WO2012163544A1 - Élimination du récepteur 2 soluble du facteur onconécrosant (stnfr2) - Google Patents

Élimination du récepteur 2 soluble du facteur onconécrosant (stnfr2) Download PDF

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Publication number
WO2012163544A1
WO2012163544A1 PCT/EP2012/002340 EP2012002340W WO2012163544A1 WO 2012163544 A1 WO2012163544 A1 WO 2012163544A1 EP 2012002340 W EP2012002340 W EP 2012002340W WO 2012163544 A1 WO2012163544 A1 WO 2012163544A1
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WIPO (PCT)
Prior art keywords
stnfr2
blood
patient
binding
plasma
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PCT/EP2012/002340
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English (en)
Inventor
Günther Heinrich
Timo L.M. TEN HAGEN
Alexander EGGERMONT
Peter Wiesner
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Biopheresis Technologies, Inc.
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Application filed by Biopheresis Technologies, Inc. filed Critical Biopheresis Technologies, Inc.
Publication of WO2012163544A1 publication Critical patent/WO2012163544A1/fr
Priority to PCT/IB2013/001583 priority Critical patent/WO2013179143A2/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
    • A61M1/3486—Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a device having molecules binding to soluble tumor necrosis factor receptor 2 (sTNFR2, TNFRSFIB) immobilized on a solid support, wherein no molecules binding to soluble tumor necrosis factor receptor 1 (sTNFRl) are immobilized. Further, the present invention relates to a method for the removal of sTNFR2 from blood, plasma or a blood fraction. Moreover, the present invention relates to a molecule specifically binding to sTNFR2, but not binding to sTNFRl, for use in a method for treating the human or animal body and to blood, plasma or a blood fraction obtainable from the method of the present invention for use in a method for treating cancer.
  • cancer is one of the major causes of death throughout the population. Therefore, various therapeutics have been developed since decades. However, so far, no therapeutic approach is fully satisfying.
  • cancer therapy is mainly based on chemotherapy, targeted small molecules, radiation therapy, surgery, immunotherapy, monoclonal antibody therapy and/or other methods.
  • Conventional chemotherapeutic cancer therapy is based on the use of agents that have cytotoxic effects predominantly on neoplastic cells. The predominant killing of neoplastic cells occurs due to the fact that cancer cells replicate faster than most other cells of the adult human body. However, it is widely known that also other cell types replicate relatively fast, such as, e.g., hair follicle cells and mucosa cells.
  • these cells are also affected by cytotoxic agents and the patient is exposed to side effects, in many instances severe side effects, of the treatment.
  • Adverse events related to the chemotherapeutic treatment can lead to the premature discontinuation of the therapy, in some instances chemotherapy can even cause the death of the patient.
  • a surgical procedure may even require the amputation of a limb, a breast, a testicle, an inner organ, a part of the skin and/or parts of one or more of the aforementioned. Further, a surgical procedure may lead to an artificial anus and/or to a bladder catheter. Likewise, radiation may lead to severe symptoms of intoxication. Other treatments have been tried in an attempt to improve mortality and morbidity.
  • cancer can be treated by immunotherapy (e.g., therapeutic vaccines such as sipuleucel-T, or cytokine-based immunotherapy (e.g. Interleukin-2, Interferon-alpha)), monoclonal antibody therapy (e.g. bevacizumab), targeted small molecules (e.g., imatinib) and/or other methods, such as, e.g., cryoablation or isolated organ perfusion.
  • immunotherapy e.g., therapeutic vaccines such as sipuleucel-T, or cytokine-based immunotherapy (e.g. Interleukin-2, Interferon-alpha)
  • monoclonal antibody therapy e.g. bevacizumab
  • targeted small molecules e.g., imatinib
  • cryoablation e.g., cryoablation or isolated organ perfusion.
  • cytokines such as, e.g., tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN- ⁇ ), and interleukin-2 (IL-2) have been used clinically, but have either demonstrated durable remissions only in small numbers of patients treated, or produced no significant clinical responses in overall target populations.
  • TNF-alpha tumor necrosis factor alpha
  • IFN- ⁇ interferon gamma
  • IL-2 interleukin-2
  • sTNFRl soluble tumor necrosis factor receptor 1
  • sTNFR2 soluble tumor necrosis factor receptor 2
  • the present invention relates to the removal of soluble tumor necrosis factor receptor 2 (sTNFR2), wherein molecules binding to sTNFR2, but not binding to soluble tumor necrosis factor receptor 1 (sTNFRl), are immobilized on a solid support and wherein sTNFRl is not removed.
  • sTNFR2 soluble tumor necrosis factor receptor 2
  • sTNFRl soluble tumor necrosis factor receptor 1
  • the present invention refers to a device having molecules binding to soluble tumor necrosis factor receptor 2 (sTNFR2, TNFRSF1B) immobilized on a solid support, wherein no molecules binding to soluble tumor necrosis factor receptor 1 (sTNFRl) are immobilized.
  • sTNFR2 soluble tumor necrosis factor receptor 2
  • TNFRSF1B soluble tumor necrosis factor receptor 2
  • the term "device” may be understood in the broadest sense as any assembly known in the art to enable the purification and/or handling of liquid solutions, such as, e.g., any hollow- ware, a column, a column matrix, a filter, a membrane, in particular a dialysis membrane, a semi-permeable material, a bead, in particular a microbead or a nanobead or a tubing.
  • the device may be a therapeutic, diagnostic, medical, analytical, or laboratory device or an implant.
  • soluble tumor necrosis factor receptor 2 refers to a polypeptide that has a sequence identity of at least at least 75%, even more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95%, and most preferably 100% of the sequence of SEQ ID NO: 1.
  • sTNFR2 soluble tumor necrosis factor receptor 2
  • soluble tumor necrosis factor receptor type ⁇ soluble tumor necrosis factor receptor IB
  • soluble tumor necrosis factor receptor superfamily member IB soluble tumor necrosis factor receptor superfamily IB
  • soluble tumor necrosis factor-binding protein 2 sTNF-alpha receptor
  • TNFR1 B soluble tumor necrosis factor receptor
  • sTNFR-II soluble tumor necrosis factor receptor superfamily member IB
  • soluble tumor necrosis factor receptor superfamily IB soluble tumor necrosis factor-binding protein 2
  • sTNF-alpha receptor TNFR1 B
  • sTNFR-II TNFRSF1B
  • sTBP-2 sTBP-II
  • sTBP2 sTBPII
  • p75 p80
  • sTNF-R2 or “CD 120b”.
  • TNF tumor necrosis factor
  • TNF may be, e.g., TNF-alpha.
  • TNF tumor necrosis factor
  • cachexin or “cachectin”
  • TNF-ct and “tumor necrosis factor-alpha” may be understood interchangeably.
  • sTNFR2 may be generated by shedding, thus, by proteolytic cleavage of the full- length TNFR2 associated with the membrane. Typically, shedding will be executed by one or more matrix metalloprotease(s).
  • polypeptide may be understood in the broadest sense as a linear or branched polymer mainly composed of amino acids.
  • a polypeptide may be a protein.
  • the polypeptide may further contain posttranslational modifications.
  • Posttranslational modifications are well-known in the art and may comprise but may not be limited to lipidation, phosphorylation, sulfatation, glucosylation, truncation, cyclization of several amino acid moieties, cyclization of the polypeptide strand, oxidation, reduction, decarboxylation, acetylation, amidation, deamidation, nitration, nitrosylation, disulfide bond formation, pyroglutamate formation, amino acid addition, cofactor addition (e.g., biotinylation, heme addition) and complexation of metal ions, non-metal ions, peptides or small molecules and addition of iron-sulfide clusters.
  • cofactor addition e.g., biotinylation, heme addition
  • co-factors such as, e.g., ATP, ADP, NAD+, NADH+H + , NADP + , NADPH+H + , metal ions, cations, anions, lipids may be bound to the polypeptide, irrespective on their biological impact.
  • the protein may be elongated by one or more amino acids.
  • the sTNFR2 of the present invention may be any sTNFR2 found throughout the population, preferably throughout the population of the species of the patient that may be treated with the body-fluid from which sTNFR2 has been removed.
  • sTNFR2 may be the form of sTNFR2 that is most common throughout the population or may be a mutated form of sTNFR2, such as, e.g., a single nucleotide polymorphism (SNP) of sTNFR2.
  • mutated may include, e.g., single amino acid exchanges (point mutations), truncated and elongated sTNFR2 and/or sTNFR2 bearing posttranslational modifications.
  • sTNFR2 may or may not be fused to other molecule(s). Most preferably, sTNFR2 originates from the patient itself.
  • the sTNFR2 may be expressed by or result from enzymatic shedding from any cell type.
  • sTNFR2 may, to a large extent, be expressed by or released from malignant or benign neoplastic cells and/or by cells belonging to the immune system.
  • the cancer cells may be cells of a malignant, a semi-malignant, a pre-malignant or a benign primary tumor, or cells of secondary tumors, e.g. lymph node and distant metastases.
  • soluble tumor necrosis factor receptor 1 sTNFRl
  • sTNFRl refers to a polypeptide that has a sequence identity of at least at least 75%, even more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95%, and most preferably 100% of the sequence of SEQ ID NO:2.
  • sTNFRl soluble tumor necrosis factor receptor 1
  • soluble tumor necrosis factor receptor type I soluble tumor necrosis factor receptor 1A
  • soluble tumor necrosis factor receptor superfamily member 1A soluble tumor necrosis factor receptor superfamily 1A
  • soluble tumor necrosis factor-binding protein 1 soluble TNF-alpha receptor
  • TNFR1A soluble tumor necrosis factor receptor 1A
  • sTNFR-I soluble tumor necrosis factor receptor superfamily member 1A
  • soluble tumor necrosis factor receptor superfamily 1A soluble tumor necrosis factor-binding protein 1
  • soluble TNF-alpha receptor soluble TNF-alpha receptor
  • TNFR1A soluble tumor necrosis factor receptor type I
  • soluble tumor necrosis factor receptor 1A soluble tumor necrosis factor receptor superfamily member 1A
  • soluble tumor necrosis factor receptor superfamily 1A soluble tumor necrosis factor-binding protein 1
  • soluble TNF-alpha receptor soluble TNF-alpha receptor
  • sTNFRl may be generated by shedding, thus, by proteolytic cleavage of the full length TNFR1 associated with the membrane.
  • shedding will be executed by one or more matrix metalloprotease(s).
  • the device of the present invention may bear molecules binding to sTNFR2.
  • binding to refers to an intermolecular interaction of the sTNFR2 polypeptide with any molecule binding to sTNFR2.
  • the molecule binding sTNFR2 may be any molecule binding to sTNFR2 with a dissociation constant (Kd) of less than 10 raM, less than 1 mM, less than 100 ⁇ , less than 10 ⁇ , less than 1 ⁇ , less than 100 nM, or less than 10 nM.
  • Kd dissociation constant
  • the molecule binding sTNFR2 may bind to sTNFR2 with a Kd of less than 1 nM, more preferably less than 100 ⁇ , even more preferably less than 10 ⁇ , even more preferably less than 1 ⁇ , in particular less than 100 nM.
  • the molecule binding to sTNFR2 may be understood as any binding partner of sTNFR2 or any sTNFR2-binding molecule.
  • said molecule binding to sTNFR2 may have a higher binding affinity to sTNFR2 than to other proteins present in blood or plasma such as, e.g., albumins (e.g., serum albumin), globulins (e.g., immunoglobulins), other cytokines, interleukins, chemokines, fibrinogens, antitrypsins and/or complement factors.
  • albumins e.g., serum albumin
  • globulins e.g., immunoglobulins
  • other cytokines e.g., interleukins, chemokines, fibrinogens, antitrypsins and/or complement factors.
  • said molecule binding to sTNFR2 may bear a significantly higher affinity to sTNFR2 than to sTNFRl .
  • said molecule binding to sTNFR2 may bear more than 5fold, preferably more than lOfold, more preferably more than 50fold, even more preferably more than lOOfold higher binding affinity to sTNFR2 than to sTNFRl .
  • the molecules binding to sTNFR2 may be of natural or of synthetical origin.
  • the molecules binding to sTNFR2 may be conjugated or bound to other molecules that may refer to but may not be limited to one or more protein tag(s) (e.g., dihydrofolate, polyhistidine tag(s) ((poly)His tag(s)), streptavidin), one or more binding moiety/moieties comprising, e.g., biotin, methotrexate, glycocorticoid(s), one or more active ester(s) (e.g., N-hydroxysuccinimidyl (NHS) ester(s)), one or more isothiocyanate(s), one or more maleimide(s), one or more glutaraldehyde derivative(s), one or more carbodiimide derivative(s) or combinations thereof, one or more insoluble and/or soluble polymer(s) (e.g., polyethylene glycol (PEG), hydroxypropyl methacrylate (HPMA), polyethylene imine (PEI)), one or more antibody/
  • the device of the present invention may not comprise any molecules binding to sTNFRl with an binding affinity of a Kd of less than 10 nM, more preferably less than 100 nM, even more preferably less than 250 nM, even more preferably less than 500 nM, even more preferably less than 750 nM, even more preferably less than 1 ⁇ , even more preferably less than 2 ⁇ , , even more preferably less than 5 ⁇ , even more preferably less than 10 ⁇ , even more preferably less than 50 ⁇ , even more preferably less than 100 ⁇ .
  • the molecule binding sTNFR2 may be immobilized to a solid support by any means known in the art.
  • the term "immobilized to a solid support” means that the molecule is bound to any solid material.
  • the term "bound” means that the molecule is covalently or quasi -covalently bound.
  • a quasi-covalent bond is a non-covalent bond with a binding affinity with a Kd of less than 50 nM, such as, e.g., the dihydrofolate- methotrexate interaction, or the streptavidin-biotin interaction.
  • the molecule binding sTNFR2 may be immobilized directly or via linker. For instance a bispecific linker can bind to the surface of the solid support with one active group whereas it binds to the molecule binding sTNFR2 with another active group.
  • a glass surface of a solid support may be activated by silane conditioning as known in the art. Then, the surface of the solid support may further be conjugated with bispecific linker carrying, e.g., a maleimide or a succinimidyl ester (e.g., N- hydroxysuccinimidyl (NHS) esters) on the other end.
  • bispecific linker carrying, e.g., a maleimide or a succinimidyl ester (e.g., N- hydroxysuccinimidyl (NHS) esters) on the other end.
  • a succinimidyl ester can bind to free amino groups of the molecule binding sTNFR2
  • a maleimide preferably binds to free thiol groups of the molecule binding sTNFR2.
  • An active ester such as an acid halogenide (e.g., an acid chloride or an acid bromide) may bind to free amino groups or free hydroxyl groups of the molecule binding to sTNFR2.
  • an acid halogenide e.g., an acid chloride or an acid bromide
  • the molecule binding sTNFR2 is immobilized on the surface of the solid support.
  • antibodies binding to the molecule binding to sTNFR2 can be immobilized on the surface of a solid support.
  • a fluid containing the molecule binding to sTNFR2 is incubated with the antibody-coated surface.
  • the term "coated” may be understood in the broadest sense as the conjugation of any molecular structure(s) to the surface of the solid support.
  • the device is an extracorporeal device through which a patient's blood, plasma or blood fraction can be circulated prior to being returned into the patient.
  • extracorporeal device may be understood in the broadest sense as any device that is used ex vivo, thus, outside of the living body of the patient.
  • the extracorporeal device may be a column, optionally coated with a molecule binding to sTNFR2 and/or filled with a column matrix coated with a molecule binding to sTNFR2, a filter system coated with a molecule binding to sTNFR2, a membrane, in particular a dialysis membrane, coated with a molecule binding to sT FR2, a tubing coated with a molecule binding to sTNFR2, or any other device coated having a molecule binding to sTNFR2 immobilized on a solid support.
  • the extracorporeal device may get in contact with the body fluid containing sTNFR2 directly.
  • the body fluid containing sTNFR2 may first be subjected to a previous purification step and may subsequently get in contact with the body fluid containing sTNFR2.
  • the suspended or emulsified cells of a body fluid such as, e.g., blood cells
  • the blood plasma may get in contact with the extracorporeal device that enables the removal of sTNFR2.
  • the cells may optionally be remixed with the plasma or returned into the patient separately.
  • the separation of cells and body fluid may be used to protect the column(s), the filter or membrane device from being clogged.
  • a size exclusion filter may be suited upstream the extracorporeal device that enables the removal of sTNFR2.
  • This filter may be used to protect a column, filter or membrane device from being clogged.
  • the term "get in contact” may be understood in the broadest sense as exposing the molecules binding to sTNFR2 to the body fluid, enabling the sTNFR2 to bind to the molecules binding to sTNFR2.
  • one or more type(s) of molecule(s) or one or more type(s) of cell(s) may be removed by other means such as, e.g., affinity chromatography, anion exchange chromatography, cation exchange chromatography, hydrophobicity chromatography, or electrophoresis. This process may be conducted upstream and/or downstream to the removal of sTNFR2 or may be conducted on the same solid support as the removal of sTNFR2.
  • the extracorporeal device may be used offline, online or a combination thereof.
  • the term "offline" may be understood in the broadest sense as a system that is used batch-wise. Therefore, a certain volume of the body fluid extracted from a patient, is exposed to the device of the present invention and sTNFR2 is removed. Subsequently, the body fluid, from which sTNFR2 has been removed, is further analyzed and/or is optionally returned to the patient from whom the fluid has been obtained or to one or more other patient(s), in particular other patient(s) of the same patient as the graft patient the body fluid is obtained from.
  • the term "online” may be understood in the broadest sense as a system that is used in a continuous flow and/or is connected with the patient's blood or lymphatic vessel(s). Highly preferably, the body fluid extracted from a patient, is directly obtained from said patient, conducted through the extracorporeal device and, thereby, exposed to the molecules binding to sTNFR2 and is finally led back to said patient. This process may preferably be controlled manually and/or computer-assisted.
  • the body fluid may be brought to or kept at any temperature sufficient for treating a body fluid, preferably the body fluid may be cooled to a temperature in the range of between 2°C and 5°C, between 5°C and 10°C, between 10°C and 15°C, between 15°C and 25°C, between 25°C and 37°C, or may be kept at body temperature, preferably at approximately 37°C. More preferably, the body fluid is cooled to a temperature in the range of between 2°C and 5°C or kept at body temperature, preferably at approximately 37°C, in particular kept at approximately 37°C. When returned into the patient, the body fluid may preferably bear body temperature, thus a temperature of approximately 37°C.
  • the extracorporeal device may also serve as a combination of an offline and an online method. Then, e.g., the body fluid may be extracted from a patient in a pulsed mode, sTNFR2 may be removed in the extracorporeal device in a pulsed mode and/or the body fluid may be led back to the patient in a pulsed mode.
  • pulsed mode means that there is no continuous flow, but the sample is rather treated batch-wise every few seconds or every few minutes, whereas the process comprising extracting the body fluid and removing sTNFR2 is conducted automatically.
  • blood may be understood in the broadest sense as blood of a human or an animal.
  • the blood is the blood of the patient who receives the blood, plasma or blood fraction of which sTNFR2 has been removed.
  • the term "plasma” may be understood in the broadest sense as blood from which the cells (e.g., red blood cells (RBCs) and leucocytes) as well as the platelets have been removed.
  • the plasma is obtained from the blood of the patient who receives the plasma, blood or blood fraction of which sTNFR2 has been removed.
  • blood fraction may be understood in the broadest sense as any fraction of blood from which one or more factors have been removed. Exemplarily, the RBCs, some types of or all leucocytes, platelets, and/or one or more proteins may be removed.
  • blood fraction refers to (blood) serum, thus, plasma of which further one or more coagulation factor(s) has/have been removed.
  • serum in serum, at least fibrin and/or fibrinogen has been removed.
  • a blood fraction may also be plasma or serum of which further proteins of a certain molecular weight range have been removed. This can be proteins of a molecular weight above a certain threshold or below a certain threshold, preferably proteins above a certain threshold are removed, more preferably proteins of more than 50,000 Da, more than 100,000 Da, more than 120,000 Da, more than 150,000 Da or more than 200,000 Da. Even more preferably, proteins of a molecular weight of more than 120,000 Da may be removed from the blood fraction.
  • sTNFR2 may also be removed from any other body fluid such as, e.g., lymph (endolymph and/or perilymph), cerebrospinal fluid ⁇ liquor cerebrospinalis).
  • the blood, plasma, blood fraction or body fluid is obtained from an organism directly before or during the removal of sTNFR2. More preferably, the blood, plasma, blood fraction or body fluid is obtained from a patient. Alternatively, the blood, plasma, blood fraction or body fluid may have been obtained previously. If the body fluid was obtained previously, it may be stored by any means known in the art, e.g., the body fluid may be stored at room temperature, at 4°C, at -20°C, at -80°C, or in liquid nitrogen.
  • the body fluid may also be dried (e.g., by evaporation, vacuum evaporation, or freeze drying).
  • the residua thus, dry foam or powder, may be dissolved in water or a respective aqueous buffer as known in the art.
  • the term "patient” may refer to every living subject that may be treated.
  • the patient may be an animal, in particular a mammal including humans. Most particularly, the patient is a human.
  • the patient may be a subject that has an increased sTNFR2 level. Said increased sTNFR2 level may be due to the presence of malignant or benignant neoplastic cells and/or by cancer cells in the patient.
  • the term "obtained from” as used herein may be understood in the broadest sense as the gaining of the body fluid by any means known in the art.
  • blood, plasma, serum, cerebrospinal fluid and/or lymph may be obtained by taking a sample by means of an acus, a needle, a spicule or the like.
  • many devices for obtaining blood are well- known in the context of dialyzers and kidney machines (e.g., syringes, venipuncture devices, vacutainer) and can be used without particular expert skills.
  • the body fluid obtained from a patient may be an analytical sample of a volume of less than 10 ml, less than 1 ml, less than 100 ⁇ , less than 10 ⁇ , or even less than 1 ⁇ .
  • An analytical sample may the consumed during the analytical procedure and/or may be discarded after the analytical procedure has been conducted.
  • the obtained body fluid from which the sTNFR2 has been removed may be injected or recirculated into the patient the sample has been extracted from or into another patient, more preferably into the patient the sample has been extracted from.
  • antibodies preferably monoclonal antibodies, antibody fragments or antibody mimetics
  • cytokines in particular tumor necrosis factor alpha (sTNFSF2) or sTNFSF2 mutein;
  • synthetic polypeptides in particular Staphylococcus aureus Protein A, human LDL receptor, lipocalin or fibronectin; and/or
  • molecules binding to sTNFR2 are monoclonal antibodies, antibody fragments or single chain antibodies.
  • An antibody may be a monoclonal or a polyclonal antibody of any species or origin. It may bind to any epitope(s) comprised in the sTNFR2 polypeptide (e.g., linear epitope(s), structural epitope(s), primary epitope(s), secondary epitope(s)), including its posttranslational modifications.
  • the epitope may be accessible by the antibody in the natural configuration of the sTNFR2 or may be a hidden epitope.
  • the epitope is accessible in the natural configuration of the sTNFR2.
  • the antibodies may be of natural origin, of gene technologic origin and/or of synthetical origin.
  • the antibody may also be a CovX antibody.
  • the antibody may also be a cameloid species antibody.
  • antibody fragments may be understood in the broadest sense as any fragment of an antibody that still bears binding affinity to its target.
  • the antibody fragment may be a fragment antigen binding (Fab fragment), a truncated antibody comprising one or both complementarity determining region(s) (CDR(s)) or the variable fragment (Fv) of an antibody.
  • the antibody fragments may be of natural origin, of gene technologic origin and/or of synthetical origin.
  • antibody mimetic may be understood in the broadest sense as organic compounds that, like antibodies, can specifically bind antigens and that typically have a molecular mass in a range of from approximately 3 kDa to approximately 25 kDa.
  • Antibody mimetics may be, e.g., Affibody molecules (Affibodies), Affilins, Affitins, Anticalins, Avimers, DARPins, Fynomers, Kunitz domain peptides, single-domain antibodies (e.g., VHH antibodies or V AR antibodies) Monobodies, Diabodies, Triabodies, flexibodies and tandabs.
  • the antibody mimetics may be of natural origin, of gene technologic origin and/or of synthetical origin.
  • cofactor may be understood in the broadest sense as a molecule binding to sTNFR2 in the natural environment to facilitate or enhance binding affinity or any other function thereof.
  • cytokine may be understood in the broadest as any small protein, peptide, or glycoprotein secreted in the body to signal in intercellular communication, that may bind to sTNFR2, such as, e.g., tumor necrosis factor alpha (STNFSF2).
  • STNFSF2 tumor necrosis factor alpha
  • the term "mutein” refers to any mutated protein.
  • the amino acid sequence of the mutein may comprise alterations or substitutions in the primary amino acid residues, may be truncated and/or may be elongated compared to the corresponding wildtype protein.
  • the mutein may have more than 50%, preferably more than 60%, more preferably more than 70%, even more preferably more than 80%, even more preferably more than 90%, most preferably more than 95% sequence homology to the corresponding wildtype protein.
  • synthetic polypeptide refers to any polypeptide that binds to sTNFR2.
  • a synthetic polypeptide may be obtained from chemical synthesis or from gene technological processes.
  • a synthetic polypeptide may be, e.g., Staphylococcus aureus Protein A, low-density lipoprotein (LDL) receptor, lipocalin or fibronectin.
  • LDL low-density lipoprotein
  • small molecule refers to any molecule that binds to sTNFR2 that has a molecular mass of less than 5000 Da, preferably less than 2000 Da, more preferably less than 1500 Da, even more preferably less than 1000 Da, even more preferably less than 800 Da.
  • the small molecule may be, e.g., an ensemblin, a macrocyclic scaffold (e.g., an ensemblin), an Aptamer and/or a peptide staple. Further, the small molecule may also be any other small molecule. It may be obtained from a natural source and be identified in a screening process.
  • the small molecule may also be conjugated to a polymeric scaffold, such as, e.g., hydroxypropyl methacrylamide (HPMA), polyethylene imine (PEI), carboxymethyl cellulose (CMC), polyethylene glycol (PEG), collagen fiber, a silk fiber, an agarose fiber, or a micro- or nanobead.
  • a polymeric scaffold such as, e.g., hydroxypropyl methacrylamide (HPMA), polyethylene imine (PEI), carboxymethyl cellulose (CMC), polyethylene glycol (PEG), collagen fiber, a silk fiber, an agarose fiber, or a micro- or nanobead.
  • the device of the present invention may comprise monoclonal antibodies targeted against sTNFR2.
  • the molecules binding to sTNFR2 may be selected from the group consisting of
  • antibodies preferably monoclonal antibodies, antibody fragments or antibody mimetics
  • cytokines in particular tumor necrosis factor alpha (TNFSF2) or TNFSF2 mutein;
  • molecules binding to sTNFR2 are monoclonal antibodies, antibody fragments or single chain antibodies.
  • the molecules binding to sTNFR2 are immobilized on
  • a filter in particular a capillary membrane filter with a pore size of between about 0.04 and 0.05 ⁇ or a parallel plate filter with a pore size of between about 0.04 and 0.08 ⁇ ;
  • semi-permeable material preferably a membrane, in particular a dialysis membrane;
  • a bead in particular a microbead or a nanobead
  • the term “column” refers to any hollow chromatography device that is itself coated with a molecule binding to sTNFR2 and/or filled with a column matrix bearing a molecule binding to sTNFR2.
  • the term “column matrix” refers to any chromatographic material and may preferably be a bead material.
  • the beads may be spherical or may bear any other shape known in the art to conduct chromatographic material.
  • the beads may be of any material known in the art to be useful for preparing chromatographic material such as, e.g., silica, sugar-based bead material (e.g., agarose, sepharose), plastic bead material (e.g., polystyrene).
  • the beads may bear a neutral, a positive or a negative zeta potential.
  • the column may be a flow-through device or may be used batch-wise.
  • the column may be, e.g, an ultrapheresis column, a high performance liquid chromatography (HPLC) column, a fast protein liquid chromatography (FPLC) column, a flash chromatography (flash) column, a Rapid Refluid Liquid Chromatography (RRLC) column, a Rapid Separation Liquid Chromatography (RSLC) column, an Ultra Fast Liquid Chromatography (UFLC) column, an Ultra Performance Liquid Chromatography (UPLC) column or any other chromatography column known by those skilled in the art.
  • HPLC high performance liquid chromatography
  • FPLC fast protein liquid chromatography
  • flash flash
  • RRLC Rapid Refluid Liquid Chromatography
  • RSLC Rapid Separation Liquid Chromatography
  • ULC Ultra Fast Liquid Chromatography
  • Chromatography is widely used in protein purification.
  • a chromatographic device is obtained.
  • this device may concomitantly separate molecules by size exclusion chromatography, hydrophobicity chromatography, etc.
  • the chromatographic methods may be combined with one or more filter(s), membrane(s) and/or semi-permeable material(s).
  • the term "filter” as used herein may refer to any device bearing pores.
  • the pores may have an average pore size of an average pore size in the range of few nanometers or even less for separating high-molecular weight molecules, such as proteins, of different molecular weights from another or the pores may have an average pore size of few micrometers for separating solid particles such as cells (e.g., red blood cells (RBCs), leucocytes, tumor cells), from another and/or from the liquid compartments of a body fluid (e.g., blood or lymph).
  • cells e.g., red blood cells (RBCs), leucocytes, tumor cells
  • a body fluid e.g., blood or lymph
  • the filter may have a molecular exclusion size that excludes molecules of less than 1 ,000 Da, less than 10,000 Da, less than 25,000 Da, less than 50,000 Da, less than 75,000 Da, less than 100,000 Da less than 125,000 Da, less than 150,000 Da, less than 175,000 Da, less than 200,000 Da, less than 250,000 Da, or less than 300,000 Da.
  • the filter may preferably be a capillary membrane filter with a pore size of between 0.001 and 10 ⁇ , more preferably of between 0.01 and 1 ⁇ , even more preferably of between 0.01 and 0.1 ⁇ , even more preferably of between 0.01 and 0.09 ⁇ , ⁇ , even more preferably of between 0.01 and 0.08 ⁇ , even more preferably of between 0.01 and 0.07, even more preferably of between 0.02 and 0.07 ⁇ , even more preferably of between 0.02 and 0.06, even more preferably of between 0.03 and 0.06 ⁇ , even more preferably of between 0.04 and 0.06 ⁇ , and most preferably of between 0.04 and 0.05 ⁇ .
  • the a preferred filter may be a parallel plate filter with a pore size of between 0.001 and 10 ⁇ , more preferably of between 0.01 and 1 ⁇ , even more preferably of between 0.01 and 0.1 ⁇ , even more preferably of between 0.01 and 0.09 ⁇ , even more preferably of between 0.01 and 0.08 ⁇ , even more preferably of between 0.01 and 0.07 ⁇ , even more preferably of between 0.02 and 0.1 ⁇ , even more preferably of between 0.02 and 0.09 ⁇ , even more preferably of between 0.04 and 0.08 ⁇ , even more preferably of between 0.04 and 0.07 ⁇ , and most preferably of between 0.04 and 0.06 ⁇ .
  • filters with the same, similar or different pore size(s) may be combined with another.
  • the filter may be any kind of filter.
  • the filter may be of any material, such as, e.g., plastic (e.g., nylon, polysterene), metal, alloy, glass, ceramics, cellophane, cellulose, or composite material.
  • the filter may be hydrophobic or hydrophilic.
  • the surface of the filter may be neutral or positively charged or negatively charged.
  • the filter may be a part of a plasmapheresis and/or an ultrapheresis device as known in the art (see, e.g., WO 99/61085 and WO 01/37873).
  • the filter may be a dead-end filter.
  • the filter may also be a cross- flow filter.
  • cross-flow filter As used herein, the terms “cross-flow filter”, “crossflow filter”, “tangential flow filter” may be understood interchangeably. Filtration may be conducted batch-wise of in a continuous flow method. Preferably, the filtration is conducted in a continuous flow method. The filter may be combined with one or more column(s), membrane(s) and/or semi-permeable material (s).
  • membrane as used in the context of the solid support may be understood in the broadest sense as any thin, flexible solid material.
  • the membrane may contain pores and serve as filter. Then at least part of the fluid flow goes through the membrane. Alternatively, the membrane may also be impermeable. Then, the fluid flow passes by the membrane on which molecules binding to sTNFR2 are immobilized.
  • Several or even numerous membranes may be used in one device and form a functional array of membranes.
  • the membrane may be a dialysis membrane. Then the membrane is permeable for some molecules (in particular small molecules) (semi-permeable). Dialysis is based on diffusion and osmosis, respectively, and is well known in the art.
  • the membrane may be of any material, such as, e.g., plastic (e.g., nylon, polysterene), metal, alloy, glass, ceramics, cellophane, cellulose, or composite material.
  • the membrane may be hydrophobic or hydrophilic.
  • the surface of the membrane may be neutral or positively charged or negatively charged.
  • the membrane may be combined with one or more column(s), filter(s) and/or semi-permeable material(s).
  • the term "semi-permeable material” may refer to any material that allows the passage of some molecules whereas other molecules can not or nearly not pass.
  • the semi- permeability can base, e.g., on size exclusion and/or on the charge of the semi-permeable material.
  • the semi-permeable material may be a solid material.
  • the semi-permeable material may be a membrane or a thick material and may be of any material, such as, e.g., plastic (e.g., nylon, polysterene), metal, alloy, glass, ceramics, cellophane, cellulose, or composite material.
  • the semi-permeable material may be hydrophobic or hydrophilic.
  • the surface of the semi-permeable material may be neutral or positively charged or negatively charged.
  • the semi-permeable material may have a smooth or porous surface structure.
  • the semi-permeable material may be combined with one or more column(s), filter(s) and/or membrane(s).
  • bead may refer to any small spherical particle.
  • a bead may be a microbead or a nanobead.
  • a microbead typically bears an average diameter in the range of approximately from 1 ⁇ and 1000 ⁇ .
  • a nanobead typically bears an average diameter in the range of approximately from 1 nm and 1000 nm.
  • the bead may be of any material such as, e.g., of silica, of metal- or alloy-based material, of sugar-based material (e.g., agarose, sepharose), of plastic (e.g., polystyrene) or may be a quantumdot.
  • the bead may be hydrophobic or hydrophilic.
  • the surface of the bead may have a neutral, a positive or a negative zeta potential.
  • the beads may be compact or may be porous.
  • a bead may be used in a column or may be used in fluid.
  • the beads may be combined with one or more column(s), filter(s), semi-permeable material(s) and/or membrane(s).
  • the term "tubing" may be understood as any hollow solid material through which a fluid may flow. It may be flexible or inflexible.
  • a tubing may be column filed with a matrix, but may also be not filled with a matrix.
  • the tubing may be the tubing of a capillary electrophoresis (CE).
  • CE capillary electrophoresis
  • the tubing may also be any kind of semi-permeable material.
  • the tubing may be of any material, such as, e.g., plastic (e.g., nylon, polysterene), metal, alloy, glass, ceramics, cellophane, cellulose, or composite material and may be hydrophobic or hydrophilic.
  • the surface of the tubing may be neutral, positively charged or negatively charged.
  • a tubing may be combined with one or more column(s), filter(s), semi-permeable material(s) and/or membrane(s).
  • the term "surface of a device" may refer to any kind of device. In particular, the device may be a therapeutic, a medical, or a laboratory device.
  • the surface of the device may be of any material, such as, e.g., plastic (e.g., nylon, polysterene), metal, alloy, glass, ceramics, cellophane, cellulose, or composite material.
  • the surface of the device may be hydrophobic or hydrophilic.
  • the surface of the device may be neutral or positively charged or negatively charged.
  • the molecules binding to sTNFR2 may be immobilized on a solid support selected from the group consisting of
  • a filter in particular a capillary membrane filter with a pore size of between about 0.04 and 0.05 ⁇ or a parallel plate filter with a pore size of between about 0.04 and 0.08 ⁇ ;
  • semi-permeable material preferably a membrane, in particular a dialysis membrane
  • a bead in particular a microbead or a nanobead
  • the device further comprises
  • the term "primary filter” may be understood as a filter that is connected upstream to the solid support on which the sTNFR2 -binding molecules are immobilized.
  • the primary filter may protect said solid support from cells.
  • the term “ultrafi Urate” may be understood in the broadest sense as a solution, emulsion or suspension from which parts of the high-molecular weight components have been removed.
  • the ultrafiltrate is a solution from which at least the blood cells (e.g., red blood cells (RBCs) and lymphocytes) have been removed.
  • the cellular fragments such as e.g., platelets have been removed.
  • the person skilled in the art will recognize plasma.
  • further one or more coagulation factors may be removed.
  • serum the person skilled in the art will recognize serum.
  • protein fraction(s) above a given size exclusion level may be removed.
  • the size exclusion level may be more than 1,000 Da, more than 10,000 Da, more than 25,000 Da, more than 50,000 Da, more than 75,000 Da, more than 100,000 Da more than 125,000 Da, more than 150,000 Da, more than 175,000 Da, more than 200,000 Da, more than 250,000 Da, or more than 300,000 Da.
  • molecules of a molecular weight of more than 120,000 Da may be removed from the ultrafiltrate.
  • the ultrafiltrate may be generated by any means known in the art. Exemplarily, it may be generated by means of a filter or by centrifugation. Centrifugation may be any centrifugation of liquids known in the art. Centrifugation may be conducted batch-wise of in a continuous flow method. Preferably, the centrifugation is conducted in a continuous flow method. Filtration and centrifugation may be combined with another, in particular in a continuous flow method, or may be combined with any other method known in the art. Optionally, centrifugation may be gradient centrifugation (e.g., sucrose gradient centrifugation, equilibrium centrifugation).
  • gradient centrifugation e.g., sucrose gradient centrifugation, equilibrium centrifugation.
  • the cells and/or protein faction(s) may optionally be reunited with the ultrafiltrate from which the sTNFR2 has been removed.
  • the cells and/or protein faction(s) may optionally be reunited with the ultrafiltrate from which the sTNFR2 has been removed.
  • at least most of the cells are added to the purified ultrafiltrate prior to being reinjected into the patient.
  • administering radiation to patent's tissue may comprise, but may not be limited to expose the patient, a patient's limb, a patient's organ, or a patient's tissue to any kind of radiation used for therapeutic purposes, such as, e.g., x-ray radiation, ultraviolet (UV) radiation (e.g., UV-A, UV-B, and/or UV-C radiation), alpha radiation, beta radiation, gamma radiation, or cosmic radiation.
  • UV radiation ultraviolet
  • Radiation therapy may also include, but may not be limited to Intensity-Modulated Radiation Therapy (IMRT), 3-Dimensional Conformal Radiotherapy (3DCRT), Stereotactic body radiation therapy (SBRT), Stereotactic radiosurgery (SRS), image-guided radiation therapy (IGRT), Particle Therapy (e.g, proton therapy), Brachytherapy, Radioisotope Therapy (RIT) (e.g., with iodine-131 , lutetium-177, strontium-89 and samarium ( l53 Sm) lexidronam and/or yttrium-90).
  • IMRT Intensity-Modulated Radiation Therapy
  • DCRT 3-Dimensional Conformal Radiotherapy
  • SBRT Stereotactic body radiation therapy
  • SRS Stereotactic radiosurgery
  • IGRT image-guided radiation therapy
  • Particle Therapy e.g, proton therapy
  • Brachytherapy e.g., Radioisotope Therapy (RIT
  • the device may further comprise a technical unit selected from the group consisting of
  • the device further has one or more molecules binding to other plasma protein(s) immobilized on a solid support, preferably wherein said molecules are molecules binding to cytokines, chemokines, soluble cytokine receptors, soluble chemokine receptors, other soluble decoy receptors, angiogenic factors, growth factors, and bone morphogenic factors more preferably molecules binding to soluble interleukin receptors (sILRs), in particular molecules binding to soluble interleukin-2 receptor alpha (sIL-2R).
  • sILRs soluble interleukin receptors
  • sIL-2R soluble interleukin-2 receptor alpha
  • soluble interleukin-2 receptor alpha As used herein, the terms “soluble interleukin-2 receptor alpha”, “soluble IL-2 receptor alpha”, “sIL-2R”, “sIL2aR”, “sIL2ctR”, “sIL2-R”, “sIL2-RA” and “CD25 alpha” may be understood interchangeably.
  • other plasma protein may be understood in the broadest sense as any protein found in blood plasma that may modulate an immune response and/or may control cell growth, angiogenesis and/or apoptosis, except for sTNFRl .
  • said plasma protein may be a cytokine.
  • a cytokine may be an interleukin (IL) (e.g., IL-l a, IL- ⁇ ⁇ , IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9 IL-10, IL-1 1 , IL-12, IL- 13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21 , IL-22, IL-23, IL-24, IL-25, IL- 26, macrophage-inhibitory factor- 1), a lymphokine (e.g., granulocyte-macrophage colony- stimulating factor (GM-CSF), an interferon (e.g., IFN-ct, IFN- ⁇ , IFN- ⁇ ), a chemokine (e.g., a CCL, a CXCL, an XCL, growth-related oncogene-alpha, CX3CL or
  • an "other plasma protein” may also be a soluble cytokine receptor (e.g., sIL-2R, or the soluble interferon-gamma receptor), a colony stimulating factor (e.g., M-CSF, G-CSF), an angiogenic factor, a growth factor (e.g., TGF-beta 1 , TGF-beta 3, HGF, VEGF, basic FGF, IGF-1, IGF-2, PDGFR, EGF, CTGF), a bone morphogenic factor (e.g., osteoprotegerin, osteopontin, macrophage inhibitory cytokine- 1 other soluble decoy receptors (e.g., soluble VCAM-1 , soluble E-selectin, soluble P- selectin, soluble E-cadherin, soluble ILT-3, soluble MICA, soluble MICB, sULBP2, sICAM-1 , soluble Fas) or one or more mutein(s) of the
  • the device has been sterilized and/or endotoxin has been removed from the device.
  • Sterilization may lead to a decreased concentration of pathogens and/or microorganisms such as, e.g., bacteria, viruses, fungals, moulds, bacterial spores, fungal spores, mould spores, worms, worm eggs, or eukaryotic protocoa.
  • Sterilization may be accomplished by any means known in the art such as, e.g., employment of radiation (e.g., UV radiation, gamma radiation) or one or more antimicrobic agent(s) known in the art.
  • An endotoxin may be any endotoxin known in the art, such as e.g., lipopolysaccharide (LPS) or delta endotoxin.
  • LPS lipopolysaccharide
  • delta endotoxin e.g., delta endotoxin.
  • an endotoxin originates from the cell wall of a gram- negative bacterium.
  • the present invention refers to a method for the removal of sTNFR2 from blood, plasma or a blood fraction, wherein molecules binding to sTNFR2, but not binding to sTNFRl, are immobilized on a solid support and brought into contact with the blood, plasma or a blood fraction and wherein sTNFRl is not removed.
  • the term "removal" may be understood in the broadest sense as the depletion or decrease of the concentration of sTNFR2. After removal, the concentration of the sTNFR2 may be decreased to less than 50%, less than 25%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1% of the initial concentration.
  • the initial concentration may be the concentration found in any fluid, in particular the concentration naturally found in a body fluid.
  • the molecule binding to sTNFR2 may be a monoclonal antibody targeted against sTNFR2.
  • the molecule binding to sTNFR2 is not binding to sTNFRl .
  • the term "not binding to” refers to a binding affinity of the sTNFR2-binding molecule to sTNFRl that is more than 5fold, more than l Ofold, more than 50fold, more than lOOfold, more than 500fold, more than lOOOfold, or more than 1 OOOOfold weaker than to sTNFR2.
  • the solid support may not comprise any molecules binding to sTNFRl with an binding affinity of a Kd of less than 10 nM, more preferably less than 100 nM, even more preferably less than 250 nM, even more preferably less than 500 nM, even more preferably less than 750 nM, even more preferably less than 1 ⁇ , even more preferably less than 2 ⁇ , even more preferably less than 5 ⁇ , even more preferably less than 10 ⁇ , even more preferably less than 50 ⁇ , even more preferably less than 100 ⁇ .
  • the solid support that bears the sTNFR2-binding molecules may further bear molecules binding to other plasma proteins except molecules binding to sTNFRl .
  • the method is conducted by means of a device of the present invention.
  • sTNFR2 is removed from a patient's blood, plasma or blood fraction ex vivo in an extracorporeal device.
  • the patient is suffering from cancer.
  • the term "suffering from” may be understood in the broadest sense as having a certain disease.
  • the patient may or may not bear any symptoms of said disease.
  • the disease may be any disease, in particular a tumorous disease, cancer.
  • the patient may or may not show any further symptoms caused by increased sTNFR2 level such as faster tumor growth, depleted immune response against tumorous or neoplastic tissue.
  • cancer as used herein may be understood in the broadest sense as any type of a cancerous, neoplastic and/or tumorous disease. It may refer to the formation of malignant, semi-malignant, pre-malignant or benignant neoplastic tissue, herein designated as “tumor” or may lead to the formation of a malignant cell in suspension.
  • a tumor may be any kind of tumor, such as a solid tumor or a metastasis.
  • the tumor may be a primary tumor or a secondary tumor.
  • tumor as used herein, the terms “tumor”, “cancerous swelling”, “neoplasia”, “lesion” and “carcinoma in situ” may be understood interchangeably.
  • the tumor may be a benign, pre-malignant or malignant tumor.
  • the tumor may origin from any tissue that can develop a tumor, such as, e.g., sarcoma (e.g., myxosarcoma, histiocytoma, liposarcoma, chondrosarcoma, osteosarcoma, angiosarcoma, leiomyosarcoma, rhabdomyosarcoma, fibrosarcoma, synovialcarcinoma, Ewing sarcoma, hemangiosarcoma, lymphangiosarcoma, adenosarcoma, carciosarcoma), bronchiocarcinoma, prostate carcinoma, cervix carcinoma, ovarian carcinoma, mamma carcinoma, bronchial carcinoma, melanoma, esophagus carcinoma, rectal carcinoma, pancreas carcinoma, bladder carcinoma, kidney carcinoma, blastoma (e.g., hepatoblastoma
  • the cancer may be located in any organ, such as, e.g., brain, eye, skin, lung, liver, oral cavity, pharynx, stomach, small intestine, duodenum, colon, urinary bladder, kidney, gall bladder, pancreas, vaginal tract, testicles, breast, a muscle, blood, lymph, a lymph node, esophagus, heart, a bone, bone marrow, spleen, a blood vessel, a lymphatic vessel, cervix, uterus, spinal cord, or an ovary or may be located in connective tissue, mucosa tissue, or nerve tissue.
  • organ such as, e.g., brain, eye, skin, lung, liver, oral cavity, pharynx, stomach, small intestine, duodenum, colon, urinary bladder, kidney, gall bladder, pancreas, vaginal tract, testicles, breast, a muscle, blood, lymph, a lymph node, esophagus, heart,
  • the patient who is treated is suffering from another disease associated with an increased sTNFR2 level.
  • the term "increased sTNFR2 level” may be understood in the broadest sense as an elevated concentration of sTNFR2 in a body fluid when compared to the sTNFR2 level found throughout the population.
  • the increased sTNFR2 level may be a sTNFR2 level that is more than 1.5fold, more than 2fold, more than 5fold, more than lOfold, more than 50fold, or even more than lOOfold higher than the sTNFR2 level found throughout the population.
  • the method is combined with the removal of one or more other plasma protein(s), preferably cytokines, chemokines, soluble cytokine receptors, other soluble decoy receptors, angiogenic factors, growth factors, and bone morphogenic factors more preferably molecules binding to sILRs, in particular molecules binding to sIL-2R.
  • a further aspect of the present invention refers to a molecule specifically binding to sTNFR2, but not binding to sTNFRl , for use in a method for treating the human or animal body. Most preferably, this molecule may be a monoclonal antibody targeted against sTNFR2.
  • the treating is treating cancer.
  • the molecule is used in a method of the present invention.
  • the molecule is part of a device of the present invention or is immobilized on a bead or an implant, preferably wherein said bead or implant is in contact with the blood stream, the lymph or the extracellular matrix, in particular in contact with the blood stream.
  • blood stream may be understood in the broadest sense as circulating blood.
  • the blood stream may be in a vessel of a patient or may be in a tube, a filter, a column or any other device outside of the body.
  • the method further comprises the removal of one or more other plasma protein(s), preferably cytokines, chemokines, soluble cytokine receptors, other soluble decoy receptors, angiogenic factors, growth factors, and bone morphogenic factors more preferably molecules binding to sILRs, in particular molecules binding to soluble interleukin-2 receptor alpha (sIL-2R).
  • plasma protein(s) preferably cytokines, chemokines, soluble cytokine receptors, other soluble decoy receptors, angiogenic factors, growth factors, and bone morphogenic factors more preferably molecules binding to sILRs, in particular molecules binding to soluble interleukin-2 receptor alpha (sIL-2R).
  • the present invention refers to blood, plasma or a blood fraction obtainable from a method of the present invention for use in a method for treating cancer.
  • the blood, plasma or a blood fraction of which sTNFR2 has been removed may be injected or recirculated into the patient by any means known in the art.
  • the sample may be injected by means of a tubing and/or an acus, a needle, a spicule or the like. These means are well-known in the context of dialyzers and kidney machines and can be used without particular expert skills.
  • the method of the present invention removes sTNFR2 from a blood, plasma or a blood fraction
  • the method may have an impact on the whole organism systemically, independent on where the tumor is located. Therefore, the method is independent on barriers, such as the blood-brain barrier, the blood-testis barrier, the blood-milk barrier or the mother- embryo/fetus barrier. Therefore, the method may also enable the systemic treatment of target tissue beyond the barrier.
  • a patient suffering from a brain disease such as, e.g., e brain tumor (e.g., an astrocytome, or a glioblastome) may be treated by systemic treatment without targeting the brain directly.
  • a fetus or embryo may be treated indirectly by treating the pregnant mother systemically.
  • a body fluid such as, e.g., blood
  • a body fluid such as, e.g., blood
  • the extracorporeal device of the present invention may be extracted somewhere from the patient's body (e.g., from the basilica vein), conducted through the extracorporeal device of the present invention and, subsequently, being injected or recirculated somewhere in the patient's body (e.g., recirculated in the same or the other basilica vein), whereas the tissue to be treated (e.g., cancer tissue) may be located somewhere else in the patient's body (e.g., somewhere in the inner organs).
  • the treatment may be successful as a body fluid such as blood is circulating through the entire body of the patient.
  • a treatment may be successful when the local concentration, but also when the overall concentration of sTNFR2 in the patient is depleted.
  • the treatment as described herein may be the sole treatment of the patient or may be combined with one or more other treatment(s) of the patient. Additional treatment may be any treatment known in the art, such as, e.g., therapy with one or more chemotherapeutic(s), other anti cancer drug(s) and/or agent(s) (e.g., alkylating agents (e.g., mechlorethamine, cyclophosphamide, chlorambucil, Ifosfamide), anti-metabolites (e.g., 5- fluorouracil, azathioprine, 6-mercaptopurine, mercaptopurine, pyrimidines, thioguanine, fludarabine, floxuridine, cytosine arabinoside (cytarabine), pemetrexed, raltitrexed, pralatrexate, methotrexate), plant alkaloids and terpenoids (e.g., vinca alkaloids (vincristine, vinblast
  • the therapy may also include the oral intake of an agent or a pharmaceutically acceptable composition thereof, the injections of an agent or a pharmaceutically acceptable composition thereof, the perfusion of an agent or a pharmaceutically acceptable composition thereof.
  • the removal of sT FR2 may be combined with any surgical procedure known in the art such as, e.g., the section or resection of the tumor, the amputation of a limb, a breast, a testicle, or a certain tissue or parts thereof.
  • the removal of sTNFR2 may be combined with radiation therapy.
  • soluble TNF receptor 1 soluble TNF receptor 1
  • sIL-2R soluble IL-2 receptor
  • sTNFRl and sTNFR2 are removed from the blood of the patients.
  • sTNFRl , sTNFR2 and sIL-2R are removed from the blood of the patients.
  • the present invention also relates to a method for sensitizing a tumor patient to a treatment with a chemotherapeutic agent, comprising the step of removing soluble TNF receptor 2 (sTNFR2) from the blood of said patient.
  • sTNFR2 soluble TNF receptor 2
  • chemotherapeutic drugs can be used in the methods or uses of the invention. These compounds fall into several different categories, including, for example, alkylating agents, antineoplastic antibiotics, antimetabolites, and natural source derivatives.
  • alkylating agents include busulfan, caroplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide (i.e., Cytoxan), dacarbazine, ifosfamide, lomustine, mecholarethamine, melphalan, procarbazine, streptozocin, and thiotepa.
  • antineoplastic antibiotics include bleomycin, dactinomycin, daunorubicin, doxorubicin, idarubicin, mitomycin (e.g., mitomycin C), mitoxantrone, pentostatin, and plicamycin.
  • antimetabolites include fluorodeoxyuridine, cladribine, cytarabine, floxuridine, fludarabine, flurouracil (e.g., 5-fluorouracil (5FU)), gemcitabine, hydroxyurea, mercaptopurine, methotrexate, and thioguanine.
  • natural source derivatives include docetaxel, etoposide, irinotecan, taxanes (e.g. paclitaxel), teniposide, topotecan, vinblastine, vincristine, vinorelbine, prednisone, and tamoxifen.
  • chemotherapeutic agents that can be used in the invention include asparaginase and mitotane. Furthermore, also C2 ceramide can be used. In an especially preferred embodiment, the chemotherapeutic drug is selected from the group consisting of actinomycin-D, mitomycin C, cisplatin, doxorubicin, etoposide, verapamil, podophyllotoxin, 5-FU, taxans such as paclitaxel, and carboplatin.
  • sTNFR2 can be removed by any means known to the person skilled in the art. Preferably, sTNFR2 is removed with the help of a molecule binding to sTNFR2. Such molecules are discussed in detail above. Furthermore, such molecules also include molecules that do not bind specifically to sTNFR2, as e.g. polyclonal antibodies recognizing soluble TNF receptor 2 and soluble TNF receptor 1.
  • said molecule is an antibody against sTNFR2, preferably a monoclonal antibody against sTNFR2.
  • sTNFR2 is removed with the help of a device of the invention.
  • the invention further relates to a molecule binding to sTNR2 for use in a method for sensitizing a tumor patient to a treatment with a chemotherapeutic agent.
  • a molecule binding to sTNR2 for use in a method for sensitizing a tumor patient to a treatment with a chemotherapeutic agent.
  • the molecule is an antibody against sTNFR2, preferably a monoclonal antibody against sTNFR2.
  • the invention further relates to a method for treating a tumor in a patient, comprising administering to a patient a chemotherapeutic drug in an amount sufficient for the treatment of the tumor, wherein from the blood of said patient sTNFR2 has been removed.
  • chemotherapeutic agents is a standard procedure known to the person skilled in the art. All embodiments defined above also apply to this aspect of the invention. Examples of chemotherapeutic agents which can be used in the context of the present invention are given above.
  • the present invention also relates to a chemotherapeutic agent for use in a method for treating a tumor in a patient, wherein from the blood of said patient sTNFR2 has been removed. All embodiments discussed above also apply to this aspect of the invention.
  • the invention is further explained by the following example and figures, which are intended to illustrate, but not limit the scope of the present invention.
  • Figure 1 shows the treatment scheme
  • Figure 2 shows the apheresis equipment.
  • blood was pumped from the animal (A. carotis) via a plasma separator and retraced to the animal by a venous catheter.
  • Figure 3 shows the mean tumor diameter in tumor-bearing Brown Norway rats treated with Sham apheresis (dashed line, open circles) or sTNFR2 apheresis (solid line, filled squares), respectively, and 0.25 mg kg melphalan.
  • Figure 4 shows the change of mean tumor diameter during course of treatment of tumor- bearing Wag/Rij rats treated with Sham apheresis and 0.25 mg/kg low dose melphalan (Sham low, solid line, diamonds) or sTNFR2 apheresis (sTNFR2 low, dotted line, squares), respectively Sham apheresis or sTNFR2 apheresis at high melphalan concentrations of 0,50 mg/kg (Sham high dotted line, triangles, respectively sTNFR2 high, solid line, circles)
  • Figure 5 shows the body weight of Wag/Rij rats during the course of treatment with low doses of melphalan (0,25 mg/kg), Sham apheresis (Sham low, solid line, diamonds), sTNFR2 apheresis (sTNFR2 low, dotted line, squares) and with high doses of melphalan (0,50 mg/kg) and Sham apheresis (Sham high, dotted line, triangles), respectively sTNFR2 apheresis /sTNFR2 high, solid line, circles).
  • Example 1 shows the influence of the removal of sTNFR2 in Brown Norway rats bearing a non-immunogenic sarcoma BN 175 on tumor growth in the presence of systemically administered melphalan.
  • the project aimed to reveal the influence of sTNFR2 on the promotion of tumor growth by removing sTNFR2 using plasmapheresis under the presence of melphalan treatment (0.25 mg/kg twice per week).
  • Melphalan is a chemotherapeutic drug that belongs to the class of nitrogen mustard alkylating agents. The effect of the adsorption of the following factors on tumor growth was investigated in the presence of melphalan:
  • TNF receptor 2 sTNFR2
  • NHS activated 1 ml Sepharose columns was purchased from GE Healthcare (Order No. 17- 0716.01). Based on the amount of antibodies used for human treatment using the OncoSorb® column, 0.12 mg of affinity purified goat anti-mouse sTNFR2 antibodies (purchased from R&D Systems Order No. AF-426-PB) were coupled according to the manufacturer's procedure to NHS activated Sepharose. The antibodies were able to remove secreted rat sTNFR2 molecules out of rat plasma as shown by affinity purification of the receptor from rat plasma. 2.3. Design
  • tumor tissue implantation On the day of tumor tissue implantation (day -x), tumor material from a single sarcoma- bearing donor rat was taken and washed in RPMI 1640 culture medium. Then, the non- immunogenic Brown Norway 175 sarcoma tissue pieces (approx. 1 mm 3 ) were implanted under the skin of the Brown Norway rats to induce cancer growth. The method described by Prof, ten Hagen from Rotterdam was employed). The day of tumor tissue transfer was October 20, 2010, for study part I and November 22, 2010, for study part II. Together with tumor tissue implantation or 1-2 days thereafter, chronical arterial and venous catheters were inserted under general anesthesia (i.p.
  • the first apheresis treatment was commenced to treat the growing tumor (day 0). This time point for the first apheresis was chosen based on the knowledge that tumors of this size - >1 1 ⁇ 1 mm in diameter - exhibit a very fast growth rate doubling their volume every two to three days.
  • Each animal was treated up to 4 times by plasmapheresis, The time between two plasmapheresis treatments was 2-5 days. During each plasmapheresis treatment, plasma was pumped through the adsorber for about one hour.
  • the adsorbers were columns containing affinity purified goat anti-mouse sTNFR2 antibodies.
  • the adsorbers for the plasmapheresis procedure were obtained from BioPheresis GmbH (Heidelberg, Germany) and had a volume of 1 ml.
  • Group 2 Plasmapheresis using a 1 ml column containing 120 ⁇ g affinity-purified goat anti-mouse-TNFR2 antibodies
  • part II of the study was performed, using Brown Norway rats bearing identical sarcomas (BN-175).
  • rats which had tumors of 1 1 ⁇ 2 mm in diameter) and which had functional catheters were divided into the following two groups:
  • Group 2 Plasmapheresis using a 1 ml column containing 120 ⁇ g affinity-purified goat anti-mouse-TNFR2 antibodies.
  • Tumor growth (diameters were measured in two different special directions (A and B)), measurement of tumor size with a caliper daily before first plasmapheresis and in between plasmapheresis treatments.
  • blood was pumped (multi-channel pump, Petro Gas Ausriistungen, Berlin, Germany) from the animal (A. carotis) via a plasma separator (Saxonia medical and Alpha Plan, Radeberg, Germany) and retraced to the animal by a venous catheter.
  • the separated plasma entered the second circuit and passed the adsorber before it was returned to the rat (V. jugularis).
  • the following parameters will be or were measured before and after each apheresis:
  • Bound sTNFR2 will be determined by elution of the respective (bound) protein from the column after each apheresis by analysis of the eluate.
  • the rats were sacrificed 21 days after first apheresis treatment. 50 % of the tumor (maximally a piece of 2 x 2 cm) was fixed in formalin to determine necrotic tissue and a comparable piece was shock-frozen and stored at -70°C for later histological investigation.
  • each column was flushed with at least 6 ml 0.9% saline. After the apheresis treatment, each column was treated in the following way:
  • the rats had a mean body weight of 265 ⁇ 1 1 g (part I) and 253 ⁇ 16 g (part II).
  • the body weight was comparable between the investigated groups.
  • the procedure of catheter insertion was followed by a decline of body weight during the following days.
  • the body weight at the beginning was reached after 4 to 7 days.
  • the start of apheresis treatments 9.4 ⁇ 1.3 (part I) and 7.9 ⁇ 0.7 days after tumor tissue transfer was followed by a slight decline in body weight, more prominently expressed in part II of the study.
  • Study part II clearly demonstrates that the mean tumor diameter in the group treated with sTNFR2 is smaller compared to the group subjected to Sham apheresis from day 10 after the first apheresis onwards.
  • the results of study part II demonstrate the inhibitory effect of sTNFR2 apheresis on tumor growth between days 1 1 and 15 following the first apheresis and from day 18 after the first apheresis onwards.
  • sTNFR2 apheresis has a positive impact on reducing the tumor size. Therefore, sTNFR2 apheresis as described herein is usable in a method for treating and preventing a tumorous disease in a patient in need thereof.
  • apheresis and melphalan treatment were discontinued, the tumors began to grow again, as had been expected on the basis of previous experiments using identical tumor tissue in the same rat strain, Brown Norway, with isolated limb perfusion with TNF-a and melphalan.
  • Body weight There are nearly no changes in body weight during apheresis.
  • Hematocrit Apheresis induced a comparable decrease of hematocrit in both groups.
  • White blood cell counts Apheresis induced a comparable decrease of white blood cell counts in both groups.
  • Body temperature Body temperature before and 1 h after the plasmapheresis treatment was comparable in both groups.
  • Extracorporeal adsorbed plasma volumes during each apheresis in tumor-bearing Brown Norway rats treated with Sham apheresis or sTNFR2 apheresis, respectively, are shown. Data for each animal and each apheresis and means are given. Extracorporeal (filtered) plasma volumes during apheresis (in ml)
  • Example 2 shows the influence of the removal of sTNFR2 in Wag Rij rats bearing the immunogenic ROS-1 osteosarcoma on tumor growth and animal weight in the presence of systemically administered melphalan.
  • the project aimed to confirm the efficacy of the combination of Melphalan chemotherapy and the removal of sTNFR2 by apheresis as described in example 1 in a second tumor model using Wag Rij rats bearing the immunogenic ROS-1 osteosarcoma.
  • the experiments also aimed to find the optimal dosage of highly toxic Melphalan, combined with apheresis treatment.
  • Frozen ROS-1 tumor cells delivered from Prof. T. Ten Hagen in March 2012 and stored at -70°C up to the culturing, were thawed on 3 rd of March and transferred in Minimum Essential Medium Eagle (SIGMA- ALDRICH, M4655) containing 10% fetal calf serum (FCS) 2012. After cultivation in a culture flask with DMEM and 10% FCS during 8 days, the cells were adhered by trypsination and counted. 1.5 Mill, cells per animal were injected subcutaneously in tested Wag/rij rats on 1 1 th of April.
  • SIGMA- ALDRICH, M4655 Minimum Essential Medium Eagle
  • FCS fetal calf serum
  • ROS-1 tumor cells (1.500.000 in 500 ⁇ per animal) were injected under the skin of the left flank region of the WAG rat to induce cancer growth (the method was detailed by Prof, ten Hagen; Rotterdam). Rats with palpable tumors were instrumented with a chronic arterial and venous catheter. The catheters were inserted under general anaesthesia (i.p. injection of 0.8 mg Rompun ® , Bayer and 4 mg Ketamin ® , Sanofi, Germany) into the Arteria carotis and the Vena jugularis. Catheters were flushed with heparinized saline three times per week before the study.
  • general anaesthesia i.p. injection of 0.8 mg Rompun ® , Bayer and 4 mg Ketamin ® , Sanofi, Germany
  • Apheresis equipment and procedure of apheresis treatment was identical as for example 1.
  • apheresis treatment was combined with intra- venous chemotherapy directly after the apheresis treatment . All animals were repeatedly administered a chemotherapeutic drug (Melphalan: Alkeran ® , GlaxoSmithKline).
  • Each animal was treated with up to 6 apheresis cycles in intervals of 2-3 days (2-3 cycles per week). The duration of each plasmapheresis was one hour.
  • the adsorbers for the plasmapheresis procedure with a volume of 1 ml were provided by BioPheresis GmbH.
  • the first apheresis therapy was initiated directly when the tumor was grown to a mean diameter of 1 1 ⁇ 3 mm, followed by application of melphalan chemotherapy (day 0).
  • day 0 the second apheresis was performed and also the second Melphalan injection was administered.
  • Melphalan was administered two times per week, for two weeks (four injections). Apheresis treatments were performed three times per week, for two weeks. The animals were monitored without further treatment up to day 21.
  • Tumour growth (delta mean tumour diameter)
  • the animals met inclusion criteria (mean diameter 1 1 ⁇ 3 mm) 26 to 29 days after tumor cell injection.
  • tumour size increased continuously during the twenty-one days of monitoring.
  • sTNFR2 / melphalan group a tendency to a reduced tumour growth was shown from day 5 on.
  • Sham low and Sham high are control data where animals have been treated with "empty HiTrap columns” (containing 1 ml NHS activated Sepharose, that have undergone the same blocking procedure as antibody loaded columns), and repetitive administration of 0,25 mg/kg (low) respectively 0,50 mg/ml (high).
  • sTNFR2 high and low, respectively are data where animals have been treated with apheresis using specifically loaded apheresis columns that can specifically bind sNTNFR2.
  • Delta mean tumor diameter the difference to tumor diameter measured at each animal at the days of the first apheresis, in mm.
  • Sham low and Sham high are control data where animals have been treated with "empty HiTrap columns" (containing 1 ml NHS activated Sepharose, that have undergone the same blocking procedure as antibody loaded columns), and repetitive administration of 0,25 mg/kg (low) respectively 0,50 mg/ml (high).
  • sTNFR2 high and low, respectively, are data where animals have been treated with apheresis using specifically loaded apheresis columns that can specifically bind sNTNFR2.
  • the rats had a body weight of 242 ⁇ 8 g.
  • the procedure of catheter insertion was followed by a decline of body weight during the next days and the initial body weight was reached again after 4 to 7 days.
  • the start of apheresis treatments and Melphalan applications was followed by a decline in body weight gain surprisingly only in the Sham apheresis control group.
  • the interruption of Melphalan treatment from day 2 to 7 followed by a slight reincrease of body weight in the both groups and the treatment with chemotherapeutic on day 7 induced a slight reduction again.
  • Sham low and Sham high are control data where animals have been treated with "empty HiTrap columns” (containing 1 ml NHS activated Sepharose, that have undergone the same blocking procedure as antibody loaded columns), and repetitive administration of 0,25 mg/kg (low) respectively 0,50 mg/ml (high).
  • sTNFR2 high and low, respectively are data where animals have been treated with apheresis using specifically loaded apheresis columns that can specifically bind sNTNFR2.
  • Body weight (g) during the course of treatment The first apheresis started on day 0. Sham low and Sham high are control data where animals have been treated with "empty HiTrap columns" (containing 1 ml NHS activated Sepharose, that have undergone the same blocking procedure as antibody loaded columns), and repetitive administration of 0,25 mg kg (low) respectively 0,50 mg/ml (high).

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Abstract

La présente invention concerne un dispositif ayant des molécules se liant au récepteur 2 soluble du facteur onconécrosant (sTNFR2, TNFRSF1B) immobilisé sur un support solide, sur lequel aucune molécule se liant au récepteur 1 soluble du facteur onconécrosant (sTNFR1) n'est immobilisée. La présente invention concerne en outre un procédé d'élimination du sTNFR2 du sang, du plasma ou d'une fraction sanguine. La présente invention concerne en outre une molécule se liant spécifiquement au sTNFR2, mais ne se liant pas au sTNFR1, destinée à être utilisée dans le traitement du corps animal ou humain et du sang, du plasma ou d'une fraction sanguine pouvant être obtenus par le procédé de la présente invention pour une utilisation dans un procédé destiné au traitement du cancer.
PCT/EP2012/002340 2011-06-01 2012-06-01 Élimination du récepteur 2 soluble du facteur onconécrosant (stnfr2) WO2012163544A1 (fr)

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WO2013179143A3 (fr) * 2012-06-01 2014-05-01 Biopheresis Technologies, Inc. Sensibilisation de cellules cancéreuses par l'élimination des récepteurs solubles de facteur de nécrose tumorale
JP2017006508A (ja) * 2015-06-25 2017-01-12 ネフロジェネシス・リミテッド・ライアビリティ・カンパニー 腎臓透析および体外解毒に関する方法および装置
WO2019053031A1 (fr) * 2017-09-13 2019-03-21 Bavarian Immunology Association GmbH Sang purifié pour utilisation en thérapie anticancéreuse
US10420817B2 (en) 2014-10-03 2019-09-24 Nanotics, Llc Compositions and methods for inhibiting the biological activity of soluble biomolecules
US10653790B2 (en) 2015-07-29 2020-05-19 Nanotics, Llc Compositions and methods related to scavenger particles
JP2021013846A (ja) * 2020-11-16 2021-02-12 ハイバー・マイクロサイエンシズ・リミテッド・ライアビリティ・カンパニー 腎臓透析および体外解毒に関する方法および装置
CN112691252A (zh) * 2013-12-27 2021-04-23 艾莱兹疗法股份有限公司 血浆分离装置
US11065345B2 (en) 2017-01-04 2021-07-20 Nanotics, Llc Methods for assembling scavenging particles
US11224858B1 (en) 2020-10-01 2022-01-18 Immunicom, Inc. Reduced leaching of a ligand
WO2022071960A1 (fr) * 2020-10-01 2022-04-07 Immunicom, Inc. Lixiviation réduite d'un ligand
US11529445B2 (en) 2013-12-20 2022-12-20 Hibar Microsciences Llc Methods and apparatus for kidney dialysis and extracorporeal detoxification

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013179143A3 (fr) * 2012-06-01 2014-05-01 Biopheresis Technologies, Inc. Sensibilisation de cellules cancéreuses par l'élimination des récepteurs solubles de facteur de nécrose tumorale
US11529445B2 (en) 2013-12-20 2022-12-20 Hibar Microsciences Llc Methods and apparatus for kidney dialysis and extracorporeal detoxification
US20210138143A1 (en) * 2013-12-27 2021-05-13 Eliaz Therapeutics, Inc. Plasmapheresis device
CN112691252A (zh) * 2013-12-27 2021-04-23 艾莱兹疗法股份有限公司 血浆分离装置
US11771744B2 (en) 2014-10-03 2023-10-03 Nanotics, Llc Compositions and methods for inhibiting the biological activity of soluble biomolecules
US10420817B2 (en) 2014-10-03 2019-09-24 Nanotics, Llc Compositions and methods for inhibiting the biological activity of soluble biomolecules
US10888602B2 (en) 2014-10-03 2021-01-12 Nanotics, Llc Compositions and methods for inhibiting the biological activity of soluble biomolecules
JP2017006508A (ja) * 2015-06-25 2017-01-12 ネフロジェネシス・リミテッド・ライアビリティ・カンパニー 腎臓透析および体外解毒に関する方法および装置
US10653790B2 (en) 2015-07-29 2020-05-19 Nanotics, Llc Compositions and methods related to scavenger particles
US11065345B2 (en) 2017-01-04 2021-07-20 Nanotics, Llc Methods for assembling scavenging particles
US12083186B2 (en) 2017-01-04 2024-09-10 Nanotics, Llc Methods for assembling scavenging particles
WO2019053031A1 (fr) * 2017-09-13 2019-03-21 Bavarian Immunology Association GmbH Sang purifié pour utilisation en thérapie anticancéreuse
US11224858B1 (en) 2020-10-01 2022-01-18 Immunicom, Inc. Reduced leaching of a ligand
WO2022071960A1 (fr) * 2020-10-01 2022-04-07 Immunicom, Inc. Lixiviation réduite d'un ligand
US11458236B2 (en) 2020-10-01 2022-10-04 Immunicom, Inc. Reduced leaching of a ligand
JP2021013846A (ja) * 2020-11-16 2021-02-12 ハイバー・マイクロサイエンシズ・リミテッド・ライアビリティ・カンパニー 腎臓透析および体外解毒に関する方法および装置

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