Lets just say the therapeutic potential of Raptiva just expanded a bit. How many potential uses can you count?
>Field of the Invention
The present invention relates generally to a method for the treating a lymphocyte function associated (LFA)-t mediated disorder or a tumor necrosis factor (TNF)-a mediated disorder by administering effective amounts of an LFA-I antagonist and a TNF-a antagonist. The invention also relates to treatment of arthritis and psoriasis with an LFA-I antagonist and a TNF-a antagonist.
>D. Therapeutic Utility
It is contemplated that the compounds of the invention may be used to treat various LFA-1 and or TNFa mediated diseases or disorders. including degenerative cartilagenous disorders such as rheumatoid arthritis. juvenile chronic arthritis (e. g., Polyarticular-Course Juvenile Rheumatoid Arthritis (JRA)) and spondyloarthropathies. RA refractory to or intolerant of methotrexate can also be treated with the LFA-1 and
TNF-a antagonists of the invention.
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disease that mainly involves the synovial membrane of multiple joints with resultant injury to the articular cartilage. The pathogenesis is T lymphocyte dependent and is associated with the production of rheumatoid factors, auto-antibodies directed against self IgG, with the resultant formation of immune complexes that attain high levels in joint fluid and blood. These complexes in the joint may induce the marked infiltrate of lymphocytes and monocytes into the synovium and subsequent marked synovial changes : the joint space/fluid is infiltrated by similar cells with the addition of numerous neutrophils. Tissues affected are primarily the joints, often in symmetrical pattern.
However, extra-articular disease also occurs in two major forms. One form is the development of extra-articular lesions with ongoing progressive joint disease and typical lesions of pulmonary fibrosis, vasculitis, and cutaneous ulcers. The second form of extra-articular disease is the so called Felts syndrome which occurs late in the RA disease course, sometimes after joint disease has become quiescent. and involves the presence of neutropenia. thrombocytopenia and splenomegaly. This can be accompanied by vasculitis in multiple organs with formations of infarcts, skin ulcers and gangrene. Patients often also develop rheumatoid nodules in the subcutis tissue overlying affected joints ; the nodules late stage have necrotic centers surrounded by a mixed inflammatory cell infiltrate. Other manifestations which can occur in RA include: pericarditis, pleuritis, coronary arteritis. intestitial pneumonitis with pulmonary fibrosis, keratoconjunctivitis sicca, and rheumatoid nodules.
Juvenile chronic arthritis is a chronic idiopathic inflammatory disease which begins often at less than 6
years of age. Its phenotype has some similarities to RA : some patients which are rhematoid factor positive are
classified as juvenile rheumatoid arthritis. The disease is sub-classified into three major categories: pauciarticular, polyarticular, and systemic. The arthritis can be severe and is typically destructive and leads to joint ankylosis and retarded growth. Other manifestations can include chronic anterior uveitis and systemic
amyloidosis.
The degenerative cartilagenous disorder osteoarthritis (OA) is a localized degenerative disease that affects the articular structure and results in pain and diminished function. OA is characterized by pertubations in the cartilage surface followed by clefts and fibrilations and finally by loss of the entire thickness of the cartilage layer. Additional symptoms of OA include the formation of calcified outgrowths of the periarticular bone and disfigurement coincident with assymetric cartilage destruction. OA may be be classified into two types: primary and secondary. Primary OA refers to the spectrum of degenerative joint diseases for which no underlying etiology has been determined. Typically, the joint affected by primary OA are the interphalangeal joints of the hands, the first carpometacarpal joints, the hips, the knees, the spine, and some joints in the midfoot.
Interestingly, large joints. such as the ankles, elbows and shoulders tend to be spared in primary OA. In contrast. secondary OA occurs as a result of defined injury. Secondary OA is often associated with metabolic diseases such as hemochromatosis and alkaptonuria, developmental abnormalities such as developmental dysplasia of the hips (congenital dislocation of the hips) and limb-length descrepancies, including trauma. inflammatory arthritides such as rheumatoid arthritis or gout, septic arthritis, and neuropathic arthritis.
Injuries to cartilage fall into three categories: (1) microdamage or blunt trauma, (2) chondral fractures. and (3) osteochondral fractures.
Microdamage to chondrocytes and cartilage matrix may be caused by a single impact or through repetitive blunt trauma. Chondral fractures are characterized as a disruption of the articular surface without violation of the subchondral plate. Chondrocyte necrosis at the injury site occurs, followed by increased mitotic and metabolic activity of the surviving chondrocytes bordering the injury within a few days of injury. This is followed by fibrous tissue forming a lining of clefts in the surface. There is increased synthesis of extracellular matrix components and type 11 collagen for about two weeks after injury. after which the anabolism returns to normal. However, the transitory increase in mitotic and metabolic activity and the repair response resulting therefrom is suboptimal-resulting in the formation of fibrocartilage. Osteochondral fractures, the most serious of the three type of injuries, are lesions crossing the tidemark, or the underlying subchondral plate. In this type of injury, the presence of subchondral vasculature elicits the three-phase response typically encountered in vascular tissues: (1) necrosis; (2) inflammation : and (3) repair. Initially the lesion fills with blood and clots. The resulting fibrin clot activates an inflammatory response and becomes vascularized repair tissue, and the various cellular components release growth factors and cytokines including transforming growth factor beta (TGF-beta). platelet-derived growth factor (PDGF), bone morphogenic proteins. and insulin-like growth factors. Buckwalter et al., J. Am. Acad Orthop. Surg. 2 : 191-201 (1994).
Spondyloarthropathies are a group of disorders with some common clinical features and the common association with the expression of HLA-B27 gene product. The disorders include: ankylosing spondylitis,
Reiter's syndrome (reactive arthritis), arthritis associated with inflammatory bowel disease, spondylitis associated with psoriasis, juvenile onset spondyloarthropathy and undifferentiated spondyloarthropathy. Distinguishing features include sacroileitis with or without spondylitis: inflammatory asymmetric arthritis : association with
HLA-B27 (a serologically defined allele of the HLA-B locus of class I MHC): ocular inflammation. and absence
of autoantibodies associated with other rheumatoid disease. The cell most implicated as key to induction of the
disease is the CD8+ T lymphocyte, a cell which targets antigen presented by class I MHC molecules. CD8+ T
cells may react against the class I MHC allele HLA-B27 as if it were a foreign peptide expressed by MHC class 1
molecules. It has been hypothesized that an epitope of HLA-B27 may mimic a bacterial or other microbial
antigenic epitope and thus induce a CD8+ T cells response.
Other LFA-1 and/or TNF-a mediated diseases or disorders which may be treated with the combination
of the invention include (I) TNF-a mediated diseases or disorders such as (A) acute and chronic immune and
autoimmune pathologies, such as systemic lupus erythematosus (SLE) rheumatoid arthritis. thyroidosis, graft
versus host disease, scleroderma. diabetes mellitus, Graves'disease, and the like : (B) infections, including, but
not limited to, sepsis syndrome, cachexia, circulatory collapse and shock resulting from acute or chronic bacterial
infection, acute and chronic parasitic and/or infectious diseases, bacterial, viral or fungal. such as a HIV. AIDS
(including symptoms of cachexia. autoimmune disorders. AIDS dementia complex and infections); (C)
inflammatory diseases, such as chronic inflammatory pathologies and vascular inflammatory pathologies.
including chronic inflammatory pathologies such as sarcoidosis. chronic inflammatory bowel disease. ulcerative colitis, and Crohn's pathology and vascular inflammatory pathologies. such as. but not limited to. disseminated intravascular coagulation, atherosclerosis, and Kawasaki's pathology; (D) neurodegenerative diseases, including. but are not limited to, demyelinating diseases, such as multiple sclerosis and acute transverse myelitis ; extrapyramidal and cerebellar disorders'such as lesions of the corticospinal system; disorders of the basal ganglia or cerebellar disorders; hyperkinetic movement disorders such as Huntington's Chorea and senile chorea; druginduced movement disorders, such as those induced by drugs which block CNS dopamine receptors; hypokinetic movement disorders, such as Parkinson's disease; Progressive supranucleo palsy; Cerebellar and Spinocerebellar
Disorders, such as astructural lesions of the cerebellum; spinocerebellar degenerations (spinal ataxia, Friedreich's ataxia, cerebellar cortical degenerations, multiple systems degenerations (Mencel, Dejerine-Thomas, Shi-Drager. and MachadoJoseph)); and systemic disorders (Refsum's disease, abetalipoprotemia, ataxia. telangiectasia. and mitochondrial multi. system disorder) : demyelinating core disorders, such as multiple sclerosis. acute transverse myelitis : disorders of the motor unit, such as neurogenic muscular atrophies (anterior horn cell degeneration. such as amyotrophic lateral sclerosis, infantile spinal muscular atrophy and juvenile spinal muscular atrophy):
Alzheimer's disease; Down's Syndrome in middle age; Diffuse Lewy body disease ; Senile Dementia of Lewv body type ; Wernicke-Korsakoff syndrome; chronic alcoholism; Creutzfeldt-Jakob disease; Subacute sclerosing panencephalitis, Hallerrorden-Spatz disease; and Dementia pugilistica, or any subset thereof : and (2) LFA-I mediated diseases or disorders such as T cell inflammatory responses such as inflammatory skin diseases including psoriasis; responses associated with inflammatory bowel disease (such as Crohn's disease and ulcerative colitis); adult respiratory distress syndrome : dermatitis : meningitis : encephalitis: uveitic : allergic conditions such as eczema and asthma and other conditions involving infiltration of T cells and chronic inflammatory responses; skin hypersensitivity reactions (including poison ivy and poison oak): atherosclerosis: leukocyte adhesion deficiency : autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), diabetes mellitus, multiple sclerosis, Reynaud's syndrome, autoimmune thyroiditis. experimental autoimmune encephalomyelitis, Sjorgen's syndrome, juvenile onset diabetes, and immune responses associated with delayed hypersensitivity mediated by cytokines and T-lymphocytes typically found in tuberculosis, sarcoidosis, polymyositis, granulomatosis and vasculitis; pernicious anemia : diseases involving leukocvte diapedesis ; CNS inflammatory disorder, multiple organ injury syndrome secondary to septicaemia or trauma : autoimmune haemolytic anemia; myethemia gravis; antigen-antibody complex mediated diseases; all types of transplantations, including graft vs. host or host vs. graft disease; etc.
Systemic sclerosis (scleroderma) has an unknown etiology. A hallmark of the disease is induration of the skin; likely this is induced by an active inflammatory process. Scleroderma can be localized or systemic : vascular lesions are common and endothelial cell injury in the microvasculature is an early and important event in the development of systemic sclerosis; the vascular injury may be immune mediated. An immunologic basis is implied by the presence of mononuclear cell infiltrates in the cutaneous lesions and the presence of anti-nuclear antibodies in many patients. ICAM-I is often upregulated on the cell surface of fibroblasts in skin lesions suggesting that T cell interaction with these cells may have a role in the pathogenesis of the disease. Other organs involved include: the gastrointestinal tract: smooth muscle atrophy and fibrosis resulting in abnormal peristalsis/motility; kidney: concentric subendothelial intimal proliferation affecting small arcuate and interlobular arteries with resultant reduced renal cortical blood flow, results in proteinuria, azotemia and hypertension; skeletal muscle: atrophy, interstitial fibrosis; inflammation; lung : interstitial pneumonitis and interstitial fibrosis; and heart: contraction band necrosis, scarring/fibrosis.
Idiopathic inflammatory myopathies including dermatomyositis, polymyositis and others are disorders of chronic muscle inflammation of unknown etiology resulting in muscle weakness. Muscle injury/inflammation is often symmetric and progressive. Autoantibodies are associated with most forms. These myositis-specific autoantibodies are directed against and inhibit the function of components, proteins and RNAs, involved in protein synthesis.
* Sjgren's syndrome is the result of immune-mediated inflammation and subsequent functional destruction of the tear glands and salivary glands. The disease can be associated with or accompanied by inflammatory connective tissue diseases. The disease is associated with autoantibody production against Ro and
La antigens, both of which are small RNA-protein complexes. Lesions result in keratoconjunctivitis sicca, xerostomia, with other manifestations or associations including bilary cirrhosis, peripheral or sensory neuropathy, and palpable purpura.
Systemic vasculitis are diseases in which the primary lesion is inflammation and subsequent damage to blood vessels which results in ischemia/necrosis/degeneration to tissues supplied by the affected vessels and eventual end-organ dysfunction in some cases. Vasculitides can also occur as a secondary lesion or sequelae to other immune-inflammatory mediated diseases such as rheumatoid arthritis, systemic sclerosis, etc. particularly in diseases also associated with the formation of immune complexes. Diseases in the primary systemic vasculitis group include: systemic necrotizing vasculitis : polyarteritis nodosa. allergic angiitis and granulomatosis. polyangiitis; Wegener's granulomatosis ; lymphomatoid granulomatosis: and giant cell arteritis. Miscellaneous vasculitides include: mucocutaneous lymph node syndrome (MLNS or Kawasaki's disease), isolated CNS vasculitis, Behet's disease, thromboangiitis obliterans (Buerger's disease) and cutaneous necrotizing venulitis.
The pathogenic mechanism of most of the types of vasculitis listed is believed to be primarily due to the deposition of immunoglobulin complexes in the vessel wall and subsequent induction of an inflammatory response either via ADCC, complement activation, or both.
Sarcoidosis is a condition of unknown etiology which is characterized by the presence of epithelioid granulomas in nearly any tissue in the body ; involvement of the lung is most common. The pathogenesis
involves the persistence of activated macrophages and lymphoid cells at sites of the disease with subsequent chronic sequelae resultant from the release of locally and systemically active products released by these cell types.
Autoimmune hemolytic anemia including autoimmune hemolytic anemia, immune pancytopenia. and paroxysmal noctural hemoglobinuria is a result of production of antibodies that react with antigens expressed on the surface of red blood cells (and in some cases other blood cells including platelets as well) and is a reflection of the removal of those antibody coated cells via complement mediated lysis and/or ADCC/Fc-receptor-mediated mechanisms.
In autoimmune thrombocytopenia including thrombocytopenic purpura. and immune-mediated thrombocytopenia in other clinical settings, platelet destruction/removal occurs as a result of either antibodv or complement attaching to platelets and subsequent removal by complement lysis, ADCC or FC-receptor mediated mechanisms.
Thyroiditis including Grave's disease. Hashimoto's thyroiditis. juvenile lymphocytic thyroiditis. and atrophic thyroiditis. are the result of an autoimmune response against thyroid antigens with production of antibodies that react with proteins present in and often specific for the thyroid gland. Experimental models exist including spontaneous models: rats (BUF and BB rats) and chickens (obese chicken strain) : inducible models: immunization of animals with either thyroglobulin, thyroid microsomal antigen (thyroid peroxidase).
Type I diabetes mellitus or insulin-dependent diabetes is the autoimmune destruction of pancreatic islet cells ; this destruction is mediated by auto-antibodies and auto-reactive T cells. Antibodies to insulin or the insulin receptor can also produce the phenotype of insulin-non-responsiveness.
Immune mediated renal diseases, including glomerulonephritis and tubulointerstitial nephritis, are the result of antibody or T lymphocyte mediated injury to renal tissue either directly as a result of the production of autoreactive antibodies or T cells against renal antigens or indirectly as a result of the deposition of antibodies and/or immune complexes in the kidney that are reactive against other, non-renal antigens. Thus other immunemediated diseases that result in the formation of immune-complexes can also induce immune mediated renal disease as an indirect sequelae. Both direct and indirect immune mechanisms result in inflammatory response that produces/induces lesion development in renal tissues with resultant organ function impairment and in some cases progression to renal failure. Both humoral and cellular immune mechanisms can be involved in the pathogenesis of lesions.
Demyelinating diseases of the central and peripheral nervous systems, including multiple sclerosis: idiopathic demyelinating polyneuropathy or Guillain-Barre syndrome : and Chronic Inflammatory Demyelinating
Polyneuropathy. are believed to have an autoimmune basis and result in nerve demyelination as a result of damage caused to oligodendrocytes or to myelin directly. In MS there is evidence to suggest that disease induction and progression is dependent on T lymphocytes. Multiple Sclerosis is a demyelinating disease that is T lymphocyte-dependent and has either a relapsing-remitting course or a chronic progressive course. The etiology is unknown : however, viral infections, genetic predisposition, environment. and autoimmunity all contribute.
Lesions contain infiltrates of predominantly T lymphocyte mediated, microglial cells and infiltrating macrophages ; CD4+T lymphocytes are the predominant cell type at lesions. The mechanism of oligodendrocyte cell death and subsequent demyelination is not known but is likely T lymphocyte driven.
Inflammatory and Fibrotic Lung Disease, including Eosinophilic Pneumonias: Idiopathic Pulmonary Fibrosis, and Hypersensitivity Pneumonitis may involve a disregulated immune-inflammatory response.
Inhibition of that response would be of therapeutic benefit.
Autoimmune or Immune-mediated Skin Disease including Bullous Skin Diseases. Erythema
Multiforme, and Contact Dermatitis are mediated by auto-antibodies, the genesis of which is T lymphocytedependent.
Psoriasis is a T lymphocyte-mediated inflammatory disease characterized by hyperproliferation of keratinocytes and accumulation of activated T cells in the epidermis and dermis of psoriatic lesions. Lesions contain infiltrates of T lymphocytes, macrophages and antigen processing cells. and some neutrophils.
Transplantation associated diseases. including graft rejection and Graft-Versus-Host-Disease (GVHD) are T lymphocyte-dependent : inhibition of T lymphocyte function is ameliorative.
Other diseases in which intervention of the immune and/or inflammatory response have benefit are infectious disease including but not limited to viral infection (including but not limited to AIDS, hepatitis A, Bs C. D, E and herpes) bacterial infection, fungal infections, and protozoal and parasitic infections (molecules (or derivativesiagonists) which stimulate the MLR can be utilized therapeutically to enhance the immune response to infectious agents), diseases of immunodeficiency (molecules/derivatives/aaonists) which stimulate the MLR can be utilized therapeutically to enhance the immune response for conditions of inherited, acquired, infectious induced (as in HIV infection), or iatrogenic (i. e. as from chemotherapy) immunodeficiency, and neoplasia.
Additionally, inhibition of molecules with proinflammatory properties may have therapeutic benefit in reperfusion injury ; stroke ; myocardial infarction ; atherosclerosis ; acute lung injury ; hemorrhagic shock ; burn : sepsis/septic shock; acute tubular necrosis ; endometriosis ; degenerative joint disease and pancreatis.
>Suitable TNF-a antagonists include any compound which inhibits the interaction of TNF-a and a receptor therefor, in particular, the p55 receptor and the p75 receptor. The TNF-a antagonist may be a small molecule, peptide, protein, receptor extracellular domain. immunoadhesin or an anti-TNF-a antibody. for example.
The TNF-a antagonists include ENBREL. etanercept (Immunex/AHP) ; Remicade Infliximab. which is an anti-TNF chimeric Mab (Centocor/Johnson & Johnson) : anti-TNFa, D2E7 human Mab (Cambridge Antibody
Technology) ; CDP-870 which is a PEGylated antibody fragment (Celltech) : CDP 571, Humicade. which is a humanized Mab (Celltech) ; PEGylated soluble TNF-a Receptorl (Amgen) : TBP-1 which is a TNF binding protein (Ares Serono); PASSTNF-alphat which is an anti-TNF-a polyclonal antibody (Verigen) AGT-I (from
Advanced Biotherapy Concepts) which is a mixture of 3 anti-cytokine antibodies, antibodies to IFN-a. IFN-y and TNF ; TENEFUSE. lenercept which is a TNFR-Ig fusion protein (Roche) : CytoTAb (Protherics) : TACE which is a small molecule TNF-a converting enzyme inhibitor (Immunex) : small molecule TNF mRNA synthesis inhibitor (Nereus): PEGylated p75 TNFR Fc mutein (Immunex): and TNF-a antisense inhibitor
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