WO2013177098A1 - Procédé de traitement d'états neurologiques - Google Patents

Procédé de traitement d'états neurologiques Download PDF

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Publication number
WO2013177098A1
WO2013177098A1 PCT/US2013/041925 US2013041925W WO2013177098A1 WO 2013177098 A1 WO2013177098 A1 WO 2013177098A1 US 2013041925 W US2013041925 W US 2013041925W WO 2013177098 A1 WO2013177098 A1 WO 2013177098A1
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WO
WIPO (PCT)
Prior art keywords
csf
antigen
antibody
treatment
stage
Prior art date
Application number
PCT/US2013/041925
Other languages
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.)
Filing date
Publication date
Application filed by Felder Mitchell S filed Critical Felder Mitchell S
Publication of WO2013177098A1 publication Critical patent/WO2013177098A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/44—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material not provided for elsewhere, e.g. haptens, metals, DNA, RNA, amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • Excitatory neurotransmitters are implicated as causing or exacerbating multiple neurologic conditions. This application utilizes a novel methodology for reducing the symptomatology and pathology of those neurologic morbidities which are exacerbated by excitatory neurotransmitters. Those neurologic dysfunctions include:
  • TBI Traumatic brain injury
  • ALS Amyotrophic lateral sclerosis
  • a seizure is an abnormal irregular cortical discharge. Approximately 2% of all adults have a seizure at some time during their lifetime. Two thirds of these patients go on to have further seizures. About 40 million people are affected worldwide by seizure disorders. Epilepsy can arise from a variety of underlying conditions and pathophysiologic mechanisms.
  • TBI traumatic brain injury
  • CTE Chronic Traumatic Encephalopathy
  • Cerebral vascular accident (CVA/strokes) is the fourth leading cause of death in United States. About 750,000 new strokes occur every year in United States and 150,000 people die from stroke each year. The incidence of CVA increases with age, two thirds of old strokes occur in patients over 65 years of age. The incidence of stroke is higher in men than women. The care of patients who suffer morbidity from a cerebrovascular accident is a major cause underlying the rapid increase in healthcare funding in the United States. The release of excitatory
  • neurotransmitters during a cerebrovascular accident is implicated as a main etiology underlying an increase in morbidity and mortality from a CVA.
  • the present invention relates to a method of extracorporeally treating animal or human cerebrospinal fluid (CSF) for the extracorporeal removal of excitatory neurotransmitters (EN).
  • CSF cerebrospinal fluid
  • EN excitatory neurotransmitters
  • the invention pertains to a method for the extracorporeal treatment of CSF in two stages characterized by passing the CSF through a first stage; applying a treatment to at least one antigen in the CSF to create a antibody-antigen moiety during passage thereof through said first stage; passing the treated CSF through a second stage; and removing the treatment
  • the method is further characterized by targeting an a excitatory neurotransmitter antigen (EN ) in the CSF , with an antibody to allow and facilitate removal thereof in the second stage.
  • EN excitatory neurotransmitter antigen
  • the targeted excitatory neurotransmitter (EN) antigens would include one, or a combination of : glutamate, aspartate, quinolinic acid, homocysteic acid, N-acetylaspartylglutamate (NAAG), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), N-methyl-D-aspartate (NMD A), Quisqualate , Kainate, Ibotenate and Domoate
  • the method is characterized by directing a first antibody against the targeted EN antigen in the first stage; and directing a second antibody conjugated with albumin and /or a protein against the targeted antigen thereby forming an albumin-antibody-EN antigen compound in the second stage; and removing at least a portion of the albumin-antibody-EN antigen compound from the CSF.
  • the method is further characterized by removing CSF from a person to produce the extracorporeal bodily fluid; and returning the CSF to the patient after substantially removing the treatment in the second stage.
  • the method is characterized by testing the CSF to determine the efficacy of treatment before returning the CSF to the person.
  • the CSF is removed utilizing a standard lumbar puncture.
  • the CSF is treated with antibodies against the excitatory neurotransmitter (EN) antigen.
  • EN excitatory neurotransmitter
  • 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.
  • the method of the present invention comprises treating a patient's CSF extracorporeally with a designer antibody containing an albumin moiety which will allow for the efficacious dialysis of the resultant albumin-antibody-EN antigen compound (the targeted EN antigen being respectively, one or a combination of : glutamate, aspartate, quinolinic acid, homocysteic acid, N-acetylaspartylglutamate (NAAG), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), N-methyl-D-aspartate (NMD A), Quisqualate , Kainate, Ibotenate and Domoate ), utilizing standard dialysis methodologies.
  • the targeted EN antigen being respectively, one or a combination of : glutamate, aspartate, quinolinic acid, homocysteic acid, N-acetylaspartylglutamate (NAAG), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionat
  • the albumin-antibody will be directed towards the removal of the targeted EN antigen(s), (glutamate, aspartate, quinolinic acid, homocysteic acid, N-acetylaspartylglutamate (NAAG), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), N-methyl-D-aspartate (NMD A), Quisqualate, Kainate, Ibotenate and Domoate).
  • EN antigen(s) Glutamate, aspartate, quinolinic acid, homocysteic acid, N-acetylaspartylglutamate (NAAG), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), N-methyl-D-aspartate (NMD A), Quisqualate, Kainate, Ibotenate and Domoate.
  • EN antigen(s) glutamino-3-hydroxy-5-methylisoxazole-4-propionate
  • NMD A N
  • the article includes two-stages.
  • the first stage includes a treatment chamber which utilizes an antibody with an attached albumin moiety, which is added to the CSF.
  • a second stage receives the treated CSF and includes a unit for removing the treatment.
  • the method includes providing a dialysis machine with a first stage and a second stage, and sequentially passing the extracorporeal bodily fluid through the first and second stages.
  • the CSF is removed from the patient utilizing standard lumbar puncture procedure.
  • the first stage applies a treatment utilizing an antibody which was has attached to it an albumin moiety (or alternatively, a moiety which allows for the efficacious dialysis of the antibody-EN antigen), for the treatment of the CSF.
  • the second stage substantially removes the treatment.
  • the purified CSF (CSF with removed targeted EN : glutamate, aspartate, quinolinic acid, homocysteic acid, N-acetylaspartylglutamate (NAAG), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), N-methyl-D-aspartate (NMD A), Quisqualate , Kainate, Ibotenate and Domoate)- is then returned to the patient.
  • the device of the intervention includes a first stage and a second stage.
  • the first stage applies a treatment of an antibody with an attached albumin moiety targeting the EN antigen(s) specifically exacerbating the pathologic condition.
  • the second stage includes substantial removal of the treatment from the extracorporeal CSF 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 CSF can be altered by changing the dimensions of the treatment chamber, or by using a dialysis vacuum pump.
  • CSF 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 EN antigens 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 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 in order to effect a desired concentration of designer antibodies in the CSF.
  • 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 EN antigen(s) can be delivered in a concurrent or counter-current mode with reference to the CSF.
  • the CSF 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.
  • 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-antigen molecular compound from the CSF.
  • 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 technology can be used to remove small to average sized molecules from the CSF. Artificial liver filtration presently uses this technique.
  • the method can include a plurality of steps for removing the targeted EN antigens
  • 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 albumen, or alternatively a moiety which allows for efficacious dialysis.
  • the second antibody or antibody-albumen complex combines with the first antibody forming an antibody-antibody-moiety complex.
  • a third step is then utilized to remove the complex from the CSF. This removal is enabled by utilizing dialysis and/or MARS.
  • the purified CSF can then be returned to the patient.
  • a portion of the purified CSF can be tested to ensure a sufficient portion of the targeted EN antigen(s), (glutamate, aspartate, quinolinic acid, homocysteic acid,
  • N-acetylaspartylglutamate NAAG
  • alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate AMPA
  • N-methyl-D-aspartate N-methyl-D-aspartate
  • quisqualate quisqualate, kainate, ibotenate and domoate
  • the second stage to remove the antibody-moiety-targeted EN antigen complex by various techniques including, for example, 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 EN antigen(s): glutamate, aspartate, quinolinic acid, homocysteic acid, N-acetylaspartylglutamate (NAAG), alpha-amino- 3-hydroxy-5-methylisoxazole-4-propionate (AMPA), N-methyl-D-aspartate (NMDA), quisqualate, kainate, ibotenate and domoate.
  • EN antigen(s) glutamate, aspartate, quinolinic acid, homocysteic acid, N-acetylaspartylglutamate (NAAG), alpha-amino- 3-hydroxy-5-methylisoxazole-4-propionate (AMPA), N-methyl-D-aspartate (NMDA), quisqualate, kainate, ibotenate and domoate.
  • CR RT 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 CSF. 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 moiety- antibody- targeted antigen include the use of temporary acidification of the CSF utilizing organic acids to compete with protein binding sites.

Abstract

La présente invention concerne un procédé de traitement extracorporel du liquide céphalorachidien (LCR) d'un animal ou d'un être humain en vue de l'élimination extracorporelle de neurotransmetteurs excitatoires (EN). En particulier, l'invention concerne un procédé de traitement extracorporel du LCR en deux étages, caractérisé par le passage du LCR à travers un premier étage ; l'administration d'un traitement dirigé contre au moins un antigène dans le LCR pour générer un fragment anticorps-antigène lors de son passage à travers ledit premier étage ; le passage du LCR traité à travers un deuxième étage ; et l'élimination du traitement (fragment anticorps-antigène) du LCR lors du passage à travers ledit deuxième étage. Le procédé est en outre caractérisé par le ciblage d'un antigène de neurotransmetteur excitatoire (EN) dans le LCR, au moyen d'un anticorps pour permettre et faciliter son élimination dans le deuxième étage.
PCT/US2013/041925 2012-05-23 2013-05-21 Procédé de traitement d'états neurologiques WO2013177098A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201261650843P 2012-05-23 2012-05-23
US61/650,843 2012-05-23

Publications (1)

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WO2013177098A1 true WO2013177098A1 (fr) 2013-11-28

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024072910A1 (fr) * 2022-09-27 2024-04-04 Marv Enterprises, LLC Compositon pour diminuer de manière aiguë les effets physiopathologiques d'une commotion et procédé d'administration associé

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995003815A1 (fr) * 1993-07-30 1995-02-09 Georgetown University Anticorps specifiques de l'acide quinolinique
US20080195024A1 (en) * 2005-07-20 2008-08-14 Schmid-Schonbein Geert W Treating Disorders Associated with Inflammation
US20100030196A1 (en) * 2008-07-29 2010-02-04 Medtronic, Inc. Apheresis of a target molecule from cerebrospinal fluid
US20110295175A1 (en) * 2010-03-16 2011-12-01 Marv Enterprises Llc Sequential Extracoporeal Treatment of Bodily Fluids

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995003815A1 (fr) * 1993-07-30 1995-02-09 Georgetown University Anticorps specifiques de l'acide quinolinique
US20080195024A1 (en) * 2005-07-20 2008-08-14 Schmid-Schonbein Geert W Treating Disorders Associated with Inflammation
US20100030196A1 (en) * 2008-07-29 2010-02-04 Medtronic, Inc. Apheresis of a target molecule from cerebrospinal fluid
US20110295175A1 (en) * 2010-03-16 2011-12-01 Marv Enterprises Llc Sequential Extracoporeal Treatment of Bodily Fluids

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024072910A1 (fr) * 2022-09-27 2024-04-04 Marv Enterprises, LLC Compositon pour diminuer de manière aiguë les effets physiopathologiques d'une commotion et procédé d'administration associé

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