transfusion products, in particular blood, blood products or blood components that would involve the formation of unwanted, potentially toxic side products, upon sensitizer mediated pathogen reduction.
  • the present invention thus seeks to provide a method with which the risk to adversely affecting the substrate and/or the formation of unwanted, potentially toxic side products in a solid or liquid substrate, during sensitizer mediated pathogen reduction, may be reduced to a minimum.
  • the present invention in particular seeks to provide a method with which the risk to adversely affecting essential components of and/or the formation of potentially toxic side products, during sensitizer mediated pathogen reduction, in liquid transfusion products, in particular in whole blood or blood components, may be reduced to a minimum.
  • the process of the present invention is characterized in that in advance of activating the sensitizing compound, the substrate is subjected to an oxygen reduction treatment with the purpose of reducing a concentration of dissolved oxygen present in the substrate.
  • the substrate in advance of subjecting the sensitizer to an activation treatment in the presence of the substrate, the substrate is subjected to an oxygen reduction treatment with the purpose of reducing the concentration of oxygen dissolved in the substrate.
  • the electromagnetic energy is directly absorbed by the sensitizers present in the substrate, and a transition to an excited molecular state is mediated.
  • the thus excited sensitizer molecules have a short life time, they readily react with the surrounding environment, where many molecules and bio-molecules are available to directly react with the excited sensitizer molecule.
  • Dissolved molecular oxygen is assumed to be one of the first molecules to accept energy.
  • ROS reactive oxygen species
  • Reactive oxygen species may give rise to an uncontrollable cascade of reactions in the substrate, and to the formation of a cascade of reaction products, many of which are toxic.
  • derivatives such as for example singlet oxygen OO2) and/or superoxide anion (O2 " ) may be generated.
  • These derivatives are highly reactive and may lead to the formation of a wealth of downstream radicals and components, and may in a blood component for example lead to the formation of compounds including peroxynitrite (ONOO ), hydrogen peroxide (H2O2), hypochlorite (HOC1) and hydroxyl radicals (OH ), which in turn may give rise to fatty acid peroxidation chain reactions in lipids and irreversible modifications in proteins (e.g.
  • the generation of reactive oxygen species during sensitizer mediated pathogen reduction may not only effectively contribute to the biostatic action by damaging pathogenic bio-molecules, but the reactive oxygen species may also be reactive with desirable compounds in the substrate and give rise to uncontrolled reaction whereby a wide variety of unwanted side products are formed.
  • the uncontrolled reaction may give rise to the formation of toxic side products. It may be understood from the above that depending on the composition of the substrate, a wealth of reactive oxygen species may be formed, for example O2 " , H2O2 ' , OH * , HOC!', HOSCN-, ONOO-, ⁇ , NO 2 % C03-, N 2 O 3 % R-S", etc.
  • the risk to the formation of reactive oxygen species as described above may be reduced to a minimum. Therewith the risk to the formation of toxic side products and the occurrence of any further unwanted reaction of the reactive oxygen species as described above, may be minimised.
  • the oxygen reduction treatment for reducing the concentration of oxygen dissolved in the substrate will usually be carried out after the sensitizer has been added to the substrate.
  • the oxygen reduction treatment of the substrate may however been carried out to the substrate, before the sensitizer has been added to the substrate.
  • addition of the sensitizer is preferably carried out in such a way that it does not introduce any unwanted amounts of oxygen to the substrate.
  • dissolved oxygen is meant molecular oxygen dissolved in the substrate. Where relevant however, dissolved oxygen may include other oxygen containing compounds, dissolved in the substrate in as far as they contribute to the effects caused by dissolved molecular oxygen.
  • pathogen includes any viral, bacterial and/or parasitic contaminant contained in the substrate.
  • Pathogen may include any micro-organism which contains DNA or RNA, any micro-organism or infectious particle that is not surrounded by a membrane as well as any micro-organism or infectious particle which is surrounded by a membrane.
  • Pathogen may further include monoclonal or polycolonal antibodies directed against specific viral antigens, either coat proteins or envelope proteins.
  • Pathogen may be defined as any undesirable element found in blood, such as bacteria, virus, uni- or multicellular parasites and white blood cells.
  • the wording "sensitizer” includes any compound that may be activated upon absorption of energy supplied to it, for example acoustic energy or electromagnetic irradiation of one or more defined wavelengths, wherein the sensitizer utilizes the absorbed energy to carry out a chemical process for causing damage to and/or inactivating the pathogen.
  • the wording "sensitizer” within the scope of this invention includes any compound, molecule or moiety which can be activated to cause damage to unwanted pathogens contained in the substrate.
  • Sensitizers suitable for use with the present invention include in particular those which may be activated upon exposure to electromagnetic radiation, for example ionizing radiation such as X- rays or gamma-rays, IR, UV or visible light, which can penetrate the sample containing the contamination.
  • electromagnetic radiation for example ionizing radiation such as X- rays or gamma-rays, IR, UV or visible light
  • the preferred sensitizer within the scope of this invention is however a photo- sensitizer molecule or moiety which can be activated upon exposure to ultra-violet radiation generally having a wavelength of between 10 and 400 nm, often 100 - 400 nm, or IR-light generally having a wavelength of between 700 and 1 mm.
  • Senzitizers suitable for use with the present invention also include those which may be activated upon exposure to vibration of a certain energy, for example to acoustic energy in a sonodynamic activation.
  • the above- described method is suitable for in vitro treatment of a wide variety of substrates, in particular for the treatment of transfusion products such as for example whole blood, blood components or blood products including blood plasma, red blood cells, etc.
  • transfusion products such as for example whole blood, blood components or blood products including blood plasma, red blood cells, etc.
  • electromagnetic radiation in particular UV-light
  • the risk to the formation of unwanted reactive oxygen species may be reduced to a minimum.
  • the present invention in particular involves the use of sensitizer molecules which are capable of selectively binding to nucleic acids, coat proteins or membrane envelopes of the pathogen.
  • sensitizer includes any sensitizer known to the skilled person, which may either be endogenous or exogeneous, which is capable of causing damage to the unwanted pathogen upon irradiation.
  • Endogeneous sensitizers include those naturally found in the substrate that is to be treated, in particular those naturally found in a human or mammalian body, either as a result of synthesis by the body or because of ingestion as an essential foodstuff (e.g. vitamins) or formation of metabolites and/or byproducts in vivo.
  • the treated substrate may be suitable for direct use, for example the treated substrate may be suitable for direct administering to a patient.
  • it may be decided to leave the endogenous sensitizer in the substrate to be treated or to remove it, for example by filtering or adsorption.
  • exogeneous sensitizers suitable for use with the present invention include porphyrins, psoralens, dyes such as neutral red, methylene blue, acridine, toluidines, flavine (acriflavine hydrochloride) and phenothiazine derivatives, coumarins, quinolones, quinones and anthroquinones, but other exogeneous sensitzers considered suitable by the skilled person, taking into account the nature of activation energy to be used, may be used as well within the scope of this invention. Depending on its nature, it may be decided to leave the exogenous sensitizer in the substrate to be treated or to remove it, for example by filtering or adsorption.
  • sensitizers include nucleic acid binding sensitizers, which selectively target contaminating viruses and bacteria and other parasites. Since mature human and animal red blood cells and platelets lack nucleic acids necessary for their function or therapeutic efficacy, their functioning will usually not be affected by nucleic acid binding sensitizers, or to a significantly reduced extent only. Although mostly described in connection with viruses, it will be understood that the methods of the present invention are generally also useful to inactivate any biological contaminant found in stored substrates, for example whole blood, blood components or blood products, including bacteria, viruses, white blood cells and blood- transmitted parasites.
  • the amount of sensitizer to be mixed with the substrate may be defined by the skilled person by routine experimentation and will be chosen such that it is sufficient to adequately inactivate any pathogen- associated nucleic acids which may be present in the fluid, but less than a toxic or insoluble amount.
  • the amount of dissolved oxygen present in the substrate is preferably reduced to a level which is sufficiently low to minimize the risk to the formation of unwanted reactive oxygen species to a sufficiently low level, without however compromising the vital functions of the substrate.
  • the desired oxygen concentration may therefore vary with the nature of the substrate.
  • the concentration of oxygen present in the substrate will be reduced to a partial pressure of below 12.5 kPa, preferably below 10 kPa, more preferably below 5 kPa, most preferably below 2 kPa.
  • Particularly preferred oxygen partial pressures are below 1 kPa, or even below 0.75 kPa.
  • Oxygen partial pressures in the lower ranges may be preferred to compensate for some oxygen absorption upon storage of the substrate before being subjected to the pathogen reduction treatment, as the material of which the containers are made in which the substrate is stored, may show a higher or lesser oxygen permeability. Also, depending on the nature of the substrate, varying maximal acceptable oxygen pressures may be adequate.
  • the oxygen concentration in the gaseaous phase above the substrate will usually be reduced to the above described levels, in particular to a partial pressure of below 12.5 kPa, preferably below 10 kPa, more preferably below 5 kPa, most preferably below 2 kPa.
  • Particularly preferred oxygen partial pressures are below 1 kPa, or even below 0.75 kPa.
  • a substrate may however also be stored in a container in vacuum or under reduced pressure, although this is not common practice for whole blood or substrates containing blood components or blood products.
  • Suitable techniques for reducing the oxygen concentration in the substrate will usually be physical, as physical techniques are less likely to adversely affect the integrity and/or characteristics of the substrate.
  • suitable physical techniques for removing oxygen include subjecting the substrate to a reduced pressure, in particular subjecting the substrate to vacuum.
  • reduced pressure is meant a pressure of less than 10 kPa, preferably less than 5 or less than 1 kPa, preferably less than 0.5 kPa, more preferably less than 0.05 kPa, most preferably less than 0.01 kPa or even less than 0.001 kPa.
  • Subjecting the substrate to a vacuum as described above, will usually have the effect that dissolved oxygen will migrate from the substrate.
  • the substrate may be packed into a closable recipient, which is suitable for connection to a vacuum pump.
  • any gas present in the recipient may be evacuated together with any gases present in the substrate.
  • the extent to which oxygen may be removed will depend on several parameters, such as the evacuation time, pump strength and membrane tightness, evacuation temperature, oxygen concentration, the strength with which the oxygen is bound, absorbed or adsorbed in the substrate. The person skilled in the art will however be able to select the appropriate parameters to achieve the desired oxygen concentration, taking into account the nature of the substrate.
  • Examples of other suitable physical techniques for removing dissolved oxygen include subjecting the substrate to a magnetic field of a suitable strength, to an acoustic treatment or subjecting the substrate to a flow of an inert gas, wherein the inert gas may be flown over and/or through the substrate or the substrate may be sparged with the inert gas or a combination thereof.
  • a combination of two or more of the afore-mentioned physical techniques may also be used.
  • inert gases use can be made of a gas selected from the group of nitrogen, helium, argon, xenon or a mixture of two or more of these gases.
  • any other gas that is inert in the environment of the substrate may be used.
  • Subjecting the substrate to a flow of an inert gas may be achieved by packing the substrate into a container, through which an inert gas may be flown.
  • the flow rate of the inert gas may be chosen by the skilled person, depending on the size of the substrate and the envisaged oxygen reduction.
  • the substrate may be subjected to a process for chemically binding the oxygen contained in the substrate, by contacting the substrate with an oxygen binding reactant.
  • the reactant is preferably chosen such that it is inert or does not irreversibly bind oxygen, to permit oxygen release in in vivo circumstances.
  • suitable oxygen binding reactants include other oxygen binding proteins, for example myoglobin and other hemo compounds.
  • an oxygen binding reactant is used which does not need to be removed from the substrate.
  • an amount of an anti-oxidant or an anti-oxidant mixture may be added to the mixture of the substrate and the sensitizer, to provide defense against damage by free radicals that may be formed in the mixture upon irradiation.
  • blocking agent is meant a chemical compound that is capable of reducing the risk to the occurrence of deleterious side reactions such as cell surface modifications or protein modifications.
  • Addition of a blocking agent may be envisaged to block deleterious side reactions that result from irradiation-induced reactions to the photosensitizers that do not result in viral or bacterial inactivation. More specifically, of concern are reactions that occur to psoralen and coumarin backbone photosensitizers upon irradiation, which give rise to ring-opening.
  • a variety of blocking agents have been found to be suitable for this purpose, some of which are traditional antioxidants, and some of which are not.
  • Suitable examples include cysteine, N-acetyl-L-cysteine, tocopherol, ascorbic acid, etc.
  • an amount of a blocking agent may be added to the substrate in advance of activating the sensitizing compound, to block side reactions to the sensitizing compound upon activation that do not result in pathogen inactivation.
  • the amount of blocking agent that is added to the substrate may vary within wide ranges, and will be adapted by the skilled person taking into account the nature of the substrate and the nature of the sensitizer.
  • the present invention is suitable for use with a variety of substrates, which may either be liquid or solid.
  • the substrates may be of varying origin.
  • substrates suitable for use with the present invention include transfusion products, for example whole blood, blood products and blood components of human or animal origin.
  • blood products or blood components is meant blood plasma, platelets, red cells, Factor VIII, plasminogen, fibronectin, anti-thrombin m, human plasma protein fraction, albumin, immune serum globulin, prothrombin complex plasma growth hormones and other components that may be isolated from blood.
  • the present invention is also suitable for use with other transfusion products such as protein fractions, particularly blood plasma protein fractions, including, but not limited to, fractions containing clotting factors (such as Factor VIII and Factor IX), serum albumin and/or immune globulins.
  • protein fractions particularly blood plasma protein fractions
  • fractions containing clotting factors such as Factor VIII and Factor IX
  • serum albumin serum albumin
  • immune globulins clotting factors
  • the present invention is further suitable for use with reconstituted blood cell compositions comprising erythrocytes, platelets, etc, or protein fractions, and for use with cell cultures comprising recombinant plasma proteins or recombinant clotting factors.
  • suitable substrates include food products, which may be liquid or solid.
  • a sensitizer and irradiation may be used to achieve pathogen reduction to prolong the shelf life of the product, while reduction of the concentration of dissolved oxygen may assist in reducing the risk to the formation of toxic by-products.
  • the present invention allows for the substrate to be used in a transfusable state, while maintaining a high cell viability, ATP synthesis and oxygen transport in the case of cellular components and therapeutic efficiency in the case of protein factors.
  • plasma of any origin will be mixed with photo-sensitizer according to the provider's instructions. Following mixing a procedure to reduce dissolved oxygen will be applied for an appropriate time. In case of sparging with 0.5 bar of inert gas (like nitrogen gas) with mixing during 20 minutes at room temperature, the dissolved oxygen concentration may be reduced to levels sufficiently low to protect bio-molecules from damage under photosensitization-based pathogen inactivation. A similar treatment may be applied to whole blood, blood platelets and any other blood components.
  • inert gas like nitrogen gas
  • Figure 1 shows relative yields of ADAMTS13 in three pathogen reduction methods : percentage ADAMTS13 activity (Fig. la) and percentage of antigen (Fig. lb) retained in the final bag relative to the starting amount.
  • Figure 2 shows that Riboflavin based pathogen reduction has a major effect on ADAMTS13 activity (fig. 2a) and antigen (fig. 2b).
  • Figure 3 shows that pathogen reduction conditions using Riboflavin and light generate O2 " depend on 02, aq .
  • Figure 4 shows disseminated oxidative damage of plasma proteins.
  • Figure 5 shows that dissolved molecular oxygen underlies damage to ADAMTS13 (fig. 5a), fibrinogen (fig. 5b) and FVIII (fig. 5c) during pathogen reduction with riboflavin.
  • Figure 5d shows the % rescue in the Y-axis, calculated from the ratio of the absolute differences in protein before and after Mirasol® treatment in oxygenated versus nitrogen sparged plasma samples.
  • Figure 6 shows the presence of thiobarbituric acid reactive species in supernatant of platelet concentrates.
  • Figure 7 shows the evolution of the oxygen partial pressure as a function of time, upon sparging of plasma with nitrogen gas.
  • Plasma for Methylene Blue treatment 8 (Macotronic®, Macopharma) was passed over a 0.65 ⁇ membrane filter and a dry MB tablet while being transferred to an illumination bag.
  • the plasma containing approximately ⁇ MB was exposed to a light dose of 180 J/cm 2 by illumination for about 20 minutes with light of peak 590nm.
  • the treated plasma was led over an auxiliary filter to remove residual MB.
  • Plasma for Ribovlavine (RF) treatment 9 (Mirasol®, Terumo BCT) was mixed with 35 ml RF solution (approximately 50 ⁇ ) and transferred to an illumination bag which was subsequently illuminated with a UV (265-370nm) light dose of 6.24J/ml.
  • Plasma for AS treatment 10 (Intercept, Cerus) was led through a pouch containing 15ml AS solution (final approximately 250uM).
  • a UV (320-400nm) light dose of 3J/cm 2 was delivered followed by an auxiliary filter step reduce residual AS. All methods were performed following standard operating protocols.
  • ADAMTS13 enzyme activity was measured using the fluorogenic substrate FRETS-VWF73 (AnaSpec, Fremont, CA, USA) 12 with modifications 13 .
  • the final mixture contained 50mM 4-(2-hydroxyethyl)-l-piperazine- ethanesulfonic acid (HEPES) buffer, pH 7.4, supplemented with ImM CaCI 2 , 1 ⁇ ZnCI 2 , 4.2mM 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (Sigma-Aldrich) and 2 ⁇ FRETS-VWF73. Fluorescence intensity was measured every 150 seconds for 90 minutes at 25°C in a microplate reader (Infinite F200 Pro, Tecan, Mannedorf, Switzerland) equipped with a 340nm excitation and 448nm emission filter. Product formation rates were determined relative to NHP.
  • HEPES 4-(2-hydroxyethyl)-l-piperazine- ethanesulfonic acid
  • ImM CaCI 2 1 ⁇ ZnCI 2
  • ADAMTS13 antigen was used to measure ADAMTS13 antigen, following the instructions of the provider. Detection occurs by goat anti-human IgG antibody labeled with a streptavidin-horseradish peroxidase (HRP) which reacts with the perborate-3,3'-5,5'-tetramethy[benzidine (TMB) substrate that was added to generate a blue colored solution. Absorbance (450nm) was measured with the microplate reader.
  • HRP streptavidin-horseradish peroxidase
  • TMB perborate-3,3'-5,5'-tetramethy[benzidine
  • Electrophoresis was performed on stain-free precast TGX gel, 7.5% (Bio-rad, Hercufes, CA, USA) in a 2-amino-2- hydroxyrnethyJ-propane-l,3-diol Tris-glycine buffered system (25mM Tris, 192mM Glycine, 0.1% (m/v) SDS).
  • Plasma samples were diluted 1/20 in phosphate buffered saline (PBS) containing 137 mM NaCI, 2.7 niM KCI, 10 niM Na 2 HP0 4 j 2 niM KH2PO4, pH 7.4 and non reducing sample buffer containing 60mM Tris-HCI, 10% (v/v) glycerol, 2% (v/v) SDS and 0.01% (w/v) bromophenolblue. NHP was used as a negative control.
  • PBS phosphate buffered saline
  • NHP was incubated with 250 U/ml urokinase-type plasminogen activator (Sigma-Aldrich, St Louis, MO, USA) overnight at 37°C, followed by addition of ⁇ amiloride hydrochloride hydrate (Sigma-Aldrich, St. Louis, MO, USA) to stop proteolysis.
  • FVIII activity (%) was measured in a one- stage activated partial thromboplastin time based clotting assay with factor deficient plasma. Fibrinogen activity was measured by the Clauss method and both analyses were performed in duplicate on a STA-R Evolution apparatus with tools and reagents from Diagnostica Stago (Asnieres, France).
  • Carbonyl content was determined by spectro-photometric analysis of dinitrophenylhydrazone as described earlier 14 .
  • samples containing 2mg protein as determined by bicinchoninic acid assay (BCA, Thermo Fisher Scientific) were supplemented with 10 mM 2,4-dinitrophenylhydrazine (DNPH)(Sigma-A(drich) in 2M HCI (final concentrations) and incubated at room temperature with shaking for one hour in shaded vials.
  • Parallel samples contained 2M HCI to determine background.
  • samples were reanalyzed for protein concentration by BCA assay to enable expression of carbonylation as mole per milligram protein.
  • Advanced lipid end-products of the aldehyde type including malondialdehyde react with thiobarbituric acid at 100°C to form a colored product that can be measured spectrophotometrically at 530nm.
  • a standard curve was used by measuring a dilution series of 1,1,3,3-tetrametoxypropane in ultrapure water containing 30% (w/v) trichloroacetic acid.
  • Plasma exchange or infusion is a standard treatment for thrombotic thrombocytopenic purpura (TTP), a thrombotic microangiopathy caused by severe ADAMTS13 deficiency 15 .
  • ADAMTS13 activity and antigen were measured in three photosensitizer-based pathogen reduction methods as described above, using Mehtylene Blue (MB), Riboflavin (RF) and AS Treatment, in a comprehensive paired analysis as described above.
  • Figure 1 indicates the 'relative yield' which relates initial ADAMTS13 values before pathogen reduction treatment, to final ADAMTS13 values after pathogen reduction treatment.
  • Figure 1 indicates the relative yields of ADAMTS13 in three pathogen reduction methods.
  • the relative yield (%) is the percentage ADAMTS13 activity (Fig. la) or antigen (Fig. lb) retained in the final bag relative to the starting amount.
  • ADAMTS13 activity and antigen are affected most by RF-based pathogen reduction.
  • ADAMTS13 activity (fig. 2a) and antigen (fig. 2b) were determined in plasma sampled from paired bags before and after pathogen reduction treatment with respectively Methylene blue, Riboflavin and AS.
  • Statistical results of repeated measures one-way ANOVA with Bonferonni multiple comparison testing are indicated above each data set in fig. lb.
  • Figure 1 shows that despite the advantage that Riboflavin treatment does not involve volume losses, RF treatment is not necessarily superior in retaining ADAMTS13 function. This is explained by a significant decrease of the absolute ADAMTS13 activity and antigen content of 23% and 29% in RF, respectively ( Figure 2).
  • ADAMTS13 functional proteins are lost most in both MB and RF, but volume loss accounts for decreases in MB while molecular changes contribute most in the case of RF. Relative yields are most maintained by treatment with AS.
  • Oxidative stress has been measured during RF-based pathogen reduction using nitroblue tetrazolium reduction to formazan. Oxidative stress has been measured by absorbance reading before and after pathogen reduction with 5 ⁇ Riboflavin in a Mirasol apparatus. Oxidative stress before pathogen reduction is represented by the open bars, oxidative stress after pathogen reduction is represented by the closed bars.
  • anion radicals are formed when dissolved molecular oxygen (O2, aq ) accepts the excess energy from photochemically excited sensitizers. Indeed, when the O2aq concentration is experimentally lowered by nitrogen gas sparging, the O2 related NBT reduction is bypassed ( Figure 3) and taken over by direct transfer from excited Riboflavin to the reporter.
  • O2, aq dissolved molecular oxygen
  • Oxidative damage can be prevented by lowering dissolved molecular oxygen.
  • Riboflavin pathogen reduction is not restricted to its use with plasma, riboflavin may also be used for treatment of platelet concentrates. Pathogen reduction of platelet concentrates is particularly relevant since their conventional storage temperature of 22°C increases risk to opportunistic bacterial growth with time, thereby increasing the risk of infection in the recipient patient. In view hereof, shelf-life of platelet products has been restricted to maximally seven days, depending on national regulations.
  • Lipid peroxidation can be prevented by decreasing O2j aq
  • Lipid peroxidation is a chemical chain reaction that can be initiated by direct (per)oxidation of polyunsaturated fatty acids by 1 02 17 . While propagating, a diversity of by-products is generated which are termed advanced lipid end-products (ALE), some of which resemble signaling molecules (including thromboxanes) that are able to exert cellular responses 18 .
  • ALE advanced lipid end-products
  • a variety of commercially available assays measure these ALE, but the most common 'generic' assay measures thiobarbituric acid reaction products (TBARS). This assay mainly (but not solely) determines levels of malondialdehyde, which is a known indicator of oxidative stress and is one of the many products formed during lipid peroxidation.
  • Platelet concentrates prepared by pooling six buffy coats in platelet additive solution were mixed with sterilized riboflavin (RF) in saline and subsequently split in equal volumes by weight.
  • RF-based pathogen reduction causes an immediate increase of TBARS (0.47 ⁇ 0.08uM to 0.79 ⁇ 0.13uM) in the presence of ambient 02, a q (02aq nor).
  • Ciaravino V Ciaravino V
  • McCullough T Cimino G
  • Sullivan T Preclinical safety profile of plasma prepared using the INTERCEPT Blood System. Vox Sang. 2003;85(3):171-182.
  • Protein carbonyl groups as biomarkers of oxidative stress. Clinica Chimica Acta. 2003;329(l-2):23-38.
  • Furlan M Lammle B. Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease. Best Pract Res Clin Haematol. 2001;14(2):437-454.
  • Bochkov VN Oskolkova OV
  • Birukov KG Levonen AL
  • Binder CJ Stockl J. Generation and biological activities of oxidized
  • Cimino GD Gamper HB
  • Isaacs ST Hearst JE.
  • Psoralens as photoactive probes of nucleic acid structure and function: organic chemistry, photochemistry, and biochemistry. Annu Rev Biochem. 1985;54:1151-1193.
  • Bode AP Read MS. Lyophilized platelets: continued development.

Abstract

La présente invention concerne un procédé de réduction du risque d'apparition de réactions secondaires indésirables dans un substrat qui est soumis à un traitement de réduction d'agent pathogène, un composé de sensibilisation pouvant cibler ledit agent pathogène étant ajouté au substrat et le composé de sensibilisation étant activé pour cibler l'agent pathogène. Avant l'activation du composé de sensibilisation, le substrat est soumis à un traitement de réduction d'oxygène en vue de réduire une concentration en oxygène dissous présente dans le substrat. Des exemples de substrats préférés comprennent du sang total, des produits sanguins ou des éléments constitutifs du sang.
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US10603417B2 (en) 2009-10-12 2020-03-31 Hemanext Inc. System for extended storage of red blood cells and methods of use
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US10849824B2 (en) 2015-04-23 2020-12-01 Hemanext Inc. Anaerobic blood storage containers
US11013771B2 (en) 2015-05-18 2021-05-25 Hemanext Inc. Methods for the storage of whole blood, and compositions thereof
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