# US 2014/0154256 A1 · Anti-il1alpha/beta dual variable domain immunoglobulin and uses thereof

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- Number: US 2014/0154256 A1
- Document ID: US20140154256A1
- Status: Published application
- Kind: A1
- Application number: 14/177,153
- Filed: 2014-02-10
- Published: 2014-06-05
- Earliest claimed: 2005-08-19
- Assignees: AbbVie Inc.
- Applicants: AbbVie, Inc.
- Inventors: Chengbin Wu; Tariq Ghayur; Richard W. Dixon; Jochen G. Salfeld
- Web page: https://patentgrep.com/patent/US20140154256A1

## CPC

- C07K 16/468: {Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/42: Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein (oligopeptides having up to five amino acids {A61K47/183}; polyamino acids A61K47/34)
- A61K 51/1093: {conjugates with carriers being antibodies}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/04: for non-specific disorders of the connective tissue
- A61P 19/10: for osteoporosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 23/00: Anaesthetics
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/06: Antimigraine agents
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 25/32: Alcohol-abuse
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 41/00: Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
- C07K 16/22: against growth factors {; against growth regulators}
- C07K 16/24: against cytokines, lymphokines or interferons
- C07K 16/241: {Tumor Necrosis Factors}
- C07K 16/244: {Interleukins [IL]}
- C07K 16/245: {IL-1}
- C07K 16/2809: {against the T-cell receptor (TcR)-CD3 complex}
- C07K 16/2887: {against CD20}
- C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere}
- C07K 16/40: against enzymes
- C07K 16/46: Hybrid immunoglobulins (hybrids of an immunoglobulin with a peptide not being an immunoglobulin C07K19/00)
- C07K 16/467: {Igs with modifications in the FR-residues only}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/31: multispecific
- C07K 2317/51: Complete heavy chain or Fd fragment, i.e. VH + CH1
- C07K 2317/522: CH1 domain
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/64: comprising a combination of variable region and constant region components
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention relates to engineered multivalent and multispecific binding proteins, methods of making, and specifically to their uses in the prevention and/or treatment of acute and chronic inflammatory and other diseases.

## Claims

### Claim 1

A binding protein comprising a polypeptide chain, wherein said polypeptide chain comprises VD1-(X1)n-VD2-C-(X2)n, wherein VD1 is a first variable domain, VD2 is a second variable domain, C is a constant domain, X1 represents an amino acid or polypeptide, X2 represents an Fc region and n is 0 or 1, wherein said binding protein is capable of binding IL-1α and IL-1β.

### Claim 2 (depends on 1)

The binding protein according to claim 1, wherein said VD1 and VD2 are heavy chain variable domains.

### Claim at position 3

3-5. (canceled)

### Claim 6 (depends on 2)

The binding protein according to claim 2, wherein C is a heavy chain constant domain.

### Claim 7 (depends on 6)

The binding protein according to claim 6, wherein X1 is a linker with the proviso that X1 is not CH1.

### Claim 8 (depends on 7)

The binding protein according to claim 7, wherein the linker is
AKTTPKLEEGEFSEAR; AKTTPKLEEGEFSEARV; AKTTPKLGG;
SAKTTPKLGG; AKTTPKLEEGEFSEARV; SAKTTP; SAKTTPKLGG;
RADAAP; RADAAPTVS; RADAAAAGGPGS; RADAAAA(G4S)4,
SAKTTP; SAKTTPKLGG; SAKTTPKLEEGEFSEARV; ADAAP;
ADAAPTVSIFPP; TVAAP; TVAAPSVFIFPP; QPKAAP;
QPKAAPSVTLFPP; AKTTPP; AKTTPPSVTPLAP; AKTTAP;
AKTTAPSVYPLAP; ASTKGP; ASTKGPSVFPLAP;
GGGGSGGGGSGGGGS; GENKVEYAPALMALS;
GPAKELTPLKEAKVS; or GHEAAAVMQVQYPAS.

### Claim 9 (depends on 7)

The binding protein according to claim 7, wherein X2 is an Fc region.

### Claim 10 (depends on 9)

The binding protein according to claim 9, wherein said Fc region is a variant Fc region.

### Claim 11

A binding protein comprising a polypeptide chain, wherein said polypeptide chain comprises VD1-(X1)n-VD2-C-(X2)n, wherein VD1 is a first heavy chain variable domain, VD2 is a second heavy chain variable domain, C is a heavy chain constant domain, X1 is a linker with the proviso that it is not CH1, and X2 is an Fc region.

### Claim 12 (depends on 1)

The binding protein according to claim 1, wherein said VD1 and VD2 are light chain variable domains.

### Claim at position 11

13-15. (canceled)

### Claim 16 (depends on 12)

The binding protein according to claim 12, wherein C is a light chain constant domain.

### Claim 17 (depends on 16)

The binding protein according to claim 16, wherein X1 is a linker with the proviso that X1 is not CL1.

### Claim 18 (depends on 17)

The binding protein according to claim 17, wherein the linker is
AKTTPKLEEGEFSEAR; AKTTPKLEEGEFSEARV; AKTTPKLGG;
SAKTTPKLGG; AKTTPKLEEGEFSEARV; SAKTTP; SAKTTPKLGG;
RADAAP; RADAAPTVS; RADAAAAGGPGS; RADAAAA(G4S)4,
SAKTTP; SAKTTPKLGG; SAKTTPKLEEGEFSEARV; ADAAP;
ADAAPTVSIFPP; TVAAP; TVAAPSVFIFPP; QPKAAP;
QPKAAPSVTLFPP; AKTTPP; AKTTPPSVTPLAP; AKTTAP;
AKTTAPSVYPLAP; ASTKGP; ASTKGPSVFPLAP;
GGGGSGGGGSGGGGS; GENKVEYAPALMALS; GPAKELTPLKEAKVS;
or GHEAAAVMQVQYPAS.

### Claim 19 (depends on 17)

The binding protein according to claim 17, wherein the binding protein does not comprise X2.

### Claim 20

(canceled)

### Claim 21

A binding protein comprising four polypeptide chains, wherein:
a first polypeptide chain and a second polypeptide chain each comprises VD1-(X1)n-VD2-C-(X2)n, wherein VD1 is a first variable domain, VD2 is a second variable domain, C is a constant domain, X1 is a linker with the proviso that it is not a constant domain, X2 is an Fc region, and n is 0 or 1; and
a third polypeptide chain and a fourth polypeptide chain each comprises VD1-(X1)n-VD2-C, wherein VD1 is a first variable domain, VD2 is a second variable domain, C is a constant domain, and X1 is a linker with the proviso that it is not a constant domain, and n is 0 or 1;
wherein either or each of VD 1 and VD2 of said polypeptide chains is a non-immunoglobulin variable domain; and
wherein said four polypeptide chains of said binding protein form four functional binding domains, wherein said binding protein is capable of binding IL-1α and IL-1β.

### Claim 22 (depends on 21)

The binding protein according to claim 21, wherein:
VD1 of said first polypeptide chain and of said second polypeptide chain is a non-immunoglobulin variable domain,
VD2 of said first polypeptide chain and of said second polypeptide chain is an immunoglobulin variable domain,
VD1 of said third polypeptide chain and of said fourth polypeptide chain is a non-immunoglobulin variable domain, and
VD2 of said third polypeptide chain and of said fourth polypeptide chain is an immunoglobulin variable domain.

### Claim 23 (depends on 21)

The binding protein according to claim 21, wherein:
VD1 of said first polypeptide chain and of said second polypeptide chain is an immunoglobulin variable domain,
VD2 of said first polypeptide chain and of said second polypeptide chain is a non-immunoglobulin variable domain,
VD1 of said third polypeptide chain and of said fourth polypeptide chain is an immunoglobulin variable domain, and
VD2 of said third polypeptide chain and of said fourth polypeptide chain is a non-immunoglobulin variable domain.

### Claim 24 (depends on 21)

The binding protein according to claim 21, wherein:
VD1 of said first polypeptide chain and of said second polypeptide chain is a non-immunoglobulin variable domain,
VD2 of said first polypeptide chain and of said second polypeptide chain is a non-immunoglobulin variable domain,
VD1 of said third polypeptide chain and of said fourth polypeptide chain is a non-immunoglobulin variable domain, and
VD2 of said third polypeptide chain and of said fourth polypeptide chain is a non-immunoglobulin variable domain.

### Claim 25 (depends on 22)

The binding protein according to claim 22, wherein:
non-immunoglobulin variable domain VD1 of said first polypeptide chain and of said second polypeptide chain, and
non-immunoglobulin variable domain VD1 of said third polypeptide chain and of said fourth polypeptide chain,
together form two functional ligand binding domains of a receptor.

### Claim 26 (depends on 23)

The binding protein according to claim 23, wherein:
non-immunoglobulin variable domain VD2 of said first polypeptide chain and of said second polypeptide chain, and
non-immunoglobulin variable domain VD2 of said third polypeptide chain and of said fourth polypeptide chain,
together form two functional ligand binding domains of a receptor.

### Claim 27 (depends on 24)

The binding protein according to claim 24, wherein:
non-immunoglobulin variable domain VD1 of said first polypeptide chain and of said second polypeptide chain, and
non-immunoglobulin variable domain VD1 of said third polypeptide chain and of said fourth polypeptide chain,
together form two functional ligand binding domains of a receptor; and wherein:
non-immunoglobulin variable domain VD2 of said first polypeptide chain and of said second polypeptide chain, and
non-immunoglobulin variable domain VD2 of said third polypeptide chain and of said fourth polypeptide chain,
together form two functional ligand binding domains of a receptor.

### Claim 28 (depends on 21)

The binding protein according to claim 21, wherein said Fc region, X2, is a variant of a native sequence Fc region, containing mutations to disrupt dimerization of the CH3 domain.

### Claim 29 (depends on 21)

The binding protein according to claim 21, wherein X1 is
AKTTPKLEEGEFSEAR; AKTTPKLEEGEFSEARV; AKTTPKLGG;
RADAAP; RADAAPTVS; RADAAAAGGPGS; RADAAAA(G4S)4,
SAKTTP; SAKTTPKLGG; SAKTTPKLEEGEFSEARV; ADAAP;
ADAAPTVSIFPP; TVAAP; TVAAPSVFIFPP; QPKAAP;
QPKAAPSVTLFPP; AKTTPP; AKTTPPSVTPLAP; AKTTAP;
AKTTAPSVYPLAP; ASTKGP; ASTKGPSVFPLAP;
GGGGSGGGGSGGGGS; GENKVEYAPALMALS; GPAKELTPLKEAKVS;
or GHEAAAVMQVQYPAS.

### Claim 30 (depends on 21)

The binding protein according to claim 21, wherein, for (X2)n, n is 0.

### Claim at position 27

31-41. (canceled)

### Claim 42

An isolated nucleic acid comprising a coding sequence for a polypeptide chain comprising the structure VD1-(X1)n-VD2-C-(X2)n, wherein VD1 is a variable domain, VD2 is a second variable domain, C is a constant domain, X1 is a linker with the proviso that it is not a constant domain, X2 is an Fc region, and n is 0 or 1, wherein said binding protein is capable of binding IL-1α and IL-1β.

### Claim 43 (depends on 42)

The isolated nucleic acid according to claim 42, wherein said encoded polypeptide chain is capable of pairing with a polypeptide chain comprising the structure VD1-(X1)n-VD2-C, wherein VD1 is a first variable domain, VD2 is a second variable domain, C is a constant domain, X1 is a linker with the proviso that it is not a constant domain, and n is 0 or 1; to form a two-polypeptide chain binding protein comprising two functional binding domains.

### Claim 44

(canceled)

### Claim 45 (depends on 42)

A vector comprising the nucleic acid according to claim 42.

### Claim at position 32

46-47. (canceled)

### Claim 48 (depends on 45)

A host cell comprising a vector according to claim 45.

### Claim at position 34

49-68. (canceled)

### Claim 69 (depends on 21)

A method of producing a four-polypeptide chain binding protein having four functional antigen binding sites comprising:
a) transfecting a host cell with a first expression vector and a second expression vector, wherein:
the first expression vector comprises a nucleic acid comprising a coding sequence for a first polypeptide chain comprising VD1-(X1)n-VD2-C-(X2)n, wherein VD1 is a first immunoglobulin heavy chain variable domain, VD2 is a second immunoglobulin heavy chain variable domain, C is a constant domain, X1 is a linker with the proviso that it is not a constant domain, X2 is an Fc region, and n is 0 or 1; and
the second expression vector comprises a nucleic acid comprising a coding sequence for a second polypeptide chain comprising VD1-(X1)n-VD2-C, wherein VD1 is a first immunoglobulin light chain variable domain, VD2 is a second immunoglobulin light chain variable domain, C is a constant domain, X1 is a linker with the proviso that it is not a constant domain, and n is 0 or 1; and
b) culturing the transfected host cell in (a) in culture medium under conditions sufficient to produce the four polypeptide chain binding protein according to claim 21 comprising the two first polypeptide chains in association with the two second polypeptide chains, wherein the four polypeptide chains of the binding protein form four functional antigen binding domains, and wherein said binding protein is capable of binding IL-1α and IL-1β.

### Claim at position 36

70-72. (canceled)

### Claim 73 (depends on 21)

A method for treating a subject for a disease or a disorder by administering to the subject the binding protein according to claim 21, such that treatment is achieved in the subject.

### Claim 74 (depends on 73)

The method of claim 73, wherein said disease or disorder is rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, septic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, spondyloarthropathy, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin dependent diabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis, dermatitis, scleroderma, graft versus host disease, organ transplant rejection, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki's disease, Grave's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Schoenlein purpurea, microscopic vasculitis of the kidneys, chronic active hepatitis, uveitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexia, infectious diseases, parasitic diseases, acute transverse myelitis, Huntington's chorea, Parkinson's disease, Alzheimer's disease, stroke, primary biliary cirrhosis, hemolytic anemia, malignancies, heart failure, myocardial infarction, Addison's disease, sporadic polyglandular deficiency type I, polyglandular deficiency type II (Schmidt's syndrome), adult (acute) respiratory distress syndrome, alopecia, alopecia greata, seronegative arthropathy, arthropathy, Reiter's disease, psoriatic arthropathy, ulcerative colitic arthropathy, enteropathic synovitis, Chlamydia-, Yersinia-, and Salmonella-associated arthropathy, spondyloarthropathy, atheromatous disease/arteriosclerosis, atopic allergy, autoimmune bullous disease, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune haemolytic anaemia, Coombs positive haemolytic anaemia, acquired pernicious anaemia, juvenile pernicious anaemia, myalgic encephalitis/Royal Free disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, acquired immunodeficiency syndrome, acquired immunodeficiency related diseases, hepatitis B, hepatitis C, common varied immunodeficiency (common variable hypogammaglobulinaemia), dilated cardiomyopathy, female infertility, ovarian failure, premature ovarian failure, fibrotic lung disease, cryptogenic fibrosing alveolitis, post-inflammatory interstitial lung disease, interstitial pneumonitis, connective tissue disease associated interstitial lung disease, mixed connective tissue disease associated lung disease, systemic sclerosis associated interstitial lung disease, rheumatoid arthritis associated interstitial lung disease, systemic lupus erythematosus associated lung disease, dermatomyositis/polymyositis associated lung disease, Sjögren's disease associated lung disease, ankylo sing spondylitis associated lung disease, vasculitic diffuse lung disease, haemosiderosis associated lung disease, drug-induced interstitial lung disease, fibrosis, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrative lung disease, postinfectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis), type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune mediated hypoglycaemia, type B insulin resistance with acanthosis nigricans, hypoparathyroidism, osteoarthrosis, primary sclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathic leucopaenia, autoimmune neutropaenia, renal disease NOS, glomerulonephritides, microscopic vasculitis of the kidneys, Lyme disease, discoid lupus erythematosus, male infertility idiopathic or NOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture's syndrome, pulmonary manifestation of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Sjörgren's syndrome, Takayasu's disease/arteritis, autoimmune thrombocytopaenia, idiopathic thrombocytopaenia, autoimmune thyroid disease, hyperthyroidism, goitrous autoimmune hypothyroidism (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxoedema, phacogenic uveitis, primary vasculitis, vitiligo, acute liver disease, chronic liver diseases, alcoholic cirrhosis, alcohol-induced liver injury, cholestasis, idiosyncratic liver disease, drug-induced hepatitis, non-alcoholic steatohepatitis, allergy, group B streptococci (GBS) infection, mental disorders (e.g., depression and schizophrenia), Th2 Type and Th1 Type mediated diseases, acute and chronic pain (different forms of pain), lung cancer, breast cancer, stomach cancer, bladder cancer, colon, pancreatic cancer, ovarian cancer, prostate cancer, rectal cancer, hematopoietic malignancies (leukemia and lymphoma), abetalipoproteinemia, acrocyanosis, acute and chronic parasitic or infectious processes, acute leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic bacterial infection, acute pancreatitis, acute renal failure, adenocarcinomas, atrial ectopic beats, AIDS dementia complex, alcohol-induced hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, allograft rejection, alpha-1-antitryp sin deficiency, amyotrophic lateral sclerosis, anemia, angina pectoris, anterior horn cell degeneration, anti-CD3 therapy, antiphospholipid syndrome, anti-receptor hypersensitivity reactions, aortic and peripheral aneurysms, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia, atrial fibrillation (sustained or paroxysmal), atrial flutter, atrioventricular block, B cell lymphoma, bone graft rejection, bone marrow transplant (BMT) rejection, bundle branch block, Burkitt's lymphoma, burns, cardiac arrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy, cardiopulmonary bypass inflammation response, cartilage transplant rejection, cerebellar cortical degenerations, cerebellar disorders, chaotic or multifocal atrial tachycardia, chemotherapy associated disorders, chronic myelocytic leukemia (CML), chronic alcoholism, chronic inflammatory pathologies, chronic lymphocytic leukemia (CLL), chronic obstructive pulmonary disease (COPD), chronic salicylate intoxication, colorectal carcinoma, congestive heart failure, conjunctivitis, contact dermatitis, cor pulmonale, coronary artery disease, Creutzfeldt-Jakob disease, culture negative sepsis, cystic fibrosis, cytokine therapy associated disorders, dementia pugilistica, demyelinating diseases, dengue hemorrhagic fever, dermatologic conditions, diabetes, diabetes mellitus, diabetic arteriosclerotic disease, diffuse Lewy body disease, dilated congestive cardiomyopathy, disorders of the basal ganglia, Down's syndrome in middle age, drug-induced movement disorders induced by drugs which block CNS dopamine receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy, epiglottitis, Epstein-Barr virus infection, erythromelalgia, extrapyramidal and cerebellar disorders, familial hemophagocytic lymphohistiocytosis, fetal thymus implant rejection, Friedreich's ataxia, functional peripheral arterial disorders, fungal sepsis, gas gangrene, gastric ulcer, glomerular nephritis, graft rejection of any organ or tissue, gram negative sepsis, gram positive sepsis, granulomas due to intracellular organisms, hairy cell leukemia, Hallervorden-Spatz disease, Hashimoto's thyroiditis, hay fever, heart transplant rejection, hemochromatosis, hemodialysis, hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura, hemorrhage, hepatitis A, His bundle arrhythmias, HIV infection/HIV neuropathy, Hodgkin's disease, hyperkinetic movement disorders, hypersensitivity reactions, hypersensitivity pneumonitis, hypertension, hypokinetic movement disorders, hypothalamic-pituitary-adrenal axis evaluation, idiopathic Addison's disease, idiopathic pulmonary fibrosis, antibody mediated cytotoxicity, asthenia, infantile spinal muscular atrophy, inflammation of the aorta, influenza A, ionizing radiation exposure, iridocyclitis/uveitis/optic neuritis, ischemia-reperfusion injury, ischemic stroke, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma, kidney transplant rejection, legionella, leishmaniasis, leprosy, lesions of the corticospinal system, lipedema, liver transplant rejection, lymphedema, malaria, malignant lymphoma, malignant histiocytosis, malignant melanoma, meningitis, meningococcemia, metabolic migraine headache, idiopathic migraine headache, mitochondrial multisystem disorder, mixed connective tissue disease, monoclonal gammopathy, multiple myeloma, multiple systems degenerations (Menzel, Dejerine-Thomas, Shy-Drager, and Machado-Joseph), myasthenia gravis, mycobacterium avium intracellulare, mycobacterium tuberculosis, myelodysplastic syndrome, myocardial infarction, myocardial ischemic disorders, nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrosis, neurodegenerative diseases, neurogenic muscular atrophies, neutropenic fever, non-Hodgkin's lymphoma, occlusion of the abdominal aorta and its branches, occlusive arterial disorders, OKT 3 therapy, orchitis/epididymitis, orchitis/vasectomy reversal procedures, organomegaly, osteoporosis, pancreas transplant rejection, pancreatic carcinoma, paraneoplastic syndrome/hypercalcemia of malignancy, parathyroid transplant rejection, pelvic inflammatory disease, perennial rhinitis, pericardial disease, peripheral atherosclerotic disease, peripheral vascular disorders, peritonitis, pernicious anemia, pneumocystis carinii pneumonia, pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), post perfusion syndrome, post pump syndrome, post-MI cardiotomy syndrome, preeclampsia, progressive supranucleo palsy, primary pulmonary hypertension, radiation therapy, Raynaud's phenomenon, Raynaud's disease, Refsum's disease, regular narrow QRS tachycardia, renovascular hypertension, reperfusion injury, restrictive cardiomyopathy, sarcomas, senile chorea, senile dementia of Lewy body type, seronegative arthropathies, shock, sickle cell anemia, skin allograft rejection, skin changes syndrome, small bowel transplant rejection, solid tumors, specific arrhythmias, spinal ataxia, spinocerebellar degenerations, streptococcal myositis, structural lesions of the cerebellum, subacute sclerosing panencephalitis, syncope, syphilis of the cardiovascular system, systemic anaphylaxis, systemic inflammatory response syndrome, systemic onset juvenile rheumatoid arthritis, T-cell or FAB ALL, telangiectasia, thromboangitis obliterans, thrombocytopenia, toxicity, transplants, trauma/hemorrhage, type III hypersensitivity reactions, type IV hypersensitivity, unstable angina, uremia, urosepsis, urticaria, valvular heart diseases, varicose veins, vasculitis, venous diseases, venous thrombosis, ventricular fibrillation, viral and fungal infections, viral encephalitis/aseptic meningitis, viral-associated hemophagocytic syndrome, Wernicke-Korsakoff syndrome, Wilson's disease, or xenograft rejection of any organ or tissue.

### Claim 75

(canceled)