Patents 131
Patent Applications on Diabetic Retinopathy
As of December 2000, U.S. patent applications are open to public viewing.9 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to diabetic retinopathy:
•Compositions and methods for treatment of angiogenesis in pathological lesions
Inventor(s): Borsi, Laura; (Genova, IT), Carnemolla, Barbara; (Genova, IT), Halin, Cornelia; (Zurich, CH), Neri, Dario; (Zurich, CH), Nilsson, Fredrik; (Stockholm, SE), Tarli, Lorenzo; (Siena, IT), Zardi, Luciano; (Genova, IT)
Correspondence: Dann, Dorfman, Herrell & Skillman; 1601 Market Street; Suite 2400; Philadelphia; PA; 19103-2307; US
Patent Application Number: 20040013640 Date filed: March 10, 2003
Abstract: Treatment of lesions of pathological angiogenesis, especially tumors, rheumatoid arthritis, diabetic retinopathy, age-related muscular degeneration. and angiomas. A conjugate is used comprising a molecule that exerts a biocidal or cytotoxic effect on target cells in the lesions and an antibody directed against an extracellular matrix component which is present in such lesions. The antibody may be directed against fibronectin-2 (IL-2), doxorubicin, interleukin-12(IL-12), Interferon-.gamma. (IFN-
.gamma.), Tumor Necrosis Factor.alpha.(TNF.alpha.) or Tissue Factor protein (which may be truncated).
Excerpt(s): The present invention relates to treatment of lesions of pathological angiogenesis, especially tumors, rheumatoid arthritis, diabetic retinopathy, age-related macular degeneration, and angiomas. Aspects of the present invention employ a conjugate or fusion of a molecule that exerts a biocidal or cytotoxic effect on target cells in the lesions and an antibody directed against an extracellular matrix component which is present in such lesions. In preferred embodiments, the antibody is directed against fibronectin ED-B. Preferred embodiments of the biocidal or cytotoxic molecule include interleukin-2 (IL-2), doxorubicin, interleukin-12 (IL-12), Interferon-.gamma. (IFN-
.gamma.), Tumor Necrosis Factor.alpha. (TNF.alpha.) also, especially with the L19 antibody (see below), tissue factor (preferably truncated). By targeting bioactive molecules to an extracellular matrix component, killing of target cells may be achieved. Tumors cannot grow beyond a certain mass without the formation of new blood vessels (angiogenesis), and a correlation between microvessel density and tumor invasiveness has been reported for a number of tumors (1). Molecules capable of selectively targeting markers of angiogenesis create clinical opportunities for the diagnosis and therapy of tumors and other diseases characterized by vascular proliferation, such as rheumatoid arthritis, diabetic retinopathy and age-related macular degeneration (2-8). The ED-B domain of fibronectin, a sequence of 91 amino acids identical in mice, rats and humans, which is inserted by alternative splicing into the fibronectin molecule, specifically accumulates around neovascular structures and represents a target for molecular intervention (9-11). Using a human recombinant antibody (L19) to the ED-B domain the possibility of in vivo neovasculature targeting has been demonstrated in different tumor models (12,13).
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9 This has been a common practice outside the United States prior to December 2000.
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•Compounds and method for the prevention and treatment of diabetic retinopathy
Inventor(s): Bodor, Nicholas Stephen; (Gainesville, FL), Grant, Maria; (Gainesville, FL)
Correspondence: Van Dyke & Associates, P.A.; Suite 252; 7200 Lake Ellenor Drive; Orlando; FL; 32809; US
Patent Application Number: 20040082501 Date filed: April 11, 2003
Abstract: The invention provides peptide derivatives designed to deliver peptides having growth factor inhibitory activity, especially somatostatin analogs, to the retina by sequential metabolism. The peptide derivatives, which comprise a dihydropyridinepyridinium salt-type redox targetor moiety, a bulky lipophilic function and an amino acid/dipeptide/tripeptid- e spacer, are used in the prevention and treatment of diabetic retinopathy.
Excerpt(s): This application is a continuation of U.S. application Ser. No. 10/175,833 filed Jun. 21, 2001, pending, which is a divisional of U.S. application Ser. No. 09/144,991, filed Sep. 1, 1998, now issued as U.S. Pat. No. 6,440,933 on Aug. 27, 2002, which claims the priority of U.S. Provisional Patent Application No. 60/058,423, filed Sep. 10, 1997. Priority is claimed to the foregoing applications and are incorporated by reference herein in their entirety and relied upon. The invention relates to peptide derivatives designed to deliver peptides having growth factor inhibitory activity into the retina by sequential metabolism. These peptide derivatives, which comprise a dihydropyridinepyridinium salt-type redox targetor moiety, a bulky lipophilic function and an amino acid/dipeptide/tripeptide spacer, are of use in the prevention and treatment of diabetic retinopathy. The leading cause of blindness in adults between the ages of 20 and 74 years is diabetic retinopathy (DR). Seven million people in the United States have diabetes. Diabetic retinopathy will affect the vast majority during their lifetime, with 8,000 to 40,000 of these people becoming blind each year. While management of diabetic retinopathy has improved as a result of landmark clinical trials, risk of complications, such as loss of visual acuity, loss of night vision and loss of peripheral vision, remains significant and treatment sometimes fails. Currently, laser photocoagulation is the most effective form of therapy for advanced disease.
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•Integrin expression inhibitors
Inventor(s): Funahashi, Yasuhiro; (Ibaraki, JP), Hamaoka, Shinichi; (Ibaraki, JP), Haneda, Toru; (Ibaraki, JP), Hata, Naoko; (Ibaraki, JP), Kamata, Junichi; (Ibaraki, JP), Nara, Kazumasa; (Ibaraki, JP), Okabe, Tadashi; (Ibaraki, JP), Owa, Takashi; (Ibaraki, JP), Semba, Taro; (Ibaraki, JP), Takahashi, Keiko; (Ibaraki, JP), Tsuruoka, Akihiko; (Ibaraki, JP), Ueda, Norihiro; (Ibaraki, JP), Wakabayashi, Toshiaki; (Ibaraki, JP), Yamamoto, Yuji; (Ibaraki, JP)
Correspondence: Birch Stewart Kolasch & Birch; PO Box 747; Falls Church; VA; 220400747; US
Patent Application Number: 20040018192 Date filed: July 18, 2002
Abstract: The present invention provides an integrin expression inhibitor, and an agent for treating arterial sclerosis, psoriasis, cancer, retinal angiogenesis, diabetic retinopathy
Patents 133
or inflammatory diseases, an anticoagulant, or a cancer metastasis suppressor on the basis of an integrin inhibitory action. Namely, it provides an integrin expression inhibitor comprising, as an active ingredient, a sulfonamide compound represented by the following formula (I), a pharmacologically acceptable salt thereof or a hydrate of them. 1In the formula, B means a C6-C10 aryl ring or 6- to 10-membered heteroaryl ring which may have a substituent and in which a part of the ring may be saturated; K means a single bond, --CH.dbd.CH-- or --(CR.sup.4bR.sup.5b).sub.m.sup.b-- (wherein R.sup.4b and R.sup.5b are the same as or different from each other and each means hydrogen atom or a C1-C4 alkyl group; and m.sup.b means an integer of 1 or 2); R.sup.1 means hydrogen atom or a C1-C6 alkyl group; Z means a single bond or --CO--NH--; and R means a C6-C10 aryl ring or 6- to 10-membered heteroaryl ring which may have a substituent and in which a part of the ring may be saturated, respectively.
Excerpt(s): The present invention relates to an integrin expression inhibitor, specifically, an integrin.alpha.2.beta.1,.alpha.3.beta.1,.alpha.5.beta.1,.alpha.6.beta.1,.alpha.v.sym.1,.alph a.v.beta.3 or.alpha.v.beta.5 expression inhibitor. Further it relates to an angiogenesis agent, an anticoagulant, an anticancer agent, a cancer metastasis suppressor, and an agent for treating retinal angiogenesis, diabetic retinopathy, inflammatory diseases, arterial sclerosis, psoriasis and osteoporosis, on the basis of integrin expression inhibitory action. Integrin structurally consists of a heterodimer in which two types of sub-unit, namely, integrin.alpha. and integrin.beta. are associated with each other by non-covalent binding. At least 16 types of.alpha. chains and 8 types of.beta. chains have been found. A variety of molecular groups differing in ligand specificity are formed by the combination of these.alpha. and.beta. chains and 22 types of integrins have been known. Integrin has a function as cell membrane receptor protein for an adhesive molecule of an animal cell, expresses on a cell membrane and participates in the adhesion between a cell and an extracellular matrix (ECM) or between cells. When the cell adhesive molecule is combined with integrin, a signaling system in a cell starts moving and as a result, not only cell adhesion, but also cell evolution, cell proliferation, apoptosis, differentiation, cytoskeleton orientation, cell migration, histogenesis, cancer infiltration and metastasis, wound healing, blood coagulation and the like operate. It has been known that among these integrins, integrin.alpha.2.beta.1 of which the adhesive molecules are collagen and laminin participates in platelet aggregation, cancer infiltration and metastasis (HAYASHI Masao & MIYAMOTO Yasunori, PROTEIN, NUCLEIC ACID, ENZYME, Vol 44, pp130-135, (1999)) and angiogenesis (Donald R. Senger et al, Proc. Natl. Acad. Sci. USA, 94, 13612-13617, (1997)). It has come to be clarified that among these symptoms, the proliferation of cancer is closely related to angiogenesis. In recent years, it has been demonstrated experimentally that an antiangiogenesis agent can inhibit and further reduce proliferative cancer and no resistant cancer is generated in a transplant cancer model and there is shown a correlation between angiogenesis and exacerbations of many solid cancers such as mammary cancer, prostatic cancer, lung cancer and colonic cancer in clinical examinations (T. Boem et al, Nature, 390 (27) 404-407, (1997)). Also,.alpha.v.beta.1 of which the adhesive molecules are fibronectin and vitronectin participates in the adhesion of a cancer cell to a substrate and.alpha.v.beta.3 of which the adhesive molecules are vitronectin and thrombospongin and.alpha.v.beta.5 of which the adhesive molecule is vitronectin participate in angiogenesis, cancer metastasis and the regeneration of bone (Shattil, S. J., Thromb. Haemost., 74, 149-155, (1995), Friedlander M, et al, Sceience, 270, 1500-1502, (1995)). Further, it has been known that.alpha.3.beta.1 of which the adhesive molecules are fibronectin, collagen, laminin, laminin 5 and the like,.alpha.5.beta.1 of which the adhesive molecule is fibronectin and.alpha.6.beta.1 of
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which the adhesive molecules are laminin and laminin 5 participate in cancer infiltration and metastasis (MATSUURA Nariaki et al., JAPAN CLINIC, Vol 53, pp1643-1647, (1995), OTA Ichiro et al, CLINICAL PATHOLOGY, Vol 45, 528-533, (1997)). WO9950249 discloses the antagonist of integrin.alpha.v.beta.3, however there is no suggestion concerning the expression inhibitory action of integrin.alpha.v.beta.3. In JP-A 7-165708 and JP-A 8-231505, the same sulfonamide compound as that used in the present invention is disclosed; however, there is neither description nor hint concerning integrin expression inhibitory action. WO9301182 discloses-anti-tumor agents utilizing a specific tyrosine kinase inhibitive action of a compound having an indole skeleton. These agents are indolylmethylene-2-indolinone compounds, which differ from that of the present invention. WO964016 likewise discloses anti-tumor agents utilizing a specific tyrosine kinase inhibitory action of a compound having an indole skeleton. However, these agents are 2-indolinone-3-methylene derivatives, which differ from that of the present invention.
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•Method of treating angiogenesis-related disorders
Inventor(s): Bingaman, David P.; (Fort Worth, TX), Gamache, Daniel A.; (Arlington, TX), Graff, Gustav; (Cleburne, TX), Kapin, Michael A.; (Arlington, TX), Yanni, John M.; (Burleson, TX)
Correspondence: Alcon Research, LTD.; R&d Counsel, Q-148; 6201 South Freeway; Fort Worth; TX; 76134-2099; US
Patent Application Number: 20030187072 Date filed: February 14, 2003
Abstract: The use of 3-benzolphenylacetic acids and derivatives, including nepafenac, to treat angiogenesis-related disorders, including ophthalmic angiogenesis-related disorders such as diabetic retinopathy and exudative macular degeneration, is disclosed.
Excerpt(s): 3-benzolphenylacetic acid and certain of its derivatives are known to possess anti-inflammatory activity. U.S. Pat. Nos. 4,254,146, 4,045,576, 4,126,635, and 4,503,073, and U.K. Patent Application Nos. 2,071,086A and 2,093,027A disclose various 3- benzolphenylacetic acids, salts and esters, and hydrates thereof, having antiinflammatory activity. U.S. Pat. No. 4,568,695 discloses 2-amino-3-benzoylphenylethyl alcohols having anti-inflammatory activity. U.S. Pat. No. 4,313,949 discloses 2-amino-3- benzoyl-phenylacetamides having anti-inflammatory activity. This invention relates to the use of certain 3-benzolphenylacetic acids and derivatives to treat or prevent angiogenic diseases. Certain derivatives of 2-amino-3-benzoylbenzeneacetic acid (amfenac) and 2-amino-3-(4-chloro-benzoyl)benzeneacetic acid have also been evaluated by Walsh et al., J. Med Chem., 33:2296-2304 (1990), in an attempt to discover nonsteroidal anti-inflammatory prodrugs with minimal or no gastrointestinal side effects upon oral administration.
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Patents 135
•Method of treating diabetes
Inventor(s): Jerling, Markus; (San Francisco, CA), Wolff, Andrew; (San Francisco, CA)
Correspondence: Pauline Ann Clarke; CV Therapeutics, INC.; 3172 Porter Drive; Palo Alto; CA; 94304; US
Patent Application Number: 20040063717 Date filed: May 21, 2003
Abstract: Methods are provided for treating diabetes, lowering plasma level of HbA1c, glucose plasma levels, total cholesterol plasma level, and/or triglyceride plasma level while increasing HDL cholesterol levels and delaying onset of diabetic retinopathy in a diabetic, pre-diabetic, or non-diabetic mammal while minimizing undesirable side effects.
Excerpt(s): Priority is claimed to U.S. Provisional Application Serial No. 60/382,781, filed May 21, 2002, and to U.S. Provisional Application Serial No. 60/459,332, filed Mar. 31, 2003, the complete disclosures of which are hereby incorporated by reference. Methods are provided for treating diabetes, lowering plasma level of HbA1c, glucose plasma levels, total cholesterol plasma levels, and/or triglyceride plasma level while increasing HDL cholesterol levels and delaying onset of diabetic retinopathy in a diabetic, pre-diabetic, or non-diabetic mammal while minimizing undesirable side effects. Diabetes mellitus is a disease characterized by hyperglycemia; altered metabolism of lipids, carbohydrates and proteins; and an increased risk of complications from vascular disease. Diabetes is an increasing public health problem, as it is associated with both increasing age and obesity.
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•Methods and compositions of treating and/or preventing diabetic retinopathy with pericyte apoptosis inhibitors
Inventor(s): Denis, Ulriche; (Caluire et Cuire, FR), Lagarde, Michel; (Decines, FR), Lecomte, Marc; (Lissieu, FR), Paget, Clarisse; (Lyon, FR), Wiernsperger, Nicolas; (Orlienas, FR)
Correspondence: IP Department OF Piper Rudnick Llp; 3400 Two Logan Square; 18th And Arch Streets; Philadelphia; PA; 19103; US
Patent Application Number: 20030216290 Date filed: April 23, 2003
Abstract: A method of preventing or treating diabetic retinopathy is disclosed including administering to a mammal a therapeutically effective amount of an inhibitor of retinal pericyte apoptosis. Also disclosed is a pharmaceutical composition which treats and/or prevents diabetic retinopathy comprising as an active agent a therapeutically effective amount of at least one inhibitor of retinal pericyte apoptosis and a pharmaceutically acceptable carrier.
Excerpt(s): This is a continuation of PCT/FR01/03306 filed Oct. 26, 2001, which claims benefit from French Application No. 00/13640 filed Oct. 24, 2000. This invention relates to methods of treating and/or preventing diabetic retinopathy with pericyte apoptosis inhibitors. Diabetic retinopathy represents one of the most debilitating microvascular complications of diabetes. It can lead to blindness in its final stage (Grange, 1995; Frank, 1996; Aiello LP et al., 1998). It is the second leading cause of acquired blindness in
136 Diabetic Retinopathy
developed countries, after macular degeneration of the aged (Nathan et al., 1991). The risk of a diabetic patient becoming blind is estimated to be 25 times greater than that of the general population (Kahn and Hiller, 1974). At present there is no preventive or curative pharmacological treatment for this complication. The only treatment is laser retinal photocoagulation or vitrectomy in the most severe cases (Frank, 1995; Aiello, 1998).
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•Multipurpose diode laser system for ophthalmic laser treatments
Inventor(s): Berndt, Detlev; (Koln, DE), Maughan, Julian; (Salisbury, GB), Neuberger, Wolfgang; (F.T. Labuan, MY)
Correspondence: Bolesh J. Skutnik Phd, JD; 515 Shaker Road; East Longmeadow; MA; 01028; US
Patent Application Number: 20040116909 Date filed: December 11, 2002
Abstract: A laser device and method for treating ophthalmic diseases is enclosed. The device comprises a system for irradiating the eye with electromagnetic irradiation with a wavelength in the range of 654-681 nm. The system preferably comprises a laser source and ancillary equipment to direct and regulate the radiation. The use of this wavelength range makes the device effective for a wide variety of ophthalmic indications. It is capable of providing photocoagulation treatments for diseases such as glaucoma, diabetic retinopathy and age-related macular degeneration. The system is also useful for photodynamic therapy. Also disclosed are laser diodes with high beam quality and slit lamp adaptors to further enhance the versatility of the system.
Excerpt(s): The invention relates to ophthalmic laser treatments, particularly to devices and systems capable of performing multiple ophthalmic photocoagulation treatments. U.S. Pat. No. 5,295,989 describes a light cable in an apparatus for ophthalmic treatment consisting of a plurality of optical fibers. A preferred embodiment utilizes an Argon laser beam as a treatment light source. Many of the current photocoagulators are of an inconveniently and inefficiently high cost, size and complexity. For example, conventional Krypton and Argon lasers are capable of emitting sufficient power levels for photocoagulation but are bulky, technically complex, and are inefficient "(below 0.1%) requiring up to 40 kW of three phase power and associated water cooling" to remove excess heat. (see U.S. Pat. No. 4,917,486) Thus, these setups are expensive and often require fixed installations.
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•Preventives and remedies for complications of diabetes
Inventor(s): Kitahara, Masaki; (Minamisaitama-gun, JP), Mori, Sijiro; (Chiba-shi, JP), Saito, Yasushi; (Chiba-shi, JP), Takemoto, Minoru; (Akita-shi, JP), Tamaki, Taro; (Setagaya-ku, JP)
Correspondence: Oliff & Berridge; P O Box 19928; Alexandria; VA; 22320; US Patent Application Number: 20040087597
Date filed: July 2, 2003
Patents 137
Abstract: The present invention relates to the pharmaceutical useful for the prevention and the treatment of diabetic complications such as diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and diabetic angiopathy among others, and to the prophylaxis and/or treatment drug for diabetic complications with the compound shown in the formula (1) 1(wherein R is organic group, X is --CH.sub.2CH.sub.2-- or -- CH.dbd.CH--, and M is hydrogen atom, C.sub.1-10 alkyl group or physiologically acceptable cation group) or its lactonized form as the active ingredient.
Excerpt(s): The present invention relates to the prophylactic and therapeutic agent with compound having inhibitory effect on 3-hydroxy-3-methylglutary- l-CoA (HMG CoA) reductase activity as the active ingredient for diabetic complications. The invention especially relates to the pharmaceutical to prevent and/or treat the onset and the progression of diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and diabetic angiopathy. Diabetes mellitus is known to lead to the diabetic complications such as diabetic nephropathy, diabetic neuropathy, diabetic retinopathy or diabetic angiopathy, and the strict control of the blood glucose may be required for their prevention and treatment thereof. The fibrosis and the calcification of the tissues are often observed in these complications. Under the high blood glucose condition, glycosylated proteins which are the modulators for cell function are produced, and the accumulation of sorbitol due to the activation of intracellular polyol pathway is observed, leading to the activation of intracellular protein kinase C (PKC) which results in abnormality of glomerular cells in the kidney, nerve cells or arterial endothelial cells, and induces the accumulation of extracellular matrices and the calcification. The accelerated expression of extracellular matrices such as type IV collagen or fibronectin is well documented (Cagliero E. et al.: J. Clin. Invest., 82, 735-738 (1988), Haneda M. et al. : Diabetologia, 34, 198-200 (1991), Doi T. et al.: Proc. Natl. Acad. Sci. USA, 89, 28732877(1992)), but in recent days there are several papers reporting that the expression of osteopontin in the kidney and blood vessels markedly increases under diabetic condition and the expression of osteopontin thus accelerated may be in some ways related to diabetic nephropathy or diabetic angiopathy (Takemoto M. et al. : Arterioscler. Thromb. Vasc. Biol., 20, 624-628 (2000), Takemoto M. et al. : Ann. NY Acad. Sci., 902, 357-363 (2000)). From these findings, it is expected that the suppression of the expression of osteopontin as an extracellular matrices whose expression is accelerated in the kidney and arterial wall under the diabetic condition may be prophylactically effective on the onset or the aggravation of diabetic nephropathy or diabetic angiopathy.
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•Sigma receptor ligands and their medical uses
Inventor(s): Dexter, Michael; (London, GB), Eccles, Suzanne Amy; (Sutton, GB), Spruce, Barbara Ann; (Dundee, GB)
Correspondence: Dann, Dorfman, Herrell & Skillman; 1601 Market Street; Suite 2400; Philadelphia; PA; 19103-2307; US
Patent Application Number: 20040019060 Date filed: June 5, 2003
Abstract: The present invention is based on the finding that sigma receptor ligands can modulate endothelial cell proliferation and/or survival, and hence control angiogenesis, and in particular that sigma receptor ligand antagonists can be used to inhibit angiogenesis aid so treat conditions such as psoriasis, diabetic retinopathy and cancer. Exemplary compounds include IPAG and rimcazole.
138 Diabetic Retinopathy
Excerpt(s): The present invention relates to the use of sigma receptor ligands to modulate endothelial cell proliferation and/or survival, thereby controlling angiogenesis. In the normal adult body, most endothelial cells are quiescent, entering mitosis only in response to tissue injury or during menstruation and parturition. However, in pathological states including psoriasis and diabetic retinopathy, endothelial cells may proliferate leading to angiogenesis, the development of new blood vessels. It is also now well recognised that for any cancer to grow beyond a few millimetres in diameter, neoangiogensis is essential and that tumour cells secrete a variety of angiogenic cytokines which stimulate endothelial cell proliferation. One of the most important is vascular endothelial growth factor (VEGF) which also increases the permeability of newly formed vessels. Thus, in cancer, angiogenesis is critical for the development of solid cancers and also provides the conduit through which tumour cells may spread to other parts of the body. However, since a small area of capillary can provide nutrients for a relatively large volume of surrounding cancer cells, any inhibition of endothelial cell proliferation will "amplify" the effect on tumour cells, making this a promising approach for the treatment of cancer. Several different antiangiogenic agents have been shown to be potent inhibitors of tumour growth and spread. WO00/00599 discloses that opioid-like agents, including sigma receptor ligands, can be used to cause preferential cell cycle division arrest and apoptosis in populations of diseased cells as compared to normal cells, and in particular that apoptotic effects tend to be greater in tumour cells as compared to normal, non-diseased cells. These effects were demonstrated in this application in in vitro experiments using pure cultures of tumour cells. The results show that normal cells are insensitive to induction of cell cycle division arrest and apoptosis at doses of sigma receptor ligands that are lethal or cytostatic to tumour cells.
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•Treatment of ocular disease
Inventor(s): Peyman, Gholam A.; (New Orleans, LA)
Correspondence: Wood, Herron & Evans, Llp; 2700 Carew Tower; 441 Vine Street; Cincinnati; OH; 45202; US
Patent Application Number: 20040092435 Date filed: November 7, 2002
Abstract: A method and article to treat ocular disease with Cyclosporin A alone or with compounds related to Cyclosporin A for intraocular injection or implantation. Treatment does not result in ocular toxicity and encompasses age related macular degeneration, retinitis pigmentosa, and retinopathy such as diabetic retinopathy.
Excerpt(s): The invention is directed to therapeutic treatment of age-related macular degeneration, retinitis pigmentosa, and diabetic retinopathy with Cyclosporin A. The immunomodulator Cyclosporin A (cyclosporine, topical formulation Arrestase.RTM., Allergan Inc.) has been used to treat glaucoma, corticosteroid-induced ocular hypertension, allograft rejection, infections, and ocular surface disease. Its use has been reported for the treatment of uveitis (inflammation of the uvea) by topical, intravitreal or systemic administration with doses of 0.05%, 0.1%, and 0.5%. Cyclosporin A has good penetration into the cornea but not into the anterior chamber, and does not increase intraocular pressure or cause cataracts. Its known toxicity had previously limited its use for other ocular diseases. A method of treating age-related macular degeneration, retinitis pigmentosa, and diabetic retinopathy in the absence of substantial toxicity by
Patents 139
administering Cyclosporin A in an effective amount and in a pharmaceutically acceptable formulation. "Treating" includes preventing progression of pre-existing disease, delaying onset and/or severity of disease, and ameliorating or reducing the severity, frequency, duration, etc., of one or more symptoms of disease.
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•Vascular endothelial growth factor-2
Inventor(s): Coleman, Timothy; (Gaithersburg, MD)
Correspondence: Human Genome Sciences Inc; 9410 Key West Avenue; Rockville; MD; 20850
Patent Application Number: 20030215921 Date filed: August 3, 2001
Abstract: Disclosed are human VEGF-2 polypeptides, biologically active, diagnostically or therapeutically useful fragments, analogs, or derivatives thereof, and DNA(RNA) encoding such VEGF-2 polypeptides. Also provided are procedures for producing such polypeptides by recombinant techniques and antibodies and antagonists against such polypeptides. Such polypeptides and polynucleotides may be used therapeutically for stimulating wound healing and for vascular tissue repair. Also provided are methods of using the antibodies and antagonists to inhibit tumor angiogenesis and thus tumor growth, inflammation, diabetic retinopathy, rheumatoid arthritis, and psoriasis.
Excerpt(s): This application claims benefit of 35 U.S.C. section 119(e) based on copending U.S. Provisional Application Serial No. 60/223,276, filed Aug. 4, 2000, herein incorporated by reference in its entirety. The present invention relates to newly identified polynucleotides, polypeptides encoded by such polynucleotides, the use of such polynucleotides and polypeptides, as well as the production of such polynucleotides and polypeptides. The polypeptides of the present invention have been identified as members of the vascular endothelial growth factor family. More particularly, the polypeptides of the present invention are human vascular endothelial growth factor 2 (VEGF-2). The invention also relates to inhibiting the action of such polypeptides. The formation of new blood vessels, or angiogenesis, is essential for embryonic development, subsequent growth, and tissue repair. Angiogenesis is also an essential part of certain pathological conditions, such as neoplasia (i.e., tumors and gliomas). Abnormal angiogenesis is associated with other diseases such as inflammation, rheumatoid arthritis, psoriasis, and diabetic retinopathy (Folkman, J. and Klagsbrun, M., Science 235:442-447(1987)).
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•VEGF activity inhibitor
Inventor(s): Sato, Yasufumi; (Sendai-shi, JP), Shitara, Kenya; (Fujisawa-shi, JP)
Correspondence: Nixon & Vanderhye, PC; 1100 N Glebe Road; 8th Floor; Arlington; VA; 22201-4714; US
Patent Application Number: 20030175271 Date filed: April 30, 2003
140 Diabetic Retinopathy
Abstract: The present invention provides a therapeutic agent which is effective for solid tumors, arthritis in chronic rheumatoid arthritis, diabetic retinopathy, retinopathy of prematurity, psoriasis, or the like, comprising a combination of a substance which inhibits signal transduction mediated by human VEGF receptor Flt-1 which is useful for the diagnosis or treatment of diseases in which their morbid states progress by abnormal angiogenesis, such as proliferation or metastasis of solid tumors, arthritis in chronic rheumatoid arthritis, diabetic retinopathy, retinopathy of prematurity, psoriasis, and the like with a substance which inhibits signal transduction mediated by human VEGF receptor KDR.
Excerpt(s): The present invention relates to a medicament comprising a combination of a substance which inhibits signal transduction mediated by human VEGF receptor Flt-1 with a substance which inhibits signal transduction mediated by human VEGF receptor KDR and is useful for treatment of diseases in which their morbid states progress by abnormal angiogenesis, such as proliferation or metastasis of solid tumors, arthritis in rheumatoid arthritis, diabetic retinopathy, retinopathy of prematurity, psoriasis, and the like. Angiogenesis plays an important role in formation of a circulatory system and construction of various tissues at fetus in vertebrates, is directly involved in the formation of the corpus luteum during the sexual cycle, transient proliferation of the uterine endometrium and formation of the placenta in mature individuals (females). With regard to pathological states, angiogenesis is involved in the proliferation or metastasis of solid tumors and formation or acceleration of morbidity in diabetic retinopathy and rheumatoid arthritis [J. Biol. Chem., 267: 10931 (1992)]. Angiogenesis occurs by the secretion of an angiogenesis factor and involves the process of a tube formation and producing a new blood vessel. During this process, the basement membrane and interstitum are destroyed by a protease secreted from endothelial cells of an existing blood vessel around the secreted angiogenesis factor, followed by subsequent migration and proliferation of vascular endothelial cells [J. Biol. Chem., 267: 10931 (1992)]. Factors which induce angiogenesis include vascular permeability factor (hereinafter referred to as "VPF") and vascular endothelial growth factor (hereinafter referred to as "VEGF") (hereinafter referred to as "VPF/VEGF"). These factors are considered the most important factors in pathological and non-pathological angiogenesis [Advances in Cancer Research, 67: 281 (1995)]. VPF/VEGF is a protein having a molecular weight of about 40,000 constituted by homodimers, which had been reported to be independent molecules as vascular permeability factor (VPF) in 1983 [Science, 219: 983 (1983)] and as vascular endothelial growth factor (VEGF) in 1989 [Biochem. Biophys. Res. Comm., 161: 851 (1989)], but it has been revealed as the results of cDNA cloning that they are the same substance [Science, 246: 1306 (1989); Science, 246: 1309 (1989)] (hereinafter, the term "VPF/VEGF" is referred to as "VEGF"). Beyond the activity of VEGF upon vascular endothelial cells described above, VEGF has also been shown to have a growth enhancing activity [Biochem. Biophys. Res. Comm., 161: 851 (1989)], a migration enhancing activity [J. Immunology, 152: 4149 (1994)], a metalloprotease secretion enhancing activity [J. Cell Physiol., 153: 557 (1992)], a urokinase and tPA secretion enhancing activity [Biochem. Biophys. Res. Comm., 181: 902 (1991)], and the like. Furthermore, VEGF has been shown to have an angiogenesis enhancing activity [Circulation, 92 suppl II: 365 (1995)], a vascular permeability enhancing activity [Science, 219: 983 (1983)], and the like as its in vivo activities. It has been reported that VEGF is a growth factor having extremely high specificity for vascular endothelial cells [Biochem. Biophys. Res. Comm., 161: 851 (1989)] and that four proteins having different molecular weight are present due to alternative splicing of mRNA [J. Biol. Chem., 267: 26031 (1991)]. Among diseases accompanied by angiogenesis, it has been reported that VEGF plays an important role in the proliferation