11 The present invention claims priority to US 61/537,913 filed 22 September 2012. FIELD OF THE INVENTION

{ 002] The invention relates to a device and method for the treatment of multiple sclerosis.

BACKGROUND OF THE INVENTION

[001 J In the United States multiple sclerosis (MS) is one of the leading causes of neurologic impairmen The disease affects snore than 300,000 patients, and has its highest incidence in young adults, initial symptoms of multiple sclerosis usually commence before the age of 55 years. There is a peak incidence between the ages of 20 and 40, Women are affected approximately twice as often as men. The disease is believed to have an autoimmune etiology. Multiple sclerosis is much more common in persons of western European lineage who live in. temperate zones.

[002 ] Certain molecular organic compounds are implicated as causing or allowing multiple sclerosis, which in turn allows for the progression of the disease, with increasing morbidity and mortality.

SUMMARY OF THE INVENTION

031 In general terms, the presen t invention relates to the treatment of multiple sclerosis, hereinafter abbreviated as "MS", Specifically, the invention pertains to a method for the extracorporeal treatment of one or more body fluids (blood, cerebral-spinal fluid (CSF), or lymphatic fluid) in two stages characterized by removing a body fluid from a living bod diseased with a type of MS, passing the body fluid (blood, CSF, or lymphatic fluid) through a first stage; applying a treatment to at least one or more target MS antigen(s) in the body fluid, in. order to expedite the removal of the targeted MS antigeii(s).

1004] More specifically, the treatment comprises creating an antibody-antigen moiety during passage thereof through said first stage; passing the treated body fluid through a second stage; remo ving antibody-antigen moiety from the body fluid during passage through the second stage, and returning the purified body fluid to the body.

[005] The invention is further characterized b targeting an antigen in the bod fluid, with an antibody to allow and facilitate removal thereof in the second stage. The targeted antigens would include one, or a combination of targeted MS Antigen(s) involved in the pathologic development of MS:

[006] Iniegri

[007] Osteopontin

[00 Inter iikin-23, ititerieukin-l?, Imerieukm-12, lnterteukitv-15

[009] intrathecal immunoglobulins IgG/Oltgoclonal Bands

[010] Giutaraate

JO 1.1 J Matrix metalloprofemases (M Ps)

[012] M elin basic protein (MBP)

[0 } 3 ] Peptidy] arginine deiroiriase 2 ( AD 2)

[014] Beta-Chemokines: monocyte chemoattractant protein-.! (MCP-1); macrophage inflammatory protein (MIP): RANTES : Regulated on Activation Normal T Cell Expressed and Secreted (CCL5)

[ 15] My din-associated oligodendrocytk basic protein (MOBP)

[ 16] -Aeety!- Aspartate

[ 17 ] VLA-4 : very late antsgen-4

[018 ] Cytokines : 1L15 and LPS-cytokine

[0191 Adhesion Proteins : ALCAM (Activated Leukocyte Cell Adhesion Molecule); CD 166 (cluster of differentiation 166) ; CXCL12 (chemokine ligand 12 )

[020] Endothelin-! {022 ] Chroraogramn A

| 23 | Myelin Protein TPPP/p2S

24] sFas : soluble form of the Fas molecule

{025] MiF : macrophage migration inhibitors' factor

{026] TNF-alpha : tumor necrosis factor-alpha

{027] CL2 : chemokine ligand 2

{028 | T helper ceils : Thl and ThI7

{029] Activated T Ceils and B Cells

1030] LINGO- 1 ; Leuciae-rich repeat and fg domain containing NOGO receptor interacting protein- 1

311 sVCAM-1 : soluble vascular adhesion molecule

{ ^' 032] A ! AC : alpha- ί . antichyrooiryps

{033) A2MG : alpha- 1 macroglobulin

{034| Pibulin I

{035] NMO-!gG/ Aquaporin-4 Antibodies specifically in. the Neuromyelitis Optica (NMO) variant of MS

{036] Specifically, the method is further characterized by renwving bod fluid (blood, CSF, or lymphatic fluid) from a person to produce the extracorporeal bodily fluid;

imposing a treatment acting on one or more amigen(s) of targeted MS aniigeiifs) 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 ail of the treatment in the second stage.

{037] The method of the present invention comprises treating at least one component of a patient's body fluid extracorporea!iy with a designer antibody containing an albumin- moiety which will create an alb min-antibody-MS antigen moiety, allowing for the efficacious dialysis of the resultant albimiin-antibody-MS antigen compound.

[038 j More specifically, the method is characterized by removing body fluid from a person to produce the extracorporeal bodily fluid; directing a first antibody against the targeted MS antigen irt the first stage of extra-corporeal treatment in. the body fluid; in. the second stage directing a second antibody conjugated with albumin and/or a protein against the targeted MS antigen thereby forming an aibmitin-antibody-MS antigen compound; removing at least a substantial portion of the albumin-antibody-MS antigen compound from the body fluid by dialysis, other filtering, or other means; and returning the body fluid to the patient.

039] Also, the method is characterized by testing the blood and/or CSF or lymphatic fluid to determine the efficacy of treatment before returning the body fluid to the patient. BRIEF DESCRIPTION OF THE DRAWINGS

(040) Figure 1 is a partial cross sectional view of a cylinder and tubing used to deli ver a treatment to a bodily fluid.

[041 ] Figure 2 is a partial cross sectional view showing additional detail of the cylinder and tubing of Figure 1.

DETAILED DESCRIPTION OF THE INVENTION

[042] In. the first stage of treatment, a selected body fluid is removed us ing a standard catheter and/or lumbar puncture. In the second stage, the body fluid i treated with antibodies against the targeted MS antigen.

[043 } 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-MS antigen moiety allowing for the efficacious dialysis, filtering or other means of removal of the resultant albumhi-antibody-MS antigen compound,

[ 0441 The albumin-antibody will be directed towards facilitating removal of the targeted MS antigen(s): After die removal of the MS antigen(s) , die cleansed body fluid will b returned to the patient. The frequency of treatment and the specifically targeted MS anttgen(s) to be removed would depend upon the underlying symptomatology and pathology of the patient, and would be determined by the patient's physician.

[045] 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.

J046J The method includes providing a dialysis or other filtering machine whh 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 moiet which allows for the efficacious dialysis or removal by other techniques of the antibody-aiburain-MS antigen), for the treatment of the body fluid. The second stage substantially removes the treatment. The purified body fluid (body fluid with removed targeted MS anrigen(s) is then, tested for the efficacy of removal of the MS anttgen(s) and returned to the patient

j 047 } An alternative methodology of the present intervention would utilize a designer antibody with an attached maeromoleeular moiety instead of an albumin moiety. The macrornolecnlar moiety attached to the antibody would have a large size such as, for example, between about I .(MX) mm to 0.005 mm in diameter. The large size permits removal of the ani.ibody-maeromoiecu.5ar moiety-targeted antigen complex, using physical screen techniques. For example, a series of raieroscreens can define openings with diameters less than about 50% to more than 9 % less than the diame ter of the designer antibody-macxomotecitiar moiety. The microscreen opctitng(s) must have a diameter of at least 25 micrometers in order to a!iow for the passage and return to circulation of the nonpathoiogic inducing body fluid constituents,

[048] Alternatively, the target MS antigen(s) ma be captured by utilizing antibod mieroarrays which contain antibodies to targeted MS antigens. The antibody mieroarrays comprise a plurality of identical monoclonal antibodies attached at high density on glass or plastic slides. Densities can exceed one million microarrays per square centimeter. After sufficient extracorporeal exposure of the targeted MS antigens to the antibody mieroarrays, the antibody raicroarrays-targeted MS antigens may be disposed of utilizing standard medical practice

[049] Another alternative -methodology of the present intervention comprises removing one or more of the targeted MS 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 field.

[050] 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 MS antigen(s) specifically exacerbating the pathologic condition. The second stage includes substantial removal of the treatment from the extracorporeal body fluid bodily fluid. As shown in Figure 1 , 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 _s body fluid enters the inlet 3, passes through the treatment chamber 5, and exits the outlet 4. In embodiments, the treatment of an antibody with an attached albumin moiety targeting the MS antigeriis) can be applied from a deiivery tube 6 located within the treatoent chamber 5. An inferior wail 9 defines die deiivery tube 6. The deiivery tube 6 can include at least one lead 7, 8. The lead 7, 8 can deliver die treatment to the treatment chamber 5.

Conveniently, the deiivery tubes 6 will have a high contact surface area with the blood and/or CSF. As shown, die deiivery tube 6 comprises a helical cod,

[051 ] With reference to Figure 2, when the treatment includes the administration of a designer antibody, the delivery tube 6 can be hollow and the interior wall 9 can define a plurality of holes 21. The designer antibodies can he pumped through the delivery tube 6 in order to effect a desired concentration of designer and bodies in the bod fluid. The designer antibodies can perfuse through the boles 21 . The delivery tube 6 can include any suitable material including, for example, nietal plastic, ceramic or combinations thereof. The delivery tube 6 can also be rigid or flexible. In one embodiment, the delivery tube 6 is a metal tube perforated with a plurality of holes. Alternatively, the delivery tube can be plastic. The antibody with attached albumin moiety, targeting the MS antigen(s) can be delivered in a concurrent or counter-current mode with reference to die body fluid, in counter -current mode, the body fluid enters the treatment chamber 5 at the inlet 3, The designer antibody can enter through a first, lead 8 near the outiet 4 of the treatoent chamber 5. The body fluid then passes to the outiet 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-MS antigen molecular compound from the body fluid.

[0521 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 including, for example, a molecular adsorbents recirculating system (MARS) that may be compatible and/or synergistic with dialysis equipment MARS technology can be used to remove small to average sized molecules from the body fluid. Artificial liver filtration presently uses this technique,

f 053 j The method can include a plurality of steps for removing the targeted MS 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-MS antigen from the body fluid. The second antibody or anti ody-albumen complex combines with the first antibod forming an anribody-antibody-moiery complex, A third, step is then used to remove the complex from the body fluid. This removal is enabled by using dialysis and/or MARS. The purified body fluid is then returned to the patient.

|054] In practice, a portion of the purified body fluid can be tested t ensure a sufficient portion of the targeted MS antigen(s) ha ve been successfully removed from the body fluid. Testing can determine the length of treatment and evaluate the efficacy of the sequential dialysis methodology to removin the targeted MS antigen(s) and suggest the need for further treatment. Body fluid with an unacceptably large concentration of complex remaining can then be retreated and reft!tered before returning the body fluid to the patient.

[055] In embodiments, the second stage to remove the antibody-moiery-targcted MS 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. For example, 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 poIyaeiytonitriSe, polysulfone, polyamides, cellulose, cellulose acetate, polyacrylates, polymethylmethacrylates, and combinations thereof, increasing the flow rate or diasy!ate flow rate can increase the rate of removal of the antibody with attached albumin moiety targeting the MS antigen(s }.

[056] Further techniques can include continuous renal replacement therapy (CRRT) which can remove large quantities of filterable moiecuies from the extracorporeal body fluid. CRRT would be particularly use ul for molecular compounds that are not strongly bound to plasma, proteins. Categories of CRRT include continuous arteriovenous heraofiliration, continuous ven venous he ofUtration, 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 antibody-targeted antigen moiety include the use of temporar acidification of the body fluid extraeorporeaiiy using organic acids to compete with protein binding sites.