MXPA06002528A - Rage-related methods and compositions for treating glomerular injury - Google Patents

Abstract

This invention provides methods, compositions and articles of manufacture for inhibiting the onset of and treating glomerular injury. The instant invention is based on the blockade of RAGE and/or RAGE G82S function.

Description

METHODS RELATED TO RAGES AND COMPOSITIONS TO TREAT GLMERAL LESIONS FIELD OF THE INVENTION Primary or secondary focal segmental glomerulosclerosis (FSGS - focal segmental glomerulosclerosis) encompasses a range of diseases characterized by glomerular and tubulointestinal fibrosis that frequently progresses, without pauses, to irreversible scarring and renal failure in human patients (1) . Secondary cases of FSGS may emerge in the light of chronic diseases (hemodynamic, immunological or metabolic). However, in both cases of primary and secondary disease, despite many years of study, there is no definitive view of the molecular mechanisms underlying these conditions. As such, ideas to avoid / treat these conditions have not been illustrated.

BACKGROUND OF THE INVENTION However, the steps to identify rational therapeutic targets for these studies may come from animal studies. The development of FSGS by agents that incite the trajectories linked to glomerular fibrosis and hyperpermeability are useful as a means to track the initial events and the subsequent, amplified consequences of proteinuria and renal scarring. In this context, numerous experts have used the administration of agents such as puromycin or adriamycin (ADR) in rats to induce processes similar to human FSGS in the kidney (2-4). In addition, other studies in rats have included the induction of Heymann's passive nephritis as a means to induce irreversible glomerular lesions (5). Taken together, these studies in rats have been frustrated by the inability to precisely link the activation of specific cells to the pathogenesis and / or progression of GS after induction of the disease. There was a shortage of mouse models for the study of FSGS-type diseases until the first description of ADR-induced toxicity in mice (6-7). In 2000, Wang and colleagues reported the impact of ADR up to 42 days (6 weeks) after administration of ADR (9). Male BALB / c mice, 20 to 25 gm, were injected with ADR, 10.5 mg / kg, by IV injection. These investigations occurred carefully with the course of events in mice treated with ADR and the following was observed (9). First, open proteinuria was developed in all mice on day 5. Proteinuria persisted throughout 6 weeks of study. Only 35.7% of mice developed hematuria but 53.6% developed leukocyturia. Second, serum albumin levels were consistently lower in mice treated with 7ADR against controls that begin one week after ADR treatment. Third, the clearance of creatinine declined with time and decreased significantly compared to the control mice 4 weeks after ADR. Fourth, in week 6, tubular atrophy and intratubular cylinder formation with interstitial expansion occurred and was widely observed in the cortex. There was extensive FGS and severe interstitial fibrosis and inflammation. Global sclerosis was observed in many glomeruli. Fifth, by EM, the elimination of foot processes of podocytes occurred. In week 1, the elimination was segmental, but overall by week 6. The control mice failed to demonstrate any abnormality of the epithelial cells at any point. Considerably, in this study, cellular infiltration and inflammation were examined. Sixth, the ADR, CD4 + and CD8 + T cells and macrophages in the kidneys of the ADR-treated mice were significantly increased in the initial and subsequent moments. These types of cells were found both in the interstitium as well as in the glomeruli posterior to the lesion. Infiltration of inflammatory cells was observed long before ADR, within the first 24 hours, and persisted until weeks after the ADR. These findings support the premise that inflammation, at least in part, contributes as an initial activation, and / or factor of subsequent progression in the molecular trajectories that lead to sustained glomerular disturbance, fibrosis and albuminuria that converge on a renal dysfunction. These studies highlighted that even 6 weeks after ADR, progressive renal lesions, proteinuria and a decreased clearance of creatinine were characteristic of the diseases. In addition, new ideas on the pro-inflammatory mechanisms in the disease process were revealed by the examination of the time course of cellular infiltration after ADR. Other studies, in fact, have confirmed the infiltration of inflammatory cells within the kidney treated with ADR (9) In fact, the observation that human FSGS is typified by the differentiation of podocytes in MP-type cells, together with the infiltration of inflammatory cells from the periphery (MP and T lymphocytes) in the interstitium, periglomerular regions and glomeruli (1, 10-12) is compatible with the concept set forth in the FSGS ADR-induced mouse model, ie, it is plausible that inflammatory stimuli contribute markedly to the pathogenesis and / or progress of FSGS. In parallel with progressive renal dysfunction and scarring in primary or secondary FSGS syndromes in human patients (and mouse models), the lesions and depletion of glomerular podocytes, following an "insufficiency" of podocytes and capillary collapse, have been implicated as important steps in the development of FSGS (13, 14). In most cases of nephrotic syndrome, the elimination of the podocyte foot process is considered an initial manifestation of the lesion, and is followed by a continuous spectrum of progressive podocyte injury characterized by vacuolization, pseudocysts formation, detachment of podocytes coming from the GBM; processes that lead to an irreversible loss / apoptosis of podocytes (15). The key evidence that podocytes are not mere bystanders, but rather active participants in the molecular trajectories of the lesions, was highlighted by recent studies in transgenic mice overexpressing TGF-β. In these mice, marked upregulation of Smad 7 was observed in the damaged podocytes. Both TGF-β and Smad7 were associated with apoptosis in cultured podocytes. In the previous case, activation of MAP kinase p38 and caspase-3 were key intermediary steps in apoptosis induced by TGF-β. In the latter case, the suppressed nuclear translocation of the cell survival factor NF-kB led to an apoptosis (16) of podocytes induced by Smad7. These studies highlight the concept that the activation of cell signaling and the modulation of gene expression in podocytes can be initial events in the development of FSGS, and consequently, can contribute to the pathogenesis of this disease. It is important to note that the concept of key roles in podocytes in the pathogenesis / progress of glomerular dysfunction has parallels in diabetes. Diabetes is a highly complex environment in which multiple contribution trajectories, such as accumulation / activation of Advanced Glycation End-products, activation of PKC, especially the β isoform, as well as hyperglycemia itself are involved in the pathogenesis of this condition (17-19). There is increasing evidence that podocytes are initially disturbed in diabetes, and that their products, such as VEGF, can contribute to cellular dysfunction in this condition (20-25). As in the conditions of FSGS and FSGS types, the case of podocyte as a spectator against a contributing agent for the pathogenesis and progression of glomerular lesions continues to be rigorously tested. Although the RAGEs (Receptor for Advanced Glycated Endproducts - Receptor of advanced glycated end products) have been implicated in treating the symptoms of diabetes (35), the literature does not provide a basis for concluding that the inhibition of the binding of RAGEs to its binders may play a role in treating or preventing glomerular injuries.

SUMMARY OF THE INVENTION This invention provides a method for inhibiting the onset of a glomerular lesion in a patient comprising administering to the patient a prophylactically effective amount of an agent that inhibits the binding between RAGE and RAGE G82S and a ligand thereof. This invention further provides a method for treating a glomerular lesion in a patient comprising administering to the patient a therapeutically effective amount of an agent that inhibits binding between RAGE and / or RAGE G82S and a ligand thereof.

This invention further provides a method for inhibiting the onset of glomerulosclerosis, proteinuria or albunuria in a patient comprising administering to the patient a prophylactically effective amount of an agent that inhibits binding between RAGE and / or RAGE G82S and a ligand thereof. . This invention further provides a method for treating glomerulosclerosis, proteinuria or albunuria in a patient comprising administering to the patient a therapeutically effective amount of an agent that inhibits the binding between RAGE and / or RAGE G82S and a ligand thereof. This invention further provides an article of manufacture comprising a packaging material having therein an agent that inhibits the binding between the RAGE and / or RAGE G82S and a binder thereof, wherein the packaging material has fixed thereto a label indicating the use of the agent to inhibit the onset of glomerular injury in a patient. This invention further provides an article of manufacture comprising a packaging material having therein an agent that inhibits the binding between the RAGE and / or RAGE G82S and a binder thereof, wherein the packaging material has fixed thereto a label indicating the use of the agent to inhibit the onset of glomerulosclerosis, proteinuria or albuminuria in a patient. This invention further provides an article of manufacture comprising a packaging material having therein an agent that inhibits the binding between the RAGE and / or RAGE G82S and a binder thereof, wherein the packaging material has fixed thereto a label indicating the use of the agent to treat a glomerular lesion in a patient. Finally, this invention provides an article of manufacture comprising a packaging material having therein an agent that inhibits the binding between the RAGE and / or RAGE G82S and a binder thereof, where the packaging material has attached thereto. a label indicating the use of the agent to treat glomerulosclerosis, proteinuria or albuminuria in a patient.

BRIEF DESCRIPTION OF THE FIGURES Figure 1. Administration of ADR to mice BALB / c: effects of sRAGE. BALB / c mice were treated with ADR or control (brine). Mice treated with ADR received sRAGE or PBS. At 2 weeks after ADR, the weight ratio of the kidney / body weight and the mesangial area were determined. mesangial / glomerular fraction. N = 5 mice / group. Statistical considerations are indicated in the figures. Figure 2. Administration of ADR to BALB / c mice: effects of sRAGE. BALB / c mice were treated with ADR or control (brine). Mice treated with ADR received sRAGE or PBS. 6 weeks after ADR, the ratio of kidney weight / body weight to mesangial area and mesangial / glomerular fraction was determined. N = 5 mice / group. Statistical considerations are indicated in the figures. Figure 3. Blocking of RAGE suppresses albuminuria after administration of ADR. 2 and 6 weeks after the ADR, the albumin / creatinine ratio was determined. N = 5 mice / group. The statistical considerations in the figures are indicated.

DETAILED DESCRIPTION OF THE INVENTION Definitions "Agent" should include, without limitation, an organic compound, a nucleic acid, a polypeptide, a lipid, and a carbohydrate. Agents include, for example, agents that are known with respect to structure and / or function, and those that are not known with respect to structure or function. "Antibody" should include, by way of example, both naturally occurring antibodies and non-naturally occurring antibodies. Specifically, this term includes polyclonal antibodies such as monoclonal, and antigen-binding fragments thereof. In addition, this term includes chimeric antibodies and fully synthetic antibodies, and antigen-binding fragments thereof. As used in this, "inhibit" when used in connection with the union between the RAGE and / or RAGE G82S with a ligand thereof, should refer to reducing such binding. In one modality, "inhibit" should refer to eliminating such a union. "Inhibit" the onset of a condition should refer to decrease the likelihood of the onset of the condition, or to avoid the onset of the condition completely. In the preferred embodiment, inhibiting the onset of a condition refers to preventing its onset altogether. "Matter" should refer to any animal, such as a human being, non-human primate, mouse, rat, guinea pig or rabbit. "Treat" a condition must refer to decrease, stop or reverse the progression of the condition. In the preferred embodiment, treating a condition means reversing the progression of the condition, ideally to the point of eliminating the condition itself. As used herein, improving a condition and treating a condition is equivalent.

Modes of the Invention This invention provides methods for inhibiting the initiation and treatment of glomerular lesions. This invention is based on the surprising discovery of a correlation between suppressive glomerular lesions in a non-diabetic patient and the blocking function of RAGE and / or RAGE G82S. Specifically, this invention provides a method for inhibiting the onset of a glomerular lesion in a patient comprising administering to the patient a prophylactically effective amount of an agent that inhibits binding between RAGE and / or RAGE G82S and a ligand thereof. In one embodiment of the present method, glomerular injury is associated with reduced elimination of toxins. In another modality, the glomerular lesion is associated with glomerulosclerosis. In an additional modality, the glomerular lesion is associated with proteinuria. In a still further modality, the glomerular lesion is associated with albuminuria. In the preferred embodiment of the present method, the patient is a human being. In one modality, the patient is affected by diabetes. In another embodiment of the present method, the patient has been afflicted with diabetes for less than 20 years. In an additional modality, the patient is not afflicted with diabetes. In a still further modality, the patient is receiving or is close to receiving a chemotherapy drug. In a still further modality, the chemotherapy drug is adriamycin. In a still further embodiment, the chemotherapy drug is selected from the following: 5-fluorouracil; Actinomycin D; Alpha interferon; Bleomycin; Cisplatin; Cyclophosphamide; Dexamethasone; Doxorubicin; Epoetin alfa; Etoposide; Gleevec; Herceptin; Alpha interferon; Interleukin-2; Interleukin-11; Methotrexate; Neupogen; Nitrogen mustard; Paclitaxel; Prednisolone; Prednisone; PROCRIT; Rituximab; Tamoxifen; Thalidomide; Vinblastine; and Vincristina. Additional chemotherapy drugs are covered and listed on chemocare.com (http: // www. Chemocare .com / bio / default. Sps). In one embodiment of the present invention, the agent is soluble RAGE. In another embodiment, the agent is soluble RAGE G82S. In a further embodiment, the agent is an antibody directed to RAGE. In a still further embodiment, the agent is an antibody directed to RAGE G82S. This invention further provides a method for treating a glomerular lesion in a patient comprising administering to the patient a therapeutically effective amount of an agent that inhibits binding between RAGE and / or RAGE G82S and a ligand thereof. In one embodiment of the present method, glomerular injury is associated with reduced elimination of toxins. In another modality, the glomerular lesion is associated with glomerulosclerosis. In an additional modality, the glomerular lesion is associated with proteinuria. In a still further modality, the glomerular lesion is associated with albuminuria. In the preferred embodiment of the present method, the patient is a human being. In one modality, the patient is not affected by diabetes. In another modality, the patient is receiving or is about to receive a chemotherapy drug. In a further embodiment, the chemotherapy drug is adriamycin. In a still further embodiment, the chemotherapy drug is selected from the following: 5-fluorouracil; Actinomycin D; Alpha interferon; Bleomycin; Cisplatin; Cyclophosphamide; Dexamethasone; Doxorubicin; Epoetin alfa; Etoposide; Gleevec; Herceptin; Alpha interferon; Interleukin-2; Interleukin-11; Methotrexate; Neupogen; Nitrogen mustard; Paclitaxel; Prednisolone; Prednisone; PROCRIT; Rituximab; Tamoxifen; Thalidomide; Vinblastine; and Vincristina. Additional chemotherapy drugs are covered and listed on chemocare.com (http: // www. Chemocare. Co / bio / default. Sps). In an embodiment of the present invention, the agent is soluble RAGE. In another embodiment, the agent is soluble RAGE G82S. In a further embodiment, the agent is an antibody directed to RAGE. In a still further embodiment, the agent is an antibody directed to RAGE G82S. This invention further provides a method for inhibiting the onset of glomerulosclerosis, proteinuria or albunuria in a patient comprising administering to the patient a therapeutically effective amount of an agent that inhibits binding between RAGE and / or RAGE G82S and a ligand thereof. . In the preferred embodiment of the present method, the patient is a human being. In one modality, the patient is afflicted with diabetes. In another embodiment of the present method, the patient has been afflicted with diabetes for less than 20 years. In an additional modality, the patient is not afflicted with diabetes. In a still further modality, the patient is not affected by diabetes. In a still further modality, the patient is receiving or soon to receive a chemotherapy drug. In a still further modality, the chemotherapy drug is adriamycin. In a still further embodiment, the chemotherapy drug is selected from the following: 5-fluorouracil; Actinomycin D; Alpha interferon; Bleomycin; Cisplatin; Cyclophosphamide; Dexamethasone; Doxorubicin; Epoetin alfa; Etoposide; Gleevec; Herceptin; Alpha interferon; Interleukin-2; Interleukin-11; Methotrexate; Neupogen; Nitrogen mustard; Paclitaxel; Prednisolone; Prednisone; PROCRIT; Rituximab; Tamoxifen; Thalidomide; Vinblastine; and Vincristina. Additional chemotherapy drugs are covered and listed on chemocare.com (http: // www. Chemocare.com / bio / default. Sps). In one embodiment of the present invention, the agent is soluble RAGE. In another embodiment, the agent is soluble RAGE G82S. In a further embodiment, the agent is an antibody directed to RAGE. In a still further embodiment, the agent is an antibody directed to RAGE G82S. This invention further provides a method for treating glomerulosclerosis, proteinuria or albunuria in a patient comprising administering to the patient a therapeutically effective amount of an agent that inhibits the binding between RAGE and / or RAGE G82S and a ligand thereof. In the preferred embodiment of the present method, the patient is a human being. In one modality, the patient is afflicted with diabetes. In another modality, the patient is receiving or is about to receive a chemotherapy drug. In a still further modality, the chemotherapy drug is adriamycin. In a still further embodiment, the chemotherapy drug is selected from the following: 5-fluorouracil; Actinomycin D; Alpha interferon; Bleomycin; Cisplatin; Cyclophosphamide Dexamethasone; Doxorubicin; Epoetin alfa; Etoposide Gleevec; Herceptin; Inferred alpha; Interleukin-2 Interleukin-11; Methotrexate; Neupogen; Nitrogen mustard; Paclitaxel; Prednisolone; Prednisone; PROCRIT; Rituximab; Tamoxifen; Thalidomide; Vinblastine; and Vincristina. Additional chemotherapy drugs are covered and listed on chemocare.com (http: // www. Chemocare.com / bio / default. Sps). In one embodiment of the present invention, the agent is soluble RAGE. In another embodiment, the agent is soluble RAGE G82S. In a further embodiment, the agent is an antibody directed to RAGE. In a still further embodiment, the agent is an antibody directed to RAGE G82S. Determining a therapeutically or prophylactically effective amount of agent can be performed based on data from animals using routine computational methods. In one embodiment, the therapeutically or prophylactically effective amount contains between about 1 ng and about 1 g of protein, as applicable. In another embodiment, the effective amount contains between approximately Ing and approximately protein Ig, as applicable. In a further embodiment, the effective amount contains between about 100 ng and about 10 mg of the protein, as applicable. In a still further embodiment, the effective amount contains between about 1 μg and about 1 μg of protein, as applicable. In a still further embodiment, the effective amount contains between about 10μg and about 100μg of the protein, as applicable. In a still further embodiment, the effective amount contains between about 100 μg and about 10 mg of the protein, as applicable. In a still further embodiment, the effective amount of agent, wherein the agent is soluble RAGE, is administered to the patient at a rate of from about 2 μg / kg / hr to about 100 μg / kg / hr (e.g. , 10, 25, 50 or 75 μg / kg / hr). In this invention, the administration of agents can be effected or carried out using any of the various methods and delivery systems known to those skilled in the art. The administration can be carried out, for example, intravenously, orally, by implantation, transmucosally, transdermally, intramuscularly, and subcutaneously. The following delivery systems, which employ a number of pharmaceutical carriers routinely used, are only representative of the many embodiments encompassed to administer the present compositions. Injectable drug delivery systems include solutions, suspensions, gels, microspheres and polymeric injectables, and may comprise excipients such as solubility alteration agents (e.g., ethanol, propylene glycol and sucrose) and polymers (e.g., polycaprylactones and PLGA's) . Implantable systems include rods and discs, and may contain excipients such as PLGA and polycarpillactone. Oral delivery systems include tablets and capsules. These may contain excipients such as binders (e.g., hydroxypropylmethylcellulose. polyvinyl pyrilodone, other cellulosic materials and starch), diluents (for example, lactose and other sugars, starch, dicalcium phosphate and cellulose materials), disintegrating agents (for example, starch polymers and cellulosic materials) and lubricating agents (for example , stearates and talcum). Transmucosal delivery systems include patches, tablets, suppositories, intrauterine devices, gels and cream, and may contain excipients such as solubilizers and enhancers (e.g., propylene glycol, bile salts and amino acids), and other carriers (e.g., polyethylene glycol, esters , of fatty acid and derivatives, and hydrophilic polymers such as hydroxypropylmethylcellulose and haluronic acid). Dermal delivery systems include, for example, aqueous and non-aqueous gels, creams, multiple emulsions, microemulsions, liposomes, ointments, aqueous and non-aqueous solutions, lotions, aerosols, bases and hydrocarbon powders, and may contain excipients such as solubilizers. , permeation enhancers (eg, fatty acids, fatty acid esters, fatty alcohols and amino acids), and hydrophilic polymers (eg, polycarbophil and polyvinylpyrrolidone). In one embodiment, the pharmaceutically acceptable carrier is a liposome or a transdermal enhancer.

Solutions, suspensions and powders for reconstitutable delivery systems include carriers such as suspending agents (eg, gums, zantanos, cellulosics and sugars), humectants (eg, sorbitol), solubilizers (eg, ethanol, water, PEG and propylene glycol), surfactants (eg, sodium lauryl sulfate, Spans, Tweens, and cetyl pyridine), preservatives and antioxidants (eg, parabens, vitamins E and C, and ascorbic acid), anti-solidification agents, agents of coating, and chelating agents (for example, EDTA). In one embodiment of this invention, the delivery system used comprises more than water only, or more than just regulator. This invention further provides an article of manufacture comprising a packaging material having therein an agent that inhibits binding between the RAGE and / or RAGE G82S and a binder thereof, wherein the packaging material has attached thereto a label which indicates the use of the agent to inhibit the onset of glomerular lesions in a patient. This invention further provides an article of manufacture comprising a packaging material having therein an agent that inhibits binding between the RAGE and / or RAGE G82S and a binder thereof, wherein the packaging material has attached thereto a label which indicates the use of the agent to inhibit the agent of glomerulosclerosis, proteinuria or albuminuria in a patient. In the preferred embodiment of the present articles of manufacture, the patient is a human being. In one modality, the patient is affected by diabetes. In another embodiment of the present methods, the patient has been afflicted with diabetes for less than 20 years. In an additional modality, the patient is not afflicted with diabetes. In a still further modality, the patient is receiving or is close to receiving a chemotherapy drug. In a still further modality, the chemotherapy drug is adriamycin. In a still further embodiment, the chemotherapy drug is selected from the following: 5-fluorouracil; Actinomycin D; Alpha interferon; Bleomycin; Cisplatin; Cyclophosphamide; Dexamethasone; Doxorubicin; Epoetin alfa; Etoposide; Gleevec; Herceptin; Alpha interferon; Interleukin-2; Interleukin-11; Methotrexate; Neupogen; Nitrogen mustard; Paclitaxel; Prednisolone; Prednisone; PROCRIT; Rituximab; Tamoxifen; Thalidomide; Vinblastine; and Vincristina. Additional chemotherapy drugs are covered and listed on chemocare.com (http: // www. Chemocare.com / bio / default. Sps). In one embodiment of the present articles of manufacture, the agent is soluble RAGE. In another embodiment, the agent is soluble RAGE G82S. In a further embodiment, the agent is an antibody directed to RAGE. In a still further embodiment, the agent is an antibody directed to RAGE G82S. This invention further provides an article of manufacture comprising a packaging material having therein an agent that inhibits the binding between the RAGE and / or RAGE G82S and a binder thereof, wherein the packaging material has fixed thereto a label indicating the use of an agent to treat a glomerular lesion in a patient. Finally, this invention provides an article of manufacture comprising a packaging material having therein an agent that inhibits the binding between the RAGE and / or the RAGE G82S and a binder thereof, where the packaging material has fixed the same a label that indicates the use of an agent to treat glomerulosclerosis, proteinuria or albuminuria in a patient. In the preferred embodiment of the present articles of manufacture, the patient is a human being. In one modality, the patient is not affected by diabetes. In another modality, the patient is receiving or is close to receiving a chemotherapy drug. In a further embodiment, the chemotherapy drug is adriamycin. In a still further embodiment, the chemotherapy drug is selected from the following: 5- fluorouracil; Actinomycin D; Alpha interferon; Bleomycin; Cisplatin; Cyclophosphamide; Dexamethasone; Doxorubicin; Epoetin alfa; Etoposide; Gleevec; Herceptin; Alpha interferon; Interleukin-2; Interleukin-11; Methotrexate; Neupogen; Nitrogen mustard; Paclitaxel; Prednisolone; Prednisone; PROCRIT; Rituximab; Tamoxifen; Thalidomide; Vinblastine; and Vincristina. Additional chemotherapy drugs are covered, and listed on chemocare.com (http: // www. chemocare.com / bio / default. sps). In one embodiment of the present articles of manufacture, the agent is soluble RAGE. In another embodiment, the agent is soluble RAGE G82S. In a further embodiment, the agent is an antibody directed to RAGE. In a still further embodiment, the agent is an antibody directed to RAGE G82S. This invention is illustrated in the section on Experimental details that comes next. This section is published to aid in the understanding of the invention but does not intend, nor should it be construed, to limit in any way the invention set forth in the claims that follow.

Experimental Details Methods Animal Studies Male BALB / c mice with an age of six months received an intravenous dose of adriamycin (ADR), 10.5 mg / kg. Immediately after the ADR injection, the mice received once daily the administration of soluble mouse RAGE, the extracellular binding domain of RAGE, 100 μg per day, starting immediately at the time of ADR treatment, and continued until the day of sacrifice.

Morphological studies The dissected mice were fixed in regulated formalin (10%) overnight and then routinely processed by light microscopy. The tissues incorporated by fixed paraffin were cut (thickness of 3 μm) and installed in slices coated with 3-aminopropyltriethoxy silane (Sigma) followed by incubation at 37 ° C overnight. The microscopic views of light after staining with periodic acid Schiff (PAS) were examined in a computer and the quantification of mesangial and glomerular matrix areas was performed using a Zeiss microscope and image analysis system (MediaCybernetics). To calculate the mesangial area, only regions without nuclei were included. Forty glomeruli from each animal were randomly selected in the stained sections (20 from the outer region and 20 from the inner region). Morphometry was performed by investigators without visualization of the experimental protocol.

Functional studies A twenty-four hour collection of urine from each animal was obtained using metabolic boxes. Urine albumin and creatinine were determined using the Albuwell M and creatinine tests by Exocell (Philadelphia, PA) according to the manufacturer's instructions.

Statistical analysis The mean ± standard error (SE-standard error) of the mean is reported. Statistical significance (defined as p <0.05) was determined by ANOVA. Where indicated, a post-hoc analysis was employed using Dunnett's t test using StatView 4.0 (Abacus Concepts, Inc., Berkely, CA).

Results RAGE and cellular activation It was in the context of the roles of inflammatory cells and podocytes in the pathogenesis of FSGS that a role for the AGE Receptor was first speculated (RAGE). RAGE is a multiple ligand member of the immunoglobulin superfamily of cell surface molecules (26-27) that clumps different molecules; the RAGE interaction of binder activates the signaling pathways (such as NF-kB, p44 / p42, p38 and SAPK / JNK MAP kinases, cdc42 / rac, and JAK / STAT, for example) (28-33) which are required for effects mediated by RAGE.

Notably, removal of the cytosolic tail of RAGE imparts a dominant negative effect on cultured cells and in vivo. RAGE is expressed mainly in the podocyte in the glomerulus. The discoveries that have shown that the main site of RAGE expression in the glomerulus is the podocyte, at low levels in homeostasis (34); RAGE expression of podocytes is upregulated in human and mouse diabetes (34). In order to address the concept that RAGE may be involved in the pathogenesis of FSGS mediated by ADR, a single injection of ADR, 10.5 mg / kg, was administered for male BALB / c mice with an age of 6 weeks. ADR-treated mice received a daily administration of soluble mouse RAGE, the extracellular ligand binding domain of RAGE, 100 μg per day, starting immediately at the time of ADR treatment, and continued until the day of sacrifice. Other mice treated with ADR received the vehicle, PBS. In weeks 2 and 6 after ADR, the ratios of kidney weight / body weight decreased significantly in mice treated with sRAGE vs. those treated with PBS. Examination of the mesangial area at weeks 2 and 6 after ADR revealed that in a time-dependent manner, the administration of ADR was associated with the increased mesangial area, and the fraction of glomerular area / mesangial matrix increased by PAS staining ( Figure 1 &2, respectively). At weeks 2 and 6, the administration of sRAGE resulted in a significantly decreased mesangial area and the mesangial / glomerular area was compared to the PBS treatment (Figure 1 &2, respectively). The key test of these concepts was the degree to which the blockade of RAGE would suppress the development of albuminuria. The mice were placed in metabolic boxes and 24 hours of urine was collected. Urine levels of albumin and creatinine were determined; the results are reported as μg of albumin / μg of creatinine. At 2 weeks after ADR, mice treated with PBS exhibited a «= 10 fold increase in urinary albumin / creatinine compared to mice treated with brine that did not receive ADR (809.55 ± 365.85 vs 85.78 + 17.56 albumin / creatinine, p <0.01) (Figure 3). In mice that received ADR and sRAGE, albumin / creatinine levels were markedly reduced (191.08 + 49.93; p < 0.05 vs. mice treated with PBS received ADR) (Figure 3). At six weeks, the results were similarly surprising. Mice treated with PBS that received ADR exhibited urinary albumin / creatinine of 1,362.96 + 987.97 vs. 84.47 +49.93 in control mice that did not receive ADR; p < 0.01 (Figure 3). In the presence of sRAGE, the albuminuria mediated with ADR was significantly reduced, to 249.76 + 283.19 μg of albumin / creatinine; p < 0.01 vs. PBS / ADR (Figure 3). Taken together, these findings strongly support the hypothesis that activation of RAGE contributes significantly to mechanisms linked to glomerular lesions. The administration of soluble RAGE delivered significant protection against the morphological and functional indices of glomerular lesions after administration of glomerulosclerosis induction agents. The blockade of RAGE is proposed as a new means to avoid glomerular lesions in this class of diseases.

References 1. Bolton, W.K., and Abdel-Rahman, E. Pathogenesis of focal glomerulosclerosis (Pathogenesis of focal glomerulosclerosis). Nephron 88: 6-13, 2001. 2. Bertolatus, J.A. , and Hunsicker, L.G. Glomerular sieving of anionic and neutral bovine albumins in proteinuric rats (glomerular screening of anionic and neutral bovine albumin in proteinuric rats). Kidney International 28: 467-476, 1985. 3. Whiteside, C, Prutis, K., Cameron, R., and Thompson, J. Glomerular epithelial detachment, correlated with proteinuria in adriamycin and puromycin nephrosis. glomerular epithelial detachment, without charge density, correlates with proteinuria in adriamycin and puromycin nephrosis). Lab Investigation 61: 650-660, 1989. 4. Weening, J.J, and Rennke, H.G. Glomerular permeability and polyanion in adriamycin nephrosis in the rat (Glomerular permeability and polyanion in adriamycin nephrosis in the rat). Kidney International 24: 152-159, 1983. 5. Salant, D.J., Belok, S., Stilmant, M.M., Darby, C. and Courser, W.G. Determinants of glomerular localization of subepithelial immune deposits: effects of altered antigen to antibody ratio, steroids, vasoactive amine antagonists, and to inonucleoside of puromycin on passive Heymann nephritis in rats (Determinants of the glomerular localization of subepithelial immune deposits: effects of an altered antigen to antibody relationship, steroids, vasoactive amine antagonists, and puromycin aminonucleoside in passive nephritis of Heymann in rats). Lab. Investigation 41: 89-99, 1979. 6. Chen, A., Ding, S.L., Sheu, L.F., Song, Y.B., Shich, S.D., Shaio, M.F., Chou, W.Y., and Ho, Y.S. Experimental IgA nephropathy: enhanced deposition of glomerular IgA immune complex in proteinuric status (experimental IgA nephropathy: reinforced discarding of glomerular IgA immune complex in proteinuric state). Lab. Investigation 70: 639-647, 1995. 7. Chen, A., Wei, C.H., Sheu, L.F., Ding, S.L. and Lee, W.H. Induction of proteinuria by adriamycin or bovine serum albumin in the mouse (Induction of proteinuria by adriamycin or bovine serum albumin in the mouse). Lab. Investigation 70: 639-647, 1995. 8. Wang, Y., Wang, Y.P., Tay, Y.C., and Harris, D.C.H. Progressive adriamycin nephropathy in mice: sequence of histologic and i munohistochemical events (progressive adriamycin nephropathy in mice: sequence of histological and immunohistochemical events). Kidney International 58: 1797-1804, 2000. 9. Wang, Y., Wang, Y.P., Tay, Y.C., and Harris, D.C.H. Role of CD8 + cells in the progression of murine adriamycin nephropathy. (The role of CD8 + cells in the progression of mouse adriamycin neuropathy). Kidney International 59: 941-949, 2001. 10. Bariety, J., Nochy, D., Mandet, C, Jacquot, C, Glotz, D., and Meyrier, A. Podocytes undergo phenotypic changes and express macrophage-associated markers in idiopathic collapsing glo erulopathy (Podocytes undergo phenotypic changes and express markers associated with macrophages in idiopathic collapse glomerulopathy). Kidney International 53: 918-925, 1998. ll. Schwartz, M.M. , Evans, J., Bain, R.P., Korbet, S.M. Focal segmental glomerulosclerosis: prognostic implications of the cellular injury (abstract) (Focal segmental glomerulosclerosis: predicted implications of cell injury (summary)). J. American Society of Nephrology 10: 1900-11907, 1999. 12. Magil, A., and Cohen, A.H. : Monocytes and focal glomeruloscleerosis (monocytes and focal glomerulosclerosis). Lab Investigation 61: 404-409, 1989. 13. Fries, J.W., Sandstrom, D.J., Meyer, T.W., and Rennke, H.G. Glomerular hypertrophy and epithelial cell injury modulate progressive glomerulosclerosis in the rat (Glomerular hypertrophy and lesions of epithelial cells modulate progressive glomerulosclerosis in the rat). Lab. Investigation 60: 205-218, 1989. 14. Kriz, W., Gretz, N., and Lemley, K.V.

Progression of glomerular diseases: is the podocyte the culprit? (Progression of glomerular diseases: is the podocyte the culprit?) Kidney International 54: 687-697, 1998. 15. Kerjaschki, D. Dysfunctions of cell biological mechanisms of visceral epithelial cell (podocytes) in glomerular diseases (Dysfunctions of cellular biological mechanisms of visceral epithelial cells (podocytes) in glomerular diseases). Kidney International 45: 300-313, 1994. 16. Schiffer, M., Bitzer, M., Roberts, I.S.D., Kopp, J.B., Ten Dijke, P., Mundel, P., and Bottinger, E.P. Apoptosis in podocytes induced by TGF-β and Smad7 (apoptosis in podocytes induced by TGF-β and Smad7). J. Clinical Investigation 108: 807: 816, 2001. 17. Sharma, K., Jin, Y., Guo, J., Ziyadeh, F.N. Neutralization of TGF-β by anti-TGF-β antibody attenuates kidney hypertrophy and the enhanced extracellular matrix gene expression in stz-induced diabetic mice (Neutralization of TGF-β by anti-TGF-β antibodies attenuates kidney hypertrophy and expression Enhanced genetics of extracellular matrix in diabetic mice induced by stz). Diabetes 45: 522-530, 1996. 18. Ziyadeh, F.N., Hoffman, B.B., Han, D.C., Iglesias-De La Cruz, M.C., Hong, S.W., Isono, M., Chen, S., McGowan, T.A. , and Sharma, K. Long-term prevention of renal insufficiency and excess matrix gene expression, and glomerular menangial matrix expansion by treatment with monoclonal antitransforming growth factor-ß antibody in db / db diabetic mice, a rodent model of type 2 diabetes (Prevention a Long-term genetic expression of matrix of excess renal failure, and glomerular menangial matrix expansion by treatment with the antibody ß-monoclonal antitransformation development factor in diabetic mice db / db, a rodent model of type 2 diabetes). FASEB J 14: 439-447, 2000. 19. Koya, D., Haneda, M., Nakagawa, H., Takagi, C, Xia, P., Clermont, A., Bursell, SE, Kern, TS, Bailas , LM, Heath, WF, Strairan, LE, Feener, EP, and King, GL Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db / db mice, a rodent model of type 2 diabetes (Improvement in diabetic mesangial expansion accelerated by treatment with a PKC beta inhibitor in diabetic mice db / db, a rodent model of type 2 diabetes). FASEB J 14: 439-447, 2000. 20. Pavenstadt, H. Roles of the podocyte in glomerular function (Papers of podocytes in glomerular function). Am J Physiol Renal Physiol 278: F173-F179, 2000. 21. Nakamura, T. Ushimaya, C, Osada S., Hara, M., Shimada, N., and Koide, H. Pioglitazone reduces urinary podocyte excretion in type 2 diabetes patients with microalbuminuria (Pioglitazone reduces the excretion of urinary podocytes in patients with type 2 diabetes with microalbuminuria). Metabolism 50: 1193-1196, 2000. 22. Hoshi, S., Shu, Y., Yoshida, F., Inagaki, T., Sonoda, J., Watanable, T., Nomoto, K., and Nagata, M Podocyte injury promotes progressive nephropathy in Zucker diabetic fatty rats (Podocyte injury improves progressive nephropathy in diabetic fatty rats of Zucker). Lab. Invest. 82: 25-35, 2002. 23. Misfud, S.A., Alien, T.J., Bertram, J.F., Hulthen, U.L., Kelly, D.J., Cooper, M.E., Wilkinson-Berka, J.L., and Gilbert, R.E. Podocyte foot process broadening in experimental diabetic nephropathy: amelioration with renin-angiotensin blockade (Widening of the podocyte foot process in experimental diabetic neuropathy: improvement with renin-angiotensin block). Diabetology 44: 878-882, 2001. 24. Cooper, M.E., Vranes, D., Youssef, S., Stacker, S.A., Cox, A.J., Rizkalla, B., Casley, D.J., Bach, L.A., Kelly, D.J., and Gilbert, R.E. Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes (Increased renal expression of the vascular endothelial development factor (VEGF) and its VEGFR-2 receptor in experimental diabetes). Diabetes 48: 2229-2239, 1999. 25. De Vriese, A., Tilton, R., and Vanholder, R. Hyperfiltration and albuminuria in diabetes: role of vascular endothelial growth factor (VEGF) (Abstract) (Hyperfiltration and albuminuria in diabetes: role of the vascular endothelial development factor (VEGF) (Summary)). J. American Soc. Nephrol. 10-.A3434, 1999. 26. Schmidt, A.M. , Vianna, M., Gerlach, M., Brett, J., Ryan, J., Kao, J., Esposito, C, Hegarty, H., Hurley, W., Clauss, M., Wang, F., Pan, YC, Tsang, TC, and Stern, D. Isolation and characterization of binding proteins for advanced glycosilation endproducts from lung tissue which are present on the endothelial cell surface (Isolation and characterization of binding proteins for advanced glycosylation end products from pulmonary tissue and which are present on the endothelial cell surface). J. Biol. Chem. 267: 14987-14997, 192. 27. Neeper, M., Schmidt, AM, Brett, J., Yan, SD, Wang, F., Pan, YC, Elliston, K., Stern, D., and Shaw, A. Cloning and expression of RAGE: a cell surface receptor for advanced glycosilation end produets of proteins (Cloning and expression of RAGE: a cellular surface receptor for advanced glycosylation end products of proteins). J. Biol. Chem. 267: 14998-15004, 1992. 28. Yan, S-D-. , Schmidt, A-M. , Anderson, G., Zhang, J., Brett, J., Zou, Y-S., Pinsky, D., and Stern, D.

Enhanced cellular oxidant stress by the interaction of advanced glycation endproducts with their receptors / binding proteins (cellular oxidant stress reinforced by the interaction of advanced glycation end products with their receptors / binding proteins). J. Biol. Chem. 269: 9889-9897, 1994. 29. Lander, H.L., Tauras, J.M. , Oliste, J.S., Moss, R.A., and A.M. , Schmidt. Activation of the Receptor for Advanced Glycation Endproducts triggers to MAP Kinase pathway regulated by oxidant stress (Activation of the receptor for advanced glycation end products activates a MAP kinase pathway regulated by oxidative stress). J. Biol. Chem. 272: 17810-17814, 1997. 30. Taguchi, A., Blood, DC, del Toro, G., Canet, A., Lee, DC, Qu, W., Tanji, N., Lu, Y., Lalla, E., Fu, C, Hofmann, MA , Kislingler, T., Ingram, M., Lu, A., Tanaka, H., Hori, O., Ogawa, S., Stern, D.M., and Schmidt, A.M. Blockade of amphoterin / RAGE signaling suppresses tumor growth and metastases (Amphoteric blockade / RAGE signaling suppresses tumor development and metastasis). Nature 405: 354-360, 2000. 31. Hofmann, M.A. , Drury, S., Fu, C, Qu, W., Taguchi, A., Lu, Y., Avila, C, Kambham, N., Bierhaus, A., Nawroth, P., Neurath, MF, Slattery, T., Beach, D., McClary, J., Nagashi, M., Morser, J., Stern, D., and Schmidt, AM RAGE mediates a novel proinflammatory axis: a central cell surface receptor for SlOO / calgranulin polypeptides (RAGE mediates a novel proinflammatory axis: a central cellular surface receptor for SlOO / calgranulin polypeptides). Cell 97: 889-901, 1999. 32. Huttunen, HJ, Fages, C, Rauvala, H. RAGE-mediated neurite outgrowth and activation of NF-kB require the cytosolic domain of the receptor but different downstream signaling pathways (Derivatives of neurites mediated with RAGE and NF-kB activation require the cystosolic domain of the receptor but different paths of downstream signaling). Journal of Biological Chemistry 274: 19919-19924, 1999. 33. Kislinger, T., Fu, C, Huber, B., < Qu, W., Taguchi, A., Yan, S.D., Hofmann, M., Yan, S.F., Pischetsrider, M., Stern, D., and Schmidt, A.M. Ne (carboxymethyl) lysine modifications of proteins are ligands for RAGE that actívate cell signaling pathways and modulate gene expression (Ne (protein carboxymethyl) lysine modifications are ligands for RAGE that activate cellular signaling pathways and modulate gene expression). J. Biol. Chemistry 274: 31740-31749, 1999. 34. Tanji, N., Markowitz, G.S., Fu, C, Kislinger, T., Taguchi, A., Pischetsrieder, M., Stern, D., Schmidt, A.M., and D'Atagi, V.D. The expression of Advanced Glycation Endproducts and their cellular receptor RAGE in diabetic nephropathy and non-diabetic renal dis'ease (The expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and non-diabetic renal diseases). J. American Soc. Nephrol. 11: 1656-1666, 2000. 35. U.S. Serial No. 08 / 755,235, filed on November 22, 1996, Publication No. US-2003-0059423-Al, published March 27, 2003.

Claims (70)

1. NOVELTY OF THE INVENTION Having described the invention as antecedent, the content of the following claims is claimed as property: CLAIMS 1. A method for inhibiting the onset of a glomerular lesion in a patient comprising administering to the patient a prophylactically effective amount of an agent that inhibits the binding between RAGE and / or RAGE G82S and a ligand thereof.
2. 2. The method according to claim 1, characterized in that the glomerular lesion is associated with the reduced elimination of toxins from the patient.
3. 3. The method according to claim 1, characterized in that the glomerular lesion is associated with glomerulosclerosis.
4. 4. The method according to claim 1, characterized in that the glomerular lesion is associated with proteinuria.
5. 5. The method according to claim 1, characterized in that the glomerular lesion is associated with albuminuria.
6. 6. The method according to claim 1, characterized in that the patient is a human being.
7. The method according to claim 6, characterized in that the patient is afflicted with diabetes.
8. 8. The method according to claim 7, characterized in that the patient is afflicted with diabetes for less than 20 years.
9. The method according to claim 6, characterized in that the patient is not afflicted with diabetes.
10. The method according to claim 6, characterized in that the patient is receiving or is close to receiving a chemotherapy drug.
11. The method according to claim 10, characterized in that the chemotherapy drug is adriamycin.
12. 12. The method according to claim 1, characterized in that the agent is soluble RAGE.
13. The method according to claim 1, characterized in that the agent is soluble RAGE G82S.
14. The method according to claim 1, characterized in that the agent is an antibody directed to RAGE.
15. 15. The method according to claim 1, characterized in that the agent is an antibody directed to RAGE G82S.
16. 16. A method for treating a glomerular lesion in a patient comprising administering to the patient a therapeutically effective amount of an agent that inhibits the binding between RAGE and / or RAGE G82S and a ligand thereof.
17. 17. The method according to claim 16, characterized in that the glomerular lesion is associated with the reduced elimination of toxins from the patient.
18. 18. The method according to claim 16, characterized in that the glomerular lesion is associated with glomerulosclerosis.
19. 19. The method according to claim 16, characterized in that the glomerular lesion is associated with proteinuria.
20. 20. The method according to claim 16, characterized in that the glomerular lesion is associated with albuminuria.
21. 21. The method according to claim 16, characterized in that the patient is a human being.
22. 22. The method according to claim 21, characterized in that the patient is not afflicted with diabetes.
23. 23. The method according to claim 21, characterized in that the patient is receiving or is close to receiving a chemotherapy drug.
24. 24. The method according to claim 23, characterized in that the chemotherapy drug is adriamycin.
25. 25. The method according to claim 16, characterized in that the agent is soluble RAGE.
26. 26. The method according to claim 16, characterized in that the agent is RAGE G82S.
27. 27. The method according to claim 16, characterized in that the agent is an antibody directed to RAGE.
28. 28. The method according to claim 16, characterized in that the agent is an antibody directed to RAGE G82S.
29. 29. A method for inhibiting the onset of glomerulosclerosis, proteinuria or albunuria in a patient comprising administering to the patient a therapeutically effective amount of an agent that inhibits binding between RAGE and / or RAGE G82S and a ligand thereof.
30. 30. The method according to claim 29, characterized in that the patient is a human being.
31. 31. The method according to claim 30, characterized in that the patient is afflicted with diabetes.
32. 32. The method according to claim 31, characterized in that the patient is afflicted with diabetes for less than 20 years.
33. 33. The method according to claim 30, characterized in that the patient is not afflicted with diabetes.
34. 34. The method according to claim 30, characterized in that the patient is receiving or is close to receiving a chemotherapy drug.
35. 35. The method according to claim 34, characterized in that the chemotherapy drug is adriamycin.
36. 36. The method according to claim 29, characterized in that the agent is soluble RAGE.
37. 37. The method according to claim 29, characterized in that the agent is soluble RAGE G82S.
38. 38. The method according to claim 29, characterized in that the agent is an antibody directed to the RAGE.
39. 39. The method according to claim 29, characterized in that the agent is an antibody directed to the RAGE G82S.
40. 40. A method for treating glomerulosclerosis, proteinuria or albunuria in a patient comprising administering to the patient a therapeutically effective amount of an agent that inhibits the binding between RAGE and / or RAGE G82S and a ligand thereof.
41. 41. The method according to claim 40, characterized in that the patient is a human being.
42. 42. The method according to claim 41, characterized in that the patient is not afflicted with diabetes.
43. 43. The method according to claim 41, characterized in that the patient is receiving or is close to receiving a chemotherapy drug.
44. 44. The method according to claim 43, characterized in that the chemotherapy drug is adriamycin.
45. 45. The method according to claim 40, characterized in that the agent is soluble RAGE.
46. 46. The method according to claim 40, characterized in that the agent is soluble RAGE G82S.
47. 47. The method according to claim 40, characterized in that the agent is an antibody directed to RAGE.
48. 48. The method according to claim 40, characterized in that the agent is an antibody directed to RAGE G82S.
49. 49. An article of manufacture comprising a packaging material having therein an agent that inhibits the binding between RAGE and / or RAGE G82S and a binder thereof, characterized in that the packaging material has fixed thereto a label indicating the use of an agent to inhibit the onset of glomerular lesions in a patient.
50. 50. An article of manufacture comprising a packaging material having therein an agent that inhibits the binding between RAGE and / or RAGE G82S and a binder thereof, characterized in that the packaging material has fixed thereto a label indicating the use of an agent to inhibit the onset of glomerulosclerosis, proteinuria or albuminuria in a patient.
51. 51. The article according to claim 49 or 50, characterized in that the patient is a human being.
52. 52. The article according to claim 51, characterized in that the patient is afflicted with diabetes.
53. 53. The article according to claim 52, characterized in that the patient has been afflicted with diabetes for less than 20 years.
54. 54. The article according to claim 51, characterized in that the patient is not afflicted with diabetes.
55. 55. The article according to claim 51, characterized in that the patient is receiving or is close to receiving a chemotherapy drug.
56. 56. The article according to claim 55, characterized in that the chemotherapy drug is adriamycin.
57. 57. The article according to claim 49 or 50, characterized in that the agent is soluble RAGE.
58. 58. The article according to claim 49 or 50, characterized in that the agent is soluble RAGE G82S.
59. 59. The article according to claim 49 or 50, characterized in that the agent is an antibody directed to soluble RAGE.
60. 60. The article according to claim 49 or 50, characterized in that the agent is an antibody directed to soluble RAGE G82S.
61. 61. An article of manufacture comprising a packaging material having therein an agent that inhibits the binding between RAGE and RAGE G82S and a binder thereof., characterized in that the packaging material has attached thereto a label indicating the use of an agent to treat a glomerular lesion in a patient.
62. 62. An article of manufacture comprising a packaging material having therein an agent that inhibits the binding between RAGE and / or RAGE G82S and a binder thereof, characterized in that the packaging material has fixed thereto a label indicating the use of an agent to treat glomerulosclerosis, proteinuria or albuminuria in a patient.
63. 63. The article according to claim 61 or 62, characterized in that the patient is a human being.
64. 64. The article according to claim 63, characterized in that the patient is not afflicted with diabetes.
65. 65. The article according to claim 63, characterized in that the patient is receiving or is close to receiving a chemotherapy drug.
66. 66. The article according to claim 65, characterized in that the chemotherapy drug is adriamycin.
67. 67. The article according to claim 61 or 62, characterized in that the agent is soluble RAGE.
68. 68. The article according to claim 61 or 62, characterized in that the agent is soluble RAGE G82S.
69. 69. The article according to claim 61 or 62, characterized in that the agent is an antibody directed to soluble RAGE.
70. 70. The article according to claim 61 or 62, characterized in that the agent is an antibody directed to soluble G82S RAGE.