WO2015171270A1 - Procédé de traitement de neurofibromatose - Google Patents

Procédé de traitement de neurofibromatose Download PDF

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Publication number
WO2015171270A1
WO2015171270A1 PCT/US2015/025645 US2015025645W WO2015171270A1 WO 2015171270 A1 WO2015171270 A1 WO 2015171270A1 US 2015025645 W US2015025645 W US 2015025645W WO 2015171270 A1 WO2015171270 A1 WO 2015171270A1
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WIPO (PCT)
Prior art keywords
body fluid
antigen
antibody
treatment
ant
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Application number
PCT/US2015/025645
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English (en)
Inventor
Mitchell S. Felder
Original Assignee
Felder Mitchell S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
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Publication of WO2015171270A1 publication Critical patent/WO2015171270A1/fr

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Classifications

    • 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
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3687—Chemical treatment
    • 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
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/362—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits changing physical properties of target cells by binding them to added particles to facilitate their subsequent separation from other cells, e.g. immunoaffinity

Definitions

  • the present invention relates to an article and method of sequentially and extracorporeally applying a treatment to a patient's blood and then removing the treatment from the blood before returning the blood to the patient's bloodstream.
  • the neurofibromatoses are a set of inherited disorders, designated as neurofibromatosis type 1 (NFl), neurofibromatosis type 2 (NF2), and schwannomatosis, that classically causes the development of benign tumors of the nerve sheath.
  • NFl neurofibromatosis type 1
  • NF2 neurofibromatosis type 2
  • schwannomatosis a set of inherited disorders, designated as neurofibromatosis type 1 (NFl), neurofibromatosis type 2 (NF2), and schwannomatosis, that classically causes the development of benign tumors of the nerve sheath.
  • NFl neurofibromatosis type 1
  • NF2 neurofibromatosis type 2
  • schwannomatosis schwannomatosis
  • Neurofibromatosis type 1 is the most common of the disorders, affecting ⁇ 1 in 3500 individuals worldwide.
  • the hallmark lesion in NFl is the neurofibroma, whereas schwannomas are characteristic of NF2 and schwannomatosis. These tumors may be differentiated histologically.
  • NFl Unlike the other two disorders, NFl also includes non-tumor manifestations, making it a true multisystem disorder.
  • Neurofibromatosis (NF, neurofibromatosis type 1) is an inherited disease in which the nerve tissue grows neurofibroma tumors that may be benign, but have the potential for malignant transformation. Neurofibromas may cause severe damage by compressing nerves and other tissues.
  • Neurofibromatosis is an autosomal dominant disorder. The severity in affected individuals can vary, which is due to variable expressivity.
  • the present invention relates to a method of extracorporeal treating a patient's body fluid, including but not limited to, cerebrospinal fluid (CSF), lymph, and blood.
  • CSF cerebrospinal fluid
  • lymph including but not limited to, lymph, and blood.
  • the present invention relates to the treatment of neurofibromatoses, hereinafter abbreviated as "NF.”
  • NF neurofibromatosis
  • the present invention for the treatment of neurofibromatosis will specifically refer to neurofibromatosis type 1 (NFl), neurofibromatosis type 2 (NF2) and schwannomatosis by name, as necessary.
  • the invention pertains to a method for the extracorporeal treatment of one or more body fluids in two stages characterized by removing a body fluid from a living body diseased with a type of NF, passing the body fluid through a first stage; applying an anti- angiogenesis, anti-tumorigenesis, anti-mast cell attractant and/or activator to at least one, or more, antigen in the body fluid (blood and/or CSF).
  • the treatment comprises creating an antibody-antigen moiety during passage thereof through said first stage; passing the treated body fluid through a second stage; removing antibody-antigen moiety from the body fluid during passage through the second stage, and returning the purified body fluid to the body.
  • the invention is further characterized by targeting an antigen in the body fluid, with an antibody to allow and facilitate removal thereof in the second stage.
  • the Neurofibromatosis targeted antigen(s) targeted antigens would include at least one component selected from:
  • neurofibromas/tumor(s) (NF Ant. Ang.)
  • VEGF vascular endothelial growth factor
  • Antigens involved in causing or facilitating neurofibromas and/or tumori genesis are involved in causing or facilitating neurofibromas and/or tumori genesis;
  • m-Tor mammalian target of rapamycin
  • FGF2 Fibroblast growth factor-2
  • NGF nerve growth factor
  • E. PDGF platelet-derived growth factor
  • Tumor growth factor alpha and beta
  • SCF stem cell factor
  • Interleukin 1 interleukin-6
  • IL-8 interleukin-8
  • IL-17 interleukin-17
  • TNF-a Tumor necrosis factor-alpha
  • the method is further characterized by removing body fluid from a person to produce an extracorporeal bodily fluid; imposing a treatment acting on an antigen of NF in the body fluid, filtering or otherwise removing the treatment from the body fluid, and returning the body fluid to the patient after removing substantially all of the treatment in the second stage.
  • the method of the present invention comprises treating at least one component of a patient's body fluid extracorporeally with a designer antibody containing an albumin- moiety which will create an albumin-antibody-NF antigen moiety allowing for the efficacious dialysis of the resultant albumin-antibody-NF antigen compound (the targeted NF antigen being
  • NF Ant. Ang. NF Ant. T.
  • NF Ant. Mast NF Ant. Chem.
  • the method of the present invention also allows for the addition of therapeutic compounds during, or in tandem with, the subtractive process.
  • Neurofibromin-1 neurofibromatosis-related protein NF-1) in neurofibromatosis type 1 (NFl)
  • the method of the present invention also allows for the addition of molecular compounds during, or in tandem with, the subtractive process.
  • Neurofibromin-1 neurofibromatosis-related protein NF-1
  • NFl neurofibromatosis type 1
  • This may be produced using gene therapy, via an adenovirus, Herpes simplex virus, or retrovirus serving as the vector, thereby enabling the substitution of the NFl gene on the long arm of chromosome 17ql l.2, in neurofibromatosis type 1.
  • Schwannomin in neurofibromatosis type 2 (NF2) : This could be produced using gene therapy, via an adenovirus , Herpes simplex virus, or retrovirus serving as the vector, thereby enabling the substitution of the NF2 gene on chromosome 22ql 1.1, in neurofibromatosis type 2.
  • the method is characterized by removing body fluid from a person to produce an extracorporeal bodily fluid; directing a first antibody against the targeted NF antigen (NF Ant. Ang., NF Ant. T., NF Ant. Mast , NF Ant. Chem.) in the first stage of extracorporeal treatment in the body fluid; in the second stage directing a second antibody conjugated with albumin and/or a protein against the targeted NF antigen thereby forming an albumin-antibody- NF antigen compound; removing at least a substantial portion of the albumin-antibody-NF antigen compound from the body fluid by dialysis, other filtering, or other means; and returning the body fluid to the patient.
  • NF antigen NF Ant. Ang., NF Ant. T., NF Ant. Mast , NF Ant. Chem.
  • the method is characterized by the ability to increase the efficacy of the methodology by using magnetic resonance angiography (MRA) and magnetic resonance venography (MRV) to specifically characterize the arterial and venous flow of the patient's circulation in relation to neurofibromas and/or tumors.
  • MRA magnetic resonance angiography
  • MMV magnetic resonance venography
  • This technique may also be used for localized treatment(s), as well as total corporeal treatment.
  • the method is characterized by testing the blood and/or CSF to determine the efficacy of treatment before returning the body fluid to the patient.
  • Figure 1 is a partial cross sectional view of a cylinder and tubing used to deliver a treatment to a bodily fluid.
  • Figure 2 is a partial cross sectional view showing additional detail of the cylinder and tubing of Figure 1.
  • a selected body fluid is removed using a standard catheter and/or lumbar puncture.
  • the body fluid is treated with antibodies against the targeted NF antigen (NF Ant. Ang., NF Ant. T., NF Ant. Mast, NF Ant. Chem.).
  • the method of the present invention comprises treating at least one component of a patient's body fluid extracorporeally with a designer antibody containing an albumin- moiety to create an albumin-antibody-NF antigen moiety allowing for the efficacious dialysis, filtering or other means of removal of the resultant albumin-antibody-NF antigen compound (the targeted NF antigen being respectively, one or a combination of antigen(s) from: NF Ant. Ang., NF Ant. T., NF Ant. Mast , NF Ant. Chem.
  • the albumin-antibody will be directed towards facilitating removal of the targeted NF antigen(s): (NF Ant. Ang., NF Ant. T., NF Ant. Mast, NF Ant. Chem.).
  • the cleansed body fluid will be returned to the patient.
  • the frequency of treatment, and the specifically targeted NF antigen(s) to be removed would depend upon the underlying symptomatology and pathology of the patient, and would be determined by the patient's physician.
  • the article used in performing the method includes two-stages.
  • the first stage includes a treatment chamber for addition of an antibody with an attached albumin moiety, which is added to the body fluid.
  • a second stage receives the treated blood and/or CSF and includes a unit for removing the treatment.
  • the method includes providing a dialysis or other filtering machine with a first stage and a second stage, and sequentially passing the extracorporeal body fluid through the first and second stages.
  • the body fluid is removed from the patient using standard procedure.
  • the first stage applies a treatment using an antibody which was has attached to it an albumin moiety (or alternatively, a moiety which allows for the efficacious dialysis or removal by other techniques of the antibody-albumin-NF antigen), for the treatment of the body fluid.
  • the second stage substantially removes the treatment.
  • the purified body fluid is then tested for the efficacy of removal of the NF antigen and returned to the patient.
  • An alternative methodology of the present intervention would utilize a designer antibody with an attached macromolecular moiety instead of an albumin moiety.
  • the macromolecular moiety, attached to the antibody would be 1.000 mm to 0.005 mm in diameter.
  • the antibody- macromolecular moiety-targeted antigen complex would then be blocked from reentering the patient's body fluid circulation, by utilizing a series of microscreens which contain openings with a diameter 50.0000% to 99.9999% less than the diameter of the designer antibody- macromolecular moiety.
  • the microscreen opening(s) must have a diameter of at least 25 microns to allow for the passage and return to circulation of the non-pathology-inducing body fluid constituents.
  • the target NF antigens may be captured by using antibody microarrays which contain antibodies to targeted NF antigen(s).
  • the antibody microarrays are composed of millions of identical monoclonal antibodies attached at high density on glass or plastic slides. After sufficient extracorporeal exposure of the targeted NF antigens to the antibody microarrays, the antibody microarrays-targeted NF antigens may be disposed of, using standard medical practice.
  • Another alternative methodology of the present intervention comprises removing one or more of the targeted NF antigens from the body fluid by utilizing a designer antibody containing an iron (Fe) moiety. This will then create a Fe-antibody-antigen complex. This iron containing complex may then be efficaciously removed utilizing a strong, localized magnetic force field.
  • Fe iron
  • the device of the invention includes a first stage and a second stage.
  • the first stage applies a treatment of an antibody with an attached albumin moiety targeting the NF antigen(s) specifically exacerbating the pathologic condition.
  • the second stage includes substantial removal of the treatment from the extracorporeal body fluid bodily fluid.
  • the first stage can include an exterior wall to define a treatment chamber 5.
  • the treatment conveniently can be applied in the treatment chamber 5. Residence times of the body fluid can be altered by changing the dimensions of the treatment chamber, or by using a dialysis vacuum pump. With reference to Figure 1, body fluid enters the inlet 3, passes through the treatment chamber 5, and exits the outlet 4.
  • the treatment of an antibody with an attached albumin moiety targeting the NF antigen(s) can be applied from a delivery tube 6 located within the treatment chamber 5.
  • An inferior wall 9 defines the delivery tube 6.
  • the delivery tube 6 can include at least one lead 7, 8.
  • the lead 7, 8 can deliver the treatment to the treatment chamber 5.
  • the delivery tubes 6 will have a high contact surface area with the blood and/or CSF.
  • the delivery tube 6 comprises a helical coil.
  • the delivery tube 6 when the treatment includes the administration of a designer antibody, can be hollow and the interior wall 9 can define a plurality of holes 21.
  • the designer antibodies can be pumped through the delivery tube 6 to effect a desired concentration of designer anti bodies in the body fluid.
  • the designer antibodies can perfuse through the holes 21.
  • the delivery tube 6 can include any suitable material including, for example, metal, plastic, ceramic or combinations thereof.
  • the delivery tube 6 can also be rigid or flexible.
  • the delivery tube 6 is a metal tube perforated with a plurality of holes.
  • the delivery tube 6 can be plastic.
  • the antibody with attached albumin moiety, targeting the NF antigen(s) can be delivered in a concurrent or counter-current mode with reference to the body fluid.
  • the body fluid enters the treatment chamber 5 at the inlet 3.
  • the designer antibody can enter through a first lead 8 near the outlet 4 of the treatment chamber 5.
  • the blood and/or CSF then passes to the outlet 4 and the designer antibodies pass to the second lead 7 near the inlet 3.
  • the removal module of the second stage substantially removes the designer antibodies-NF antigen molecular compound from the body fluid.
  • the second stage can include a filter, such as a dialysis machine, which is known to one skilled in the art.
  • the second stage can include a molecular filter.
  • MARS molecular adsorbents recirculating system
  • MARS can be used to remove small to average sized molecules from the body fluid. Artificial liver filtration presently uses this technique.
  • the method can include a plurality of steps for removing the targeted NF antigen(s).
  • a first step can include directing a first antibody against the targeted antigen.
  • a second step can include a second antibody.
  • the second antibody can be conjugated with albumin, or alternatively another moiety which allows for efficacious dialysis or filtering of the antibody-NF antigen from the body fluid.
  • the second antibody or antibody-albumen complex combines with the first antibody forming an antibody- antibody-moiety complex.
  • a third step is then used to remove the complex from the blood and/or CSF. This removal is enabled by using dialysis and/or MARS.
  • the purified body fluid is then returned to the patient.
  • a portion of the purified body fluid can be tested to ensure a sufficient portion of the targeted NF antigen(s) have been successfully removed from the body fluid. Testing can determine the length of treatment and evaluate the efficacy of the sequential dialysis
  • Body fluid with an unacceptably large concentration of NF complex remaining can then be retreated and refiltered before returning the body fluid to the patient.
  • the second stage to remove the antibody-moiety-targeted NF antigen complex from the body fluid can be accomplished by various techniques including, for example, dialysis, filtering based on molecular size, protein binding, solubility, chemical reactivity, and combinations thereof.
  • a filter can include a molecular sieve, such as zeolite, or porous membranes that capture complexes comprising molecules above a certain size.
  • Membranes can comprise polyacrylonitrile, polysulfone, polyamides, cellulose, cellulose acetate, polyacrylates, polymethylmethacrylates, and combinations thereof. Increasing the flow rate or diasylate flow rate can increase the rate of removal of the antibody with attached albumin moiety targeting the NF antigen(s) such as NF Ant. Ang., NF Ant. T., NF Ant. Mast , NF Ant. Chem.).
  • NF antigen(s) such as NF Ant. Ang., NF Ant. T., NF Ant. Mast , NF Ant. Chem.
  • CRRT continuous renal replacement therapy
  • categories of CRRT include continuous arteriovenous hemofiltration, continuous venovenous hemofiltration, continuous arteriovenous hemodiafiltration, slow continuous filtration, continuous arteriovenous high-flux hemodialysis, and continuous venovenous high flux hemodialysis.
  • the sieving coefficient (SC) is the ratio of the molecular concentration in the filtrate to the incoming body fluid. A SC close to zero implies that the moiety-antibody-targeted antigen complex will not pass through the filter. A filtration rate of 50 ml per minute is generally satisfactory.
  • Other methods of increasing the removability of the antibody-targeted antigen moiety include the use of temporary acidification of the body fluid extracorporeally using organic acids to compete with protein binding sites.
  • Embodiments of the present invention include the following:
  • a method for the extracorporeal treatment of a body fluid comprising:
  • a method for the extracorporeal treatment of a body fluid comprising:
  • NF antigen selected from a group consisting of angiogenesis (NF Ant.
  • Ang. tumorigenesis
  • NF Ant. Mast localized mast cell chemoattraction
  • NF Ant. Chem. decreased chemotherapeutic efficacy
  • a method for the extracorporeal treatment of a body fluid comprising:
  • a method for the extracorporeal treatment of a body fluid comprising:
  • the protein comprises albumin.
  • a method for the extracorporeal treatment of a body fluid comprising:
  • the body fluid is removed from a patient before applying the treatment and the body fluid is returned to the patient after substantially removing the antibody-NF antigen moiety from the body fluid.
  • a method for the extracorporeal treatment of a body fluid comprising:
  • the body fluid is removed from a patient before applying the treatment and the body fluid is returned to the patient after substantially removing the antibody-NF antigen moiety from the body fluid

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  • Health & Medical Sciences (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Cardiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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Abstract

La présente invention concerne un procédé de traitement des neurofibromatoses. Les neurofibromatoses sont un ensemble de troubles héréditaires, comprenant la neurofibromatose de type 1 (NF1), la neurofibromatose de type 2 (NF2), et la schwannomatose, qui causent le développement de tumeurs bénignes de la gaine nerveuse. Spécifiquement, le procédé de traitement met en œuvre le traitement extracorporel d'un ou plusieurs fluides corporels en deux étapes, caractérisé par le retrait d'un fluide corporel depuis un corps vivant malade atteint d'un type de neurofibromatose, le passage du fluide corporel à travers une première étape, l'application d'un agent antiangiogenèse, antitumorigenèse, attracteur et/ou activateur pour au moins un antigène dans le fluide corporel, la création d'un fragment anticorps-antigène, le passage du fluide corporel traité à travers une deuxième étape, le retrait du fragment anticorps-antigène à partir du fluide corporel pendant le passage à travers la deuxième étape, et le retour du fluide corporel purifié dans le corps. Le fluide corporel qui peut être traité comprend le liquide cérébrospinal (CSF), la lymphe et le sang.
PCT/US2015/025645 2014-05-06 2015-04-14 Procédé de traitement de neurofibromatose WO2015171270A1 (fr)

Applications Claiming Priority (2)

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US201461988941P 2014-05-06 2014-05-06
US61/988,941 2014-05-06

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021207497A1 (fr) * 2020-04-08 2021-10-14 Arizona Board Of Regents On Behalf Of Arizona State University Traitement anti-choc cytokinique inflammatoire due à la covid-19

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4215688A (en) * 1979-02-09 1980-08-05 Baxter Travenol Laboratories, Inc. Apparatus for the extracorporeal treatment of disease
US20120296253A1 (en) * 2009-12-10 2012-11-22 Edward Henry Mathews Haemodialysis machine retrofit and control installation and use thereof for the treatment of proliferative disorders
WO2013028451A1 (fr) * 2011-08-19 2013-02-28 Marv Enterprises Procédé de traitement du cancer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4215688A (en) * 1979-02-09 1980-08-05 Baxter Travenol Laboratories, Inc. Apparatus for the extracorporeal treatment of disease
US20120296253A1 (en) * 2009-12-10 2012-11-22 Edward Henry Mathews Haemodialysis machine retrofit and control installation and use thereof for the treatment of proliferative disorders
WO2013028451A1 (fr) * 2011-08-19 2013-02-28 Marv Enterprises Procédé de traitement du cancer

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021207497A1 (fr) * 2020-04-08 2021-10-14 Arizona Board Of Regents On Behalf Of Arizona State University Traitement anti-choc cytokinique inflammatoire due à la covid-19

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