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Title:  Use of an antibody that blocks TNF-alpha activity for treating a nerve disorder mediated by nucleus pulposus
United States Patent: 
8,057,792
Issued: 
November 15, 2011

Inventors:
 Olmarker; Kjell (Molndal, SE), Rydevik; Bjorn (Goteborg, SE)
Assignee:
  Sciaticon AB (Molndal, SE)
Appl. No.: 
12/714,708
Filed:
 March 1, 2010


 

Executive MBA in Pharmaceutical Management, U. Colorado


Abstract

The present invention relates to a method and a pharmaceutical composition for treatment of nerve disorders comprising administration of a therapeutically effective dosage of at least two substances selected from the group consisting of TNF inhibitors, IL-1 inhibitors, IL-6 inhibitors, IL-8 inhibitors, FAS inhibitors, FAS ligand inhibitors, and IFN-gamma inhibitors. Preferably, at least one of the substances is a TNF inhibitor.

Description of the Invention

SUMMARY OF THE INVENTION

It has been found that the use of a TNF-alpha inhibitor, such as a substance selected from the group consisting of metalloproteinase inhibitors excluding methylprednisolone, tetracyclines including chemically modified tetracyclines, quinolones, corticosteroids, thalidomide, lazaroids, pentoxifylline, hydroxamic acid derivatives, carbocyclic acids, napthopyrans, soluble cytokine receptors, monoclonal antibodies towards TNF-alpha, amrinone, pimobendan, vesnarinone, phosphodiesterase inhibitors, lactoferrin and lactoferrin derived analogs, and melatonin are suitable for treatment of spinal disorders and nerve root injury caused by the liberation of TNF-alpha and compounds triggered by the liberation of or presence of TNF-alpha by inhibiting spinal disc TNF-alpha.

These substances are thus suitable for treatment of nerve root injury, and for treatment of sciatica, low back pain (LBP), and whiplash associated disorder (WAD).

TNF is one of many pro-inflammatory substances with similar action, and it is considered as a "major player" in inflammatory events. However, TNF may also in part acts through other pro-inflammatory cytokines such as for instance IL-1, IL-6, FAS, and IFN-gamma.

The present invention is based on the finding that by combining at least two different inhibitors of pro-inflammatory cytokines it is possible to provide an even better treatment of the above-mentioned diseases and conditions.

It is an object of the invention to provide novel and improved methods for inhibiting the action of cytokines for treating of nerve disorders in a subject comprising the step of administering to said subject a therapeutically effective dosage of at least two substances selected from the group consisting of TNF inhibitors, IL-1 inhibitors, IL-6 inhibitors, IL-8 inhibitors, FAS inhibitors, FAS ligand inhibitors, and IFN-gamma inhibitors.

A preferred embodiment of the invention is a method for treatment of a nerve disorder in a subject comprising administering to a subject a therapeutically effective dosage of a TNF inhibitor in combination with a second inhibitor selected from the group consisting of IL-1 inhibitors, IL-6 inhibitors, IL-8 inhibitors, FAS inhibitors, FAS ligand inhibitors, and IFN-gamma inhibitors.

Another preferred embodiment of the invention is a method for treatment of a nerve disorder in a subject comprising administering to a subject a therapeutically effective dosage of one TNF inhibitor, such as a specific TNF inhibitor, in combination with another TNF inhibitor, such as a non-specific TNF inhibitor.

Another preferred embodiment of the invention is a method for treatment of a nerve disorder in a subject comprising administering to a subject a therapeutically effective dosage of a TNF inhibitor in combination with a IL-1 inhibitor.

It is also an object of the invention to provide a novel pharmaceutical composition for treating nerve disorders in a subject comprising a therapeutically effective dosage of at least two substances selected from the group consisting of INF inhibitors, IL-1 inhibitors, IL-6 inhibitors, IL-8 inhibitors, FAS inhibitors, FAS ligand inhibitors, and IFN-gamma inhibitors.

Nerve disorders treatable with the method and the pharmaceutical composition according to the invention are nerve disorders due to a reduced nerve reduction velocity, spinal disorders, nerve root injuries, nerve disorders caused by disc herniation, sciatica, cervical rhizopathy, low back pain, whiplash associated disorder, nerve disorders involving pain, nucleus pulposus-induced nerve injuries, and spinal cord compressions.

The subject which can be treated by these methods include any vertebrate, preferably mammals, and of those, most preferably humans.

Although a break-through in the treatment of spinal pain syndromes was made in 1997 when the involvement of pro-inflammatory cytokines, in particular TNF, became evident, the current invention offers an even more efficient way to treat i.a. sciatica and low back pain by pharmacological means. Since TNF acts synergistically with other pro-inflammatory cytokines inhibition of more cytokines than TNF is more efficient in acquiring the desired clinical effect.

With the foregoing and other objects, advantages and features of the invention that will become hereinafter apparent, the nature of the invention may be more clearly understood by reference to the following detailed description of the preferred embodiments of the invention and to the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

It has now surprisingly been shown possible to be able to treat nerve root injuries, or at least alleviate the symptoms of nerve root injuries by using a pharmaceutical composition comprising a therapeutically active amount of a TNF-alpha inhibitor. TNF-alpha inhibitors, include but are not limited to, metalloproteinase (MMP) inhibitors (excluding methylprednisolone), tetracyclines, chemically modified tetracyclines, quinolones, corticosteroids, thalidomide, lazaroids, pentoxifylline, hydroxamic acid derivatives, napthopyrans, soluble cytokine receptors, monoclonal antibodies towards TNF-alpha, amrinone, pimobendan, vesnarinone, phosphodiesterase inhibitors, lactoferrin and lactoferrin derived analogous, and melatonin in the form of bases or addition salts together with a pharmaceutically acceptable carrier.

By "therapeutically active amount" and "therapeutically effective dosage" are intended to be an amount that will lead to a desired therapeutic effect, i.e., an amount that will lead to an improvement of the patient's condition. In one preferred example, an amount sufficient to ameliorate or treat a condition associated with a nerve disorder.

By "mammal" is meant to include but is not limited to primate, human, canine, porcine, equine, murine, feline, caprine, ovine, bovine, lupine, camelid, cervidae, rodent, avian and ichthyes. By animal is meant to include any vertebrate animal wherein there is a potential for nerve root injury.

As used herein, the term "antibody" is meant to refer to complete, intact antibodies, and Fab fragments, scFv, and F(ab).sub.2 fragments thereof. Complete, intact antibodies include monoclonal antibodies such as murine monoclonal antibodies (mAb), chimeric antibodies, humanized antibodies and human. The production of antibodies and the protein structures of complete, intact antibodies, Fab fragments, scFv fragments and F(ab).sub.2 fragments and the organization of the genetic sequences that encode such molecules, are well known and are described, for example, in Harlow et al., ANTIBODIES: A LABORATORY MANUAL, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. (1988) and Harlow et al., USING ANTIBODIES: A LABORATORY MANUAL, Cold Spring Harbor Press, 1999, which are herein incorporated by reference in their entirety.

By "epitope" is meant a region on an antigen molecule to which an antibody or an immunogenic fragment thereof binds specifically. The epitope can be a three dimensional epitope formed from residues on different regions of a protein antigen molecule, which, in a naive state, are closely apposed due to protein folding. "Epitope" as used herein can also mean an epitope created by a peptide or hapten portion of TNF-alpha and not a three dimensional epitope. Preferred epitopes are those wherein when bound to an immunogen (antibody, antibody fragment, or immunogenic fusion protein) results in inhibited or blocked TNF-alpha activity.

By "TNF-alpha blocking" is meant a compound or composition that blocks, inhibits or prevents the activity of TNF or TNF-alpha.

Compounds that possess TNF-alpha inhibitory activity are for example tetracyclines, (e.g., tetracycline, doxycycline, lymecycline, oxytetracycline, minocycline), and chemically modified tetracyclines (e.g., dedimethylamino-tetracycline), hydroxamic acid compounds, carbocyclic acids and derivatives, thalidomide, lazaroids, pentoxifylline, napthopyrans, soluble cytokine receptors, monoclonal antibodies towards INF-alpha, amrinone, pimobendan, vesnarinone, phosphodiesterase inhibitors, lactoferrin and lactoferrin derived analogs, melatonin, norfloxacine, ofloxacine, ciprofloxacine, gatifloxacine, pefloxacine, lomefloxacine, temafloxacine, TTP and p38 kinase inhibitors. These compounds can be present as bases or in the form of addition salts, whichever possesses the best or preferred pharmaceutical effect, and best property to be brought into a suitable pharmaceutical composition. A more complete list is given below.

As stated above, there are several different types of cytokine blocking substances and pharmacological preparations that may be used according to the invention, and those substances may be grouped in different subclasses -- see Original Patent.
Soluble cytokine receptors; Receptor antagonists; Antisense oligonucleotides Non-specific inhibitors of IL-6 MMP inhibitors (i.e. such as: matrix Tetracyclines such as: metalloproteinase Doxycycline, inhibitors) Lymecycline, Oxitetracycline, Tetracycline, Minocycline, and synthetic tetracycline derivatives, such as CMT, i.e. Chemically Modified Tetracyclines; Prinomastat (AG3340); Batimastat; Marimastat; BB-3644; KB-R7785; TIMP-1, and TIMP-2, adTIMP-1 (adenoviral delivery of TIMP-1), and adTIMP-2 (adenoviral delivery of TIMP-2); Quinolones (chinolones) such as: Norfloxacin, Levofloxacin, Enoxacin, Sparfloxacin, Temafloxacin, Moxifloxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin, Trovafloxacin, Ofloxacin, Ciprofloxacin, Pefloxacin, Lomefloxacin, Temafloxacin; Prostaglandins; Iloprost (prostacyclin); Cyclosporin Pentoxifyllin derivates; Hydroxamic acid derivates; Phosphodiesterase I, II, III, IV, and V-inhibitors; CC-1088, Ro 20-1724, rolipram, amrinone, pimobendan, vesnarinone, SB 207499; Melanin and melancortin agonists; HP-228 Inhibitors of Interleukin-8 (IL-8) Specific inhibitors of IL-8 Monoclonal antibodies; Soluble cytokine receptors; Receptor antagonists; Antisense oligonucleotides; Non-specific inhibitors of IL-8 Quinolones (chinolones) such as: Norfloxacin, Levofloxacin, Enoxacin, Sparfloxacin, Temafloxacin, Moxifloxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin, Trovafloxacin, Ofloxacin, Ciprofloxacin, Pefloxacin, Lomefloxacin, Temafloxacin: Thalidomide derivates such as: SelCID. i.e. Selective Cytokine inhibitors such as: CC-1088, CDC-501, CDC-801 and Linomide (Roquininex .RTM.); Lazaroids; Cyclosporin; Pentoxifyllin derivates; FAS Inhibitors Specific FAS inhibitors Monoclonal antibodies: Soluble cytokine receptors; Receptor antagonists; Antisense oligonucleotides; Non-specific FAS inhibitors Inhibitors of FAS ligands Specific inhibitors of FAS ligands Monoclonal antibodies; Soluble cytokine receptors; Receptor antagonists; Antisense oligonucleotides; Non-specific inhibitors of FAS ligands Inhibitors of interferon-gamma (IFN-gamma) Specific IFN-gamma inhibitors Monoclonal antibodies; Soluble cytokine receptors; Receptor antagonists; Antisense oligonucleotides; Non-specific IFN-gamma inhibitors MMP inhibitors (i.e. such as: matrix Tetracyclines such as: metalloproteinase Doxycycline, inhibitors) Trovafloxacin, Lymecycline, Oxitetracycline, Tetracycline, Minocycline, and synthetic tetracycline derivatives, such as CMT, i.e. Chemically Modified Tetracyclines; Prinomastat (AG3340); Batimastat; Marimastat; BB-3644; KB-R7785; TIMP-1, and TIMP-2, adTIMP-1 (adenoviral delivery of TIMP-1), and adTIMP-2 (adenoviral delivery of TIMP-2); Quinolones (chinolones) such as: Norfloxacin, Levofloxacin, Enoxacin, Sparfloxacin, Temafloxacin, Moxifloxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin, Trovafloxacin, Ofloxacin, Ciprofloxacin, Pefloxacin, Lomefloxacin, Temafloxacin, Rebamipide, and Nalidixic acid; Lazaroids; Pentoxifyllin derivates; Phosphodiesterase I, II, III, IV, and V-inhibitors; CC-1088, Ro 20-1724, rolipram, amrinone, pimobendan, vesnarinone, SB 207499;

Also contemplated are the pharmaceutically acceptable bases and salts of the substances listed above.

Preferred groups of TNF-alpha blocking substances for use according to the present invention are soluble cytokine receptors, monoclonal antibodies, and tetracyclines or chemically modified tetracyclines.

Two preferred substances for use according to the present invention are the monoclonal antibodies, D2E7 and CDP-870.

D2E7 is a fully humanized monoclonal antibody directed against human TNF-alpha, which has been developed by Knoll and Cambridge Antibody Technology. A transgenic recombinant version of this antibody is under development by Genzyme Transgenic. The invention contemplates any antibody that binds to the same epitope as D2E7 or that has the same TNF-alpha inhibitory effect as D2E7. Preferably the antibody is Primatized.RTM., humanized or human.

CDP-870 (or CDP 870) is a humanized antibody fragment with high affinity to TNF-alpha. It has been developed by Celltech Group plc, and is co-developed with Pharmacia Corporation. The invention contemplates any antibody, antibody fragment or immunogen that binds to the same epitope as CDP-870 or that has the same TNF-alpha inhibitory activity as CDP-870. Preferably the antibody, antibody fragment or immunogen has the same or similar TNF-alpha inhibitory activity. Preferably the antibody, antibody fragment or immunogen is primatized, humanized or human.

According to a preferred embodiment, one of the substances used is a TNF inhibitor. According to a preferred variant of this embodiment the TNF inhibitor is a monoclonal antibody directed against TNF, such as infliximab, CDP-571, D2E7 or CDP870. According to another preferred variant of this embodiment the TNF inhibitor used is a soluble cytokine TNF receptor, such as etanercept. According to another preferred variant of this embodiment the TNF inhibitor used is a binuclear DNA threading transition metal complex with anti-cancer effect. According to another preferred variant of this embodiment the TNF inhibitor used is a lactoferrin derivable peptide. According to another preferred variant of this embodiment the TNF inhibitor used is an MMP inhibitor, such as doxycycline. According to another preferred variant of this embodiment the TNF inhibitor used is a p38 kinase inhibitor. According to yet another preferred variant of this embodiment the substance used is TTP.

According to another preferred embodiment, one of the substances is a specific TNF inhibitor, such as infliximab, CDP-571, D2E7 or CDP-870, which is use in combination with a non-specific TNF inhibitor, such as doxycycline.

Doxycycline inhibits the action of TNF in a non-specific manner. TNF and other similar bioactive substances are first produced in an inactive form and transported to the cell membrane. Upon activation, the active part of the pro-TNF is cleaved and released. This process is called shedding and may be initiated by one or more enzymes. These enzymes have in common that they are metalloproteinases, i.e. dependent of a metal-ion for their function. Doxycycline and other tetracyclines are known to bind to metal-ions and will thereby inhibit the action of metalloproteinases and subsequently the release of TNF and other pro-inflammatory cytokines in a non-specific manner. A monoclonal anti-TNF antibody, on the other hand, will bind directly to TNF and thereby inhibit TNF in a more specific way than doxycycline. The inhibition may thus be assumed to be more efficient but will be restricted to TNF. However, in the work leading to the present invention, it was found that anti-TNF treatment was more efficient than doxycycline treatment. However, the most efficient way to inhibit the nucleus pulpous induced reduction in nerve root conduction velocity was found to be to combine a TNF-inhibitor and an IL-1 inhibitor. TNF is known to be orchestrating much of the inflammatory events. Except for having direct effects on target-receptors, it may also act through other cytokines by stimulation of their release. Although one may assume that specific inhibition may block both the direct effects of TNF and its stimulatory effects on other cytokines, the work leading to the present invention showed that it is possible to further inhibit the action of TNF by inhibiting cytokines that are produced and released by TNF stimulation. In addition to inhibiting the stimulatory effects of TNF, one thereby also inhibits the effects of these synergistic cytokines downstream. Since these synergistic cytokines may also induce release and production of TNF, the inhibition of these cytokines also reduces the level of TNF. According to the present invention it is shown that the use of also one or more inhibitors of other cytokines is more efficient in blocking the nucleus pulposus induced effects on adjacent nerve roots.

The combination of inhibitors of one specific cytokine with different mechanisms is also shown to be more efficient than the use of a single inhibitor. For instance, TNF may be inhibited at the synthesis-level (e.g., by pentoxifylline), at translation by antisense (e.g., by ISIS-104838), at shedding (e.g., by doxycycline), and later by antibodies (e.g., by infliximab or CDP-870) or soluble receptors (e.g., by etanercept or lenercept). Thus, there are at least five mechanisms useful for inhibiting TNF. The combination of two or more drugs that act through different mechanisms therefore induces a more efficient inhibition of that certain cytokine than the use of one single drug. A special benefit is achieved if a specific inhibitor or a key substance, for instance a monoclonal antibody against TNF, and a non-specific inhibitor that also blocks other cytokines, for instance doxycycline. This combination achieves inhibition of TNF at two levels (shedding and binding of active TNF) as well as inhibition of other synergistic cytokines.

According to another preferred embodiment one of the substances used is an IL-1 inhibitor.

According to an especially preferred embodiment one of the substances used is a TNF inhibitor and one is an IL-1 inhibitor.

Said at least two substances are preferably administered simultaneously, but they may also be administered separately.

The substances according to the invention may also be administered in combination with other drugs or compounds, provided that these other drugs or compounds do not eliminate the desired effects according to the present invention, i.e., the effect on TNF-alpha.

The invention further relates to a method for inhibiting the symptoms of nerve root injury.

The effects of doxycycline, soluble cytokine-receptors, and monoclonal cytokineantibodies have been studied and representative methods used and results obtained are disclosed below. Although the present invention has been described in detail with reference to examples herein, it is understood that various modifications call be made without departing from the spirit of the invention, and would be readily known to the skilled artisan.

The compounds of the invention can be administered in a variety of dosage forms, e.g., orally (per os), in the form of tablets, capsules, sugar or film coated tablets, liquid solutions; rectally, in the form of suppositories; parenterally, e.g., intramuscularly (i.m.), subcutaneous (s.c.), intracerebroventricular (i.c.v.), intrathecal (it.), epidurally, transepidermally or by intravenous (iv.) injection or infusion; by inhalation; or intranasally.

The therapeutic regimen for the different clinical syndromes may be adapted to the disease or condition, medical history of the subject as would be know to the skilled artisan or clinician. Factors to be considered but not limiting to the route of administration, the form in which the compound is administered, the age, weight, sex, and condition of the subject involved.

For example, the oral route is employed, in general, for all conditions, requiring such compounds. In emergency cases, preference is sometimes given to intravenous injection. For these purposes, the compounds of the invention can be administered, for example, orally at doses ranging from about 20 to about 1500 mg/day. Of course, these dosage regimens may be adjusted to provide the optimal therapeutic response depending on the subject's condition.

The nature of the pharmaceutical composition containing the compounds of the invention in association with pharmaceutically acceptable carriers or diluents will, of course, depend upon the desired route of administration. The composition may be formulated in the conventional manner with the usual ingredients. For example, the compounds of the invention may be administered in the form of aqueous or oily solutions or suspensions, tablets, pills, gelatin capsules (hard or soft ones), syrups, drops or suppositories.

For oral administration, the pharmaceutical compositions containing the compounds of the invention are preferably tablets, pills or gelatine capsules, which contain the active substance or substances together with diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose; lubricants, e.g., silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; or they may also contain binders, such as starches, gelatine, methyl cellulose, carboxymethylcellulose, gum arabic, tragacanth, polyvinylpyrrolidone; disaggregating agents such as starches, alginic acid, alginates, sodium starch glycolate, microcrystalline cellulose; effervescing agents, such a carbonates and acids; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and in general non-toxic and pharmaceutically inert substances used in the formulation of pharmaceutical compositions. Said pharmaceutical compositions may be manufactured in known manners, e.g., by means of mixing, granulating, tableting, sugar-coating or film-coating processes. Film providing compounds can be selected to provide release in the right place or at the appropriate time in the intestinal tract with regard to absorption and maximum effect. Thus pH-dependent film formers can be used to allow absorption in the intestines as such, whereby different phthalates are normally used or acrylic acid/methacrylic acid derivatives and polymers.

The liquid dispersions for oral administration may be, e.g., syrups, emulsions, and suspensions.

The syrups may contain as carrier, e.g., saccharose, or saccharose with glycerine and/or mannitol and/or sorbitol.

Suspensions and emulsions may contain as Garner, e.g., a natural gum, such as gum arabic, xanthan gum, agar, sodium alginate, pectin, methyl cellulose, carboxymethylcellulose, polyvinyl alcohol.

The suspension or solutions for intramuscular injections may contain together with the active compound, a pharmaceutically acceptable carrier, such as e.g., sterile water, olive oil (or other vegetable or nut derived oil), ethyl oleate, glycols", e.g., propylene glycol, and if so desired, a suitable amount of lidocaine hydrochloride. Adjuvants for triggering the injection effect can be added as well.

The solutions for intravenous injection or infusion may contain as carrier, e.g., sterile water, or preferably, a sterile isotonic saline solution, as well as adjuvants used in the field of injection of active compounds. Such solutions would also be suitable for i.m. and i.c.v. injection.

The suppositories may contain together with the active compounds, a pharmaceutically acceptable carrier, e.g., cocoa-butter polyethylene glycol, a polyethylene sorbitan fatty acid ester surfactant or lecithin.

Examples of suitable doses of the active agents contemplated for different administration routes are given below.

1 Per os 10-300 mg i.m. 25-100 mg i.v. 2.5-25 mg i.t. 0.1-25 mg (daily--every 3.sup.rd month) inhalation 0.2-40 mg transepidermally 10-100 mg intranasally 0.1-10 mg s.c. 5-10 mg i.c.v. 0.1-25 mg (daily--every 3.sup.rd month) epidurally 1-100 mg

These ranges are approximate (e.g., about 1 to about 100) and may vary depending on the specific agent being administered and the nature of the disorder in the subject. Thus, it is further contemplated that any dosage in between for the cited ranges may also be used.

Examples of suitable doses for different TNF-alpha inhibitors are given in the table below. Preferred dosage of TNF-alpha blocking substance and administration route Lenercept i.v. 5-200 10-100 30-80 (all given in mg for administration once every 4th week) TBP-1 i.v. 5-200 10-100 30-80 (all given in mg for administration once every 4th week) CDP-571 (HUMICADE) i.v. 1-100 5-10 5-10 (all given in mg/kg body Weight for administration as a single dose) D2E7 i.v. 0.1-50 0.5-10 1-10 s.c. 0.1-50 0.5-10 1-10 (all given in mg/kg body weight for administration as a single dose) Iloprost i.v. 0.1-2000 1-1500 100-1000 (all given in ug/kg body weight/day) intranasally 50-250 100-150 100-150 (all given in ug/day) Thalidomide 100-1200 300-1000 500-800 (all given in ug/day) CC-I088 Per os 50-1200 200-800 400-600 (all given in mg/day) CDP-870 i.v. 1-50 2-10 3-8 (all given in mg/kg body weight for administration once every 4th week) HP-228 i.v. 5-100 10-50 20-40 (all given in .mu.g/kg body weight) ISIS-10483 Per os 1-100 10-50 20-50 s.c. 1-100 10-50 20-50 i.v. 1-100 10-50 20-50 (all given in mg) ARIFLO (SB 207499 Per os 10-100 30-60 30-45 (all given in mg/day) KB-R7785 s.c. 100-500 100-300 150-250 (all given in mg/kg body weight/day) CDC-501 Per os 50-1200 200-800 400-600 (all given in mg/day) CDC-801 (ROQUININEX) Per os 50-1200 200-800 400-600 (all given in mg/day) Prinomastat, Batimastat, and Marimastat Per os 1-250 mg 5-100 mg 10-50 mg (all given in mg twice/day) Linomide Per os 0.1-25 5-20 110-15 (all given in mg/kg body weight/day) IL-1 blocking substance and administration route Anakinra (KINERET.RTM.) s.c. 10-200 50-150 100 (all given in mg/day)
 

Claim 1 of 24 Claims

1. A method of treating or alleviating one or more symptoms of a nerve disorder mediated by nucleus pulposus in a mammal comprising administering to the mammal a therapeutically effective amount of an antibody that blocks TNF-.alpha. activity, wherein the antibody is selected from the group consisting of murine monoclonal antibodies, chimeric antibodies, humanized antibodies and human monoclonal antibodies.

 

 

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