Prostaglandin e2 binding proteins and uses thereof

Abstract

The present invention encompasses prostaglandin E 2 (PGE 2 ) binding proteins. The invention relates to antibodies that are wild-type, chimeric, CDR grafted and humanized. Preferred antibodies have high affinity for prostaglandin E 2 and neutralize prostaglandin E 2 activity in vitro and in vivo. An antibody of the invention can be a full-length antibody, or an antigen-binding portion thereof. Methods of making and methods of using the antibodies of the invention are also provided. The antibodies, or antigen-binding portions, of the invention are useful for detecting prostaglandin E 2 and for inhibiting prostaglandin E 2 activity, e.g., in a human subject suffering from a disorder in which prostaglandin E 2 activity is detrimental.

1 - 92 . (canceled) 
     
     
         93 . An antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment is capable of binding prostaglandin E2 (PGE2), and the antibody or antigen-binding fragment comprises complementarity determining region (CDR) sequences of SEQ ID NO: 44 (GYTFTKYWLG, DIYPYGDYTHYNEKFKD, and SDGSSTY) and SEQ ID NO: 45 (TSSQNIVHSNGNTYLE, KVSNRFSG, and FQVSHVPYTF). 
     
     
         94 . An antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment is capable of binding prostaglandin E2, and the antibody or antigen-binding fragment comprises variable domain sequences selected from the group consisting of
 (a) SEQ ID NO: 44 and SEQ ID NO: 45; and   (b) SEQ ID NO: 40 and SEQ ID NO: 41.   
     
     
         95 . The antibody or antigen-binding fragment according to  claim 93  or  claim 94 , wherein the antibody or antigen-binding fragment
 (a) is capable of modulating a biological function of prostaglandin E 2 ; 
 (b) is capable of neutralizing prostaglandin E 2 ; 
 (c) is capable of preventing the binding of prostaglandin E 2  to one or more prostaglandin E 2  receptors selected from the group consisting of EP1, EP2, EP3, and EP4; 
 (d) is capable of preventing the binding of prostaglandin E 2  to prostaglandin E 2  receptors EP1, EP2, EP3, and EP4; 
 (e) is capable of binding prostaglandin E 2  with an EC 50  selected from the group consisting of about 1×10 −6  to about 1×10 −7  M, about 1×10 −7  to about 1×10 −8  M, about 1×10 −8  to about 1×10 −9  M, about 1×10 −9  to about 1×10 −10  M, about 1×10 −10  to about 1×10 −11  M and about 1×10 −11  to about 1×10 −12  M using an ELISA assay; and/or 
 (f) is capable of inhibiting calcium influx induced by prostaglandin E 2  to the prostaglandin E 2  receptor EP4 in an EP4 receptor mediated FLIPR assay with an IC 50  selected from the group consisting of about 1×10 −6  to about 1×10 −7  M, about 1×10 −7  to about 1×10 −8  M, about 1×10 −8  to about 1×10 −9  M, about 1×10 −9  to about 1×10 −10  M, about 1×10 −10  to about 1×10 −11  M, and about 1×10 −11  to about 1×10 −12  M. 
 
     
     
         96 . The antibody or antigen-binding fragment according to  claim 93  or  claim 94 , wherein the antibody or antigen-binding fragment has been affinity matured. 
     
     
         97 . The antibody or antigen-binding fragment according to  claim 93  or  claim 94 , further comprising a linker polypeptide. 
     
     
         98 . The binding protein according to  claim 93 , wherein the binding protein further comprises human acceptor framework sequences. 
     
     
         99 . The antibody or antigen-binding fragment according to  claim 93  or  claim 94 , wherein the antibody or antigen-binding fragment is selected from the group consisting of an immunoglobulin molecule, a disulfide linked Fv, a monoclonal antibody, an scFv, a chimeric antibody, a single domain antibody, a CDR-grafted antibody, a diabody, a humanized antibody, a multispecific antibody, a Fab, a dual specific antibody, a Fab′, a bispecific antibody, a F(ab′)2, and an Fv. 
     
     
         100 . The antibody or antigen-binding fragment according to  claim 93  or  claim 94 , further comprising a heavy chain immunoglobulin constant domain selected from the group consisting of a human IgM constant domain, a human IgG4 constant domain, a human IgG1 constant domain, a human IgE constant domain, a human IgG2 constant domain, a human IgG3 constant domain, and a human IgA constant domain 
     
     
         101 . The antibody or antigen-binding fragment according to  claim 100 , wherein the immunoglobulin constant domain has an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-4. 
     
     
         102 . An antibody conjugate comprising the antibody or antigen-binding fragment according to  claim 93  or  claim 94 , the antibody conjugate further comprising an immunoadhesion molecule, an imaging agent, a therapeutic agent, or a cytotoxic agent. 
     
     
         103 . The antibody conjugate of  claim 102 , wherein the imaging agent is a radiolabel, an enzyme, a fluorescent label, a luminescent label, a bioluminescent label, a magnetic label, or biotin. 
     
     
         104 . The antibody conjugate of  claim 103 , wherein the radiolabel is  3 H,  14 C,  35 S,  90 Y,  99 Tc,  111  In,  125 I,  131 I,  177 Lu,  166 Ho, or  153 SM. 
     
     
         105 . The antibody conjugate of  claim 102 , wherein the therapeutic or cytotoxic agent is an anti-metabolite, an alkylating agent, an antibiotic, a growth factor, a cytokine, an anti-angiogenic agent, an anti-mitotic agent, an anthracycline, a toxin, or an apoptotic agent. 
     
     
         106 . The antibody or antigen-binding fragment according to  claim 93  or  claim 94 , wherein:
 (a) the antibody or antigen-binding fragment possesses a human glycosylation pattern; 
 (b) the antibody or antigen-binding fragment is crystallized; 
 (c) the antibody or antigen-binding fragment is a carrier-free pharmaceutical controlled release crystal; 
 (d) the antibody or antigen-binding fragment of (a)-(c) has a greater half-life in vivo than a soluble counterpart; and/or 
 (e) the antibody or antigen-binding fragment of (a)-(d) retains biological activity after crystallization. 
 
     
     
         107 . An isolated nucleic acid encoding the antibody or antigen-binding fragment of  claim 93  or  claim 94 . 
     
     
         108 . A vector comprising the isolated nucleic acid according to  claim 107 , wherein the vector optionally comprises pcDNA, pTT, pTT3, pEFBOS, pBV, pJV, pBJ, or pA2. 
     
     
         109 . A host cell comprising the vector according to  claim 108 , wherein the host cell is optionally selected from the group consisting of a prokaryotic cell, an  Escherichia coli  cell, a eukaryotic cell, a protist cell, an animal cell, a plant cell, a fungal cell, a mammalian cell, an avian cell, an insect cell, a CHO cell, a COS cell, a HEK293 cell, a yeast cell, a  Saccharomyces cerevisiae  cell, and an insect Sf9 cell. 
     
     
         110 . A method of producing an antibody or antigen-binding fragment capable of binding prostaglandin E 2 , the method comprising the step of culturing the host cell of  claim 109  under conditions sufficient to produce the antibody or antigen-binding fragment. 
     
     
         111 . A composition for the release of an antibody or antigen-binding fragment, the composition comprising:
 (a) a crystallized antibody or antigen-binding fragment according to  claim 106 ;   (b) an ingredient selected from the group consisting of albumin, sucrose, trehalose, lactitol, gelatin, hydroxypropyl-β-cyclodextrin, methoxypolyethylene glycol, and polyethylene glycol; and/or   (c) at least one polymeric carrier optionally selected from the group consisting of poly (acrylic acid), poly (cyanoacrylates), poly (amino acids), poly (anhydrides), poly (depsipeptide), poly (esters), poly (lactic acid), poly (lactic-co-glycolic acid) or PLGA, poly (b-hydroxybutryate), poly (caprolactone), poly (dioxanone); poly (ethylene glycol), poly ((hydroxypropyl) methacrylamide, poly[(organo) phosphazene], poly (ortho esters), poly (vinyl alcohol), poly (vinylpyrrolidone), maleic anhydride-alkyl vinyl ether copolymers, pluronic polyols, albumin, alginate, cellulose and cellulose derivatives, collagen, fibrin, gelatin, hyaluronic acid, oligosaccharides, glycaminoglycans, sulfated polyeaccharides, and a blend and/or a copolymer thereof.   
     
     
         112 . A pharmaceutical composition comprising the antibody or antigen-binding fragment of  claim 93  or  claim 94  and a pharmaceutically acceptable carrier. 
     
     
         113 . The pharmaceutical composition of  claim 112 , wherein the pharmaceutically acceptable carrier functions as an adjuvant useful to increase the absorption or dispersion of the antibody or antigen-binding fragment thereof, wherein the adjuvant is optionally hyaluronidase. 
     
     
         114 . The pharmaceutical composition of  claim 113 , optionally further comprising an additional therapeutic agent selected from the group consisting of a therapeutic agent, an imaging agent, a cytotoxic agent, an angiogenesis inhibitor, a kinase inhibitor, a co-stimulation molecule blocker, an adhesion molecule blocker, an anti-cytokine antibody or functional fragment thereof, methotrexate, cyclosporine, rapamycin, FK506, a detectable label or reporter, a TNF antagonist, an anti-rheumatic, a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteroid, an anabolic steroid, an erythropoietin, an immunization, an immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, a radiopharmaceutical, an antidepressant, an antipsychotic, a stimulant, an asthma medication, a beta agonist, an inhaled steroid, an oral steroid, an epinephrine or analog thereof, a cytokine, and a cytokine antagonist. 
     
     
         115 . Use of the antibody or antigen-binding fragment according to  claim 93  or  claim 94  to reduce prostaglandin E 2  activity in a human subject. 
     
     
         116 . The use of  claim 115 , wherein the human subject is suffering from a disorder selected from the group consisting of an autoimmune disease, an inflammatory disease, a tumor, rheumatoid arthritis, allergic arthritis, Guillain Barre syndrome, infectious mononucleosis, a viral lymphadenopathy, a herpes virus infection, multiple sclerosis, a demyelinating disease, a hematological disorder, hemolytic anemia, thrombocytopenia, an endocrinologic disorder, diabetes mellitus, Addison's disease, idiopathic hypoparathyroidism, chronic lymphocytic thyroiditis, a collagen disorder, systemic lupus erythematosus, a reproductive disorder, amenorrhoea, infertility, recurrent abortion, eclampsia, a headneck tumor, lung cancer, gastric cancer, prostate cancer, pancreatic cancer, a gastrointestinal organ disease, inflammatory bowel disease, ulcerative colitis, Crohn's disease, pain, pain related with osteoarthritis, an ocular disorder, or age-related mascular degeneration, 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 or 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, acquired immunodeficiency syndrome, 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 and polyglandular deficiency type II, Schmidt's syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthropathy, arthropathy, Reiter's disease, psoriatic arthropathy, ulcerative colitic arthropathy, enteropathic synovitis, chlamydia, yersinia and salmonella associated arthropathy, spondyloarthopathy, 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 Disease 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, ankylosing 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, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, osteoarthrosis, primary sclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathic leucopaenia, autoimmune neutropaenia, renal disease NOS, glomerulonephritides, microscopic vasulitis 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, choleosatatis, idiosyncratic liver disease, drug-induced hepatitis, non-alcoholic steatohepatitis, allergy and asthma, group B streptococci (GBS) infection, mental disorders, depression, schizophrenia, Th2 Type and Th1 Type mediated diseases, acute pain, chronic pain, cancer, lung cancer, breast cancer, stomach cancer, bladder cancer, colon cancer, pancreatic cancer, ovarian cancer, prostate cancer, rectal cancer, hematopoietic malignancies, leukemia, lymphoma, abetalipoprotemia, 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, aerial ectopic beats, AIDS dementia complex, alcohol-induced hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, allograft rejection, alpha-1-antitrypsin deficiency, amyotrophic lateral sclerosis, anemia, angina pectoris, anterior horn cell degeneration, anti cd3 therapy, antiphospholipid syndrome, anti-receptor hypersensitivity reactions, aortic and peripheral aneuryisms, 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, dermatitis, dermatologic conditions, diabetes, diabetes mellitus, diabetic ateriosclerotic 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 hematophagocytic 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, Hallerrorden-Spatz disease, Hashimoto's thyroiditis, hay fever, heart transplant rejection, hemachromatosis, hemodialysis, hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura, hemorrhage, hepatitis A, His bundle arrythmias, HIV infection/HIV neuropathy, Hodgkin's disease, hyperkinetic movement disorders, hypersensitity 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, lymphederma, malaria, malignant lymphoma, malignant histiocytosis, malignant melanoma, meningitis, meningococcemia, metabolic/idiopathic, migraine headache, mitochondrial multi.system disorder, mixed connective tissue disease, monoclonal gammopathy, multiple myeloma, multiple systems degenerations (Mencel Dejerine-Thomas Shi-Drager and Machado-Joseph), myasthenia gravis, mycobacterium avium intracellulare, mycobacterium tuberculosis, myelodyplastic syndrome, myocardial infarction, myocardial ischemic disorders, nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrosis, neurodegenerative diseases, neurogenic I muscular atrophies, neutropenic fever, non-Hodgkins lymphoma, occlusion of the abdominal aorta and its branches, occulsive arterial disorders, okt3 therapy, orchitis/epidydimitis, 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 atherlosclerotic 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 and disease, Raynoud's disease, Refsum's disease, regular narrow QRS tachycardia, renovascular hypertension, reperfusion injury, restrictive cardiomyopathy, sarcomas, scleroderma, 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 arrythmias, spinal ataxia, spinocerebellar degenerations, streptococcal myositis, structural lesions of the cerebellum, subacute sclerosing panencephalitis, syncope, syphilis of the cardiovascular system, systemic anaphalaxis, 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, vital encephalitis/aseptic meningitis, vital-associated hemaphagocytic syndrome, Wernicke-Korsakoff syndrome, Wilson's disease, xenograft rejection of any organ or tissue, acute coronary syndromes, acute idiopathic polyneuritis, acute inflammatory demyelinating polyradiculoneuropathy, acute ischemia, adult Still's disease, alopecia areata, anaphylaxis, anti-phospholipid antibody syndrome, aplastic anemia, arteriosclerosis, atopic eczema, atopic dermatitis, autoimmune dermatitis, autoimmune disorder associated with  Streptococcus  infection, autoimmune enteropathy, autoimmune hearing loss, Autoimmune Lymphoproliferative Syndrome (ALPS), autoimmune myocarditis, autoimmune premature ovarian failure, blepharitis, bronchiectasis, bullous pemphigoid, cardiovascular disease, catastrophic antiphospholipid syndrome, celiac disease, cervical spondylosis, chronic ischemia, cicatricial pemphigoid, clinically isolated Syndrome (CIS) with risk for multiple sclerosis, conjunctivitis, childhood onset psychiatric disorder, chronic obstructive pulmonary disease (COPD), dacryocystitis, dermatomyositis, diabetic retinopathy, diabetes mellitus, disk herniation, disk prolapse, drug induced immune hemolytic anemia, endocarditis, endometriosis, endophthalmitis, episcleritis, erythema multiforme, erythema multiforme major, gestational pemphigoid, Guillain-Barré Syndrome (GBS), hay fever, Hughes syndrome, idiopathic Parkinson's disease, idiopathic interstitial pneumonia, IgE-mediated allergy, immune hemolytic anemia, inclusion body myositis, infectious ocular inflammatory disease, inflammatory demyelinating disease, inflammatory heart disease, inflammatory kidney disease, IPF/UIP, iritis, keratitis, keratojuntivitis sicca, Kussmaul disease or Kussmaul-Meier Disease, Landry's paralysis, Langerhan's cell histiocytosis, livedo reticularis, macular degeneration, microscopic polyangiitis, morbus bechterev, motor neuron disorders, mucous membrane pemphigoid, multiple organ failure, myasthenia gravis, myelodysplastic syndrome, myocarditis, nerve root disorders, neuropathy, non-A non-B hepatitis, optic neuritis, osteolysis, pauciarticular JRA, peripheral artery occlusive disease (PAOD), peripheral vascular disease (PVD), peripheral artery disease (PAD), phlebitis, polyarteritis nodosa (or periarteritis nodosa), polychondritis, polymyalgia rheumatica, poliosis, polyarticular JRA, polyendocrine deficiency syndrome, polymyositis, polymyalgia rheumatica (PMR), post-pump syndrome, primary parkinsonism, prostatitis, pure red cell aplasia, primary adrenal insufficiency, recurrent neuromyelitis optica, restenosis, rheumatic heart disease, SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis), scleroderma, secondary amyloidosis, shock lung, scleritis, sciatica, secondary adrenal insufficiency, silicone associated connective tissue disease, Sneddon-Wilkinson dermatosis, spondilitis ankylosans, Stevens-Johnson Syndrome (SJS), systemic inflammatory response syndrome, temporal arteritis, toxoplasmic retinitis, toxic epidermal necrolysis, transverse myelitis, TRAPS (Tumor Necrosis Factor Receptor Associated Periodic Syndrome), Type 1 allergic reaction, Type II diabetes, urticaria, usual interstitial pneumonia (UIP), vasculitis, vernal conjunctivitis, viral retinitis, Vogt-Koyanagi-Harada syndrome (VKH syndrome), wet macular degeneration, and wound healing. 
     
     
         117 . The use of  claim 115 , wherein the human subject is suffering from:
 (a) rheumatoid arthritis, allergic arthritis, juvenile arthritis, ankylosing spondylitis, or osteoarthritis;   (b) certain illnesses induced by viruses, optionally selected from Guillain Barre syndrome, infectious mononucleosis, other viral lymphadenopathies, and infections by herpes virus;   (c) multiple sclerosis or other demyelinating diseases;   (d) hematological disorders, optionally selected from hemolytic anemias and thrombocytopenias;   (e) endocrinologic disorders, optionally selected from diabetes mellitus, Addison's disease, idiopathic hypoparathyroidism, and chronic lymphocytic thyroiditis;   (f) collagen disorders and/or systemic lupus erythematosus;   (g) disorders of reproduction, optionally selected from amenorrhoea, infertility, recurrent abortions, and eclampsia;   (h) tumors, optionally selected from head and neck tumors, lung cancers, gastric cancers, prostate cancers, and pancreatic cancers;   (i) inflammatory bowel diseases, optionally selected from Crohn's disease and ulcerative colitis;   (j) pain associated with osteoarthritis and other disorders; or   (k) ocular disorders and/or age-related macular degeneration (AMD).   
     
     
         118 . The use of  claim 115 , wherein the antibody or antigen-binding fragment is optionally administered before, concurrently, or after the administration of a second agent, wherein the second agent is optionally selected from the group consisting of methotrexate; leflunomide; low doses of corticosteroids; prednisone; cortisone; an anti-malarial medication; hydroxychloroquine; gold; sulfasalazine; penicillamine; cyclophosphamide; cyclosporine; minocycline; acetaminophen; aspirin; ibuprofen; naproxen; celecoxib; Infliximab; etanercept; adalimumab; abatacept; rituximab; anakinra; a biologic agent or oral delivery agent targeting IL-6, IL-6R, IL-17, IL-18, IL-23, or B7.1/B7.2; acetaminophen; aspirin; ibuprofen; naproxen; celecoxib; steroids; artificial joint fluid; Synvisc™; Hyalgan™; adalimumab; Azasan™; Asacol™; azathioprine; Azulfidine™; budesonide; Entocort™; Flagyl™; Imuran™; infliximab; mercaptopurine; metronidazole; protostat; Purinethol™; Remicade™; sulfasalazine; acetocot; acetylsalicylic acid; acuprin 81; adalimumab; Aleve™; amcort; Anaprox™; Aristocort™; aspirin; aspirtab; Azmacort™; Bufferin™; buffex; Cataflam™; Celebrex™; Clinoril™; cortisone; diclofenac; Dipentum™; Easprin™; etanercept; Indocin™; indomethacin; infliximab; naproxen; triamcinolone; Voltaren™; Avonex™, Azasan™, Azathioprine, Betaseron™, Bubbli-Pred™, Copaxone™, Cotolone, Glatiramer, Imuran™, Interferon Beta-1a, Interferon Beta-1b Solution, Key-Pred, Key-Pred SP, Mitoxantrone, Natalizumab, Novantrone™, Orapred™, Orapred ODT™, Pediapred™, Pred-Ject-50, Predacort 50, Predalone 50, Predate-50, Prednisolone, Prelone™, Rebif™; Tysabri™; Abraxane™, Adriamycin, Adrucil™, Aldara™, Alemtuzumab, Alimta™, Aminolevulinic Acid, Anastrozole, Aprepitant, Arimidex™, Aromasin™, Arranon™, Arsenic Trioxide, Avastin™ (Bevacizumab), Azacitidine, Bevacizumab, Bexarotene, Bortezomib, Campath™ (Alemtuzumab), Camptosar™ (Irinotecan Hydrochloride), Capecitabine, Carboplatin, Cetuximab, Cisplatin, Clafen (Cyclophosphamide), Clofarabine, Clofarex (Clofarabine), Clolar™ (Clofarabine), Cyclophosphamide, Cytarabine, Cytosar-U (Cytarabine), Cytoxan (Cyclophosphamide), Dacogen™ (Decitabine), Dasatinib, Decitabine, DepoCyt™ (Liposomal Cytarabine), DepoFoam™ (Liposomal Cytarabine), Dexrazoxane Hydrochloride, Docetaxel, Doxil™ (Doxorubicin Hydrochloride Liposome), Doxorubicin Hydrochloride, Doxorubicin Hydrochloride Liposome, Dox-SL (Doxorubicin Hydrochloride Liposome), Efudex™ (Fluorouracil), Ellence™ (Epirubicin Hydrochloride), Eloxatin™ (Oxaliplatin), Emend™ (Aprepitant), Epirubicin Hydrochloride, Erbitux™ (Cetuximab), Erlotinib Hydrochloride, Evacet (Doxorubicin Hydrochloride Liposome), Evista™ (Raloxifene Hydrochloride), Exemestane, Faslodex™ (Fulvestrant), Femara™ (Letrozole), Fluoroplex™ (Fluorouracil), Fluorouracil, Fulvestrant, Gefitinib, Gemcitabine Hydrochloride, Gemtuzumab Ozogamicin, Gemzar™ (Gemcitabine Hydrochloride), Gleevec™ (Imatinib Mesylate), Herceptin™ (Trastuzumab), Hycamtin™ (Topotecan Hydrochloride), Imatinib Mesylate, Imiquimod, Iressa™ (Gefitinib), Irinotecan Hydrochloride, Ixabepilone, Ixempra™ (Ixabepilone), Keoxifene (Raloxifene Hydrochloride), Kepivance™ (Palifermin), Lapatinib Ditosylate, Lenalidomide, Letrozole, Levulan™ (Aminolevulinic Acid), LipoDox™(Doxorubicin Hydrochloride Liposome), Liposomal Cytarabine, Methazolastone (Temozolomide), Mylosar (Azacitidine), Mylotarg™ (Gemtuzumab Ozogamicin), Nanoparticle Paclitaxel (Paclitaxel Albumin-stabilized Nanoparticle Formulation), Nelarabine, Neosar™ (Cyclophosphamide), Nexavar™ (Sorafenib Tosylate), Nilotinib, Nolvadex (Tamoxifen Citrate), Oncaspar™ (Pegaspargase), Oxaliplatin, Paclitaxel, Paclitaxel Albumin-stabilized Nanoparticle Formulation, Palifermin, Panitumumab, Paraplat (Carboplatin), Paraplatin™ (Carboplatin), Pegaspargase, Pemetrexed Disodium, Platinol-AQ (Cisplatin), Platinol™ (Cisplatin), Raloxifene Hydrochloride, Revlimid (Lenalidomide), Rituxan™ (Rituximab), Rituximab, Sclerosol Intrapleural Aerosol (Talc), Sorafenib Tosylate, Sprycel™ (Dasatinib), Sterile Talc Powder (Talc), Steritalc™ (Talc), Sunitinib Malate, Sutent™ (Sunitinib Malate), Synovir (Thalidomide), Talc, Tamoxifen Citrate, Tarabine PFS (Cytarabine), Tarceva™ (Erlotinib Hydrochloride), Targretin™ (Bexarotene), Tasigna™ (Nilotinib), Taxol™ (Paclitaxel), Taxotere™ (Docetaxel), Temodar™ (Temozolomide), Temozolomide, Temsirolimus, Thalomid™ (Thalidomide), Thalidomide, Totect™ (Dexrazoxane Hydrochloride), Topotecan Hydrochloride, Torisel™ (Temsirolimus), Trastuzumab, Trisenox™ (Arsenic Trioxide), Tykerb™ (Lapatinib Ditosylate), Vectibix™ (Panitumumab), Velcade™ (Bortezomib), Vidaza™ (Azacitidine), Vorinostat, Xeloda™ (Capecitabine), Zinecard™ (Dexrazoxane Hydrochloride), Zoledronic Acid, Zolinza™ (Vorinostat), and Zometa™ (Zoledronic Acid);
 and/or 
 wherein the antibody or antigen-binding fragment is optionally adapted for parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermal administration. 
 
     
     
         119 . A method of determining the presence of PGE2 or fragment thereof in a test sample by an immunoassay, and/or wherein the immunoassay comprises contacting the test sample with at least one antibody or antigen-binding fragment of  claim 93  or  claim 94 , and at least one detectable label, and/or 
       wherein the method optionally comprises:
 (a) a direct assay comprising:
 (i) contacting the test sample with at least one antibody or antigen-binding fragment, wherein the antibody or antigen-binding fragment binds to an epitope on the PGE2 or fragment thereof so as to form a first complex; 
 (ii) contacting the complex with the at least one detectable label, wherein the detectable label binds to the antibody or antigen-binding fragment or an epitope on the PGE2 or fragment thereof that is not bound by the antibody or antigen-binding fragment to form a second complex; and 
 (iii) detecting the presence of the PGE2 or fragment thereof in the test sample based on the signal generated by the detectable label in the second complex, wherein the presence of the PGE2 or fragment thereof is directly correlated with the signal generated by the detectable label, 
 
 
       or
 (b) an indirect assay comprising:
 (i) contacting the test sample with at least one antibody or antigen-binding fragment, wherein the antibody or antigen-binding fragment binds to an epitope on the PGE2 or fragment thereof so as to form a first complex; 
 (ii) contacting the complex with the at least one detectable label, wherein the detectable label competes with the PGE2 or fragment thereof for binding to the antibody or antigen-binding fragment so as to form a second complex; and 
 (iii) detecting the presence of the PGE2 or fragment thereof in the test sample based on the signal generated by the detectable label in the second complex, wherein the presence of the PGE2 or fragment thereof is indirectly correlated with the signal generated by the detectable label, 
 
 
       wherein if the test sample is from a patient, the method optionally further comprises diagnosing, prognosticating, or assessing the efficiency of therapeutic/prophylactic treatment of the patient.