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Treatment of chronic kidney disease and other renal dysfunction using a gdf15 modulator

a technology of chronic kidney disease and modulator, which is applied in the field of gdf15 modulator, can solve the problems of ckd-affected patients being prone to suffer aki-like events, common and expensive kidney disease, and reducing kidney function or kidney size, so as to reduce erythropoietin production and reduce the effect of kidney function

Inactive Publication Date: 2017-05-18
AVEO PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to a method of increasing renal function in a subject with chronic kidney disease (CKD) by administering a composition containing a GDF15 inhibitor. CKD is often accompanied by comorbidities such as cachexia, chronic or congestive heart failure, anemia, diabetes, and hypertension. The invention provides a way to address these comorbidities by reducing the impact of GDF15 on their function. The invention uses an anti-GDF15 antibody as the GDF15 inhibitor, which can be humanized or synthetically produced. The antibody can be administered as a single agent or in combination with other agents such as an anti-GDF15 receptor antibody or a soluble GDF15 mimetic. The invention also includes methods of using the anti-GDF15 antibody to treat CKD and its associated comorbidities.

Problems solved by technology

Kidney disease is a common and expensive condition that is a major source of morbidity and mortality in humans.
Moreover, CKD-affected patients are prone to suffer AKI-like events.

Method used

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  • Treatment of chronic kidney disease and other renal dysfunction using a gdf15 modulator
  • Treatment of chronic kidney disease and other renal dysfunction using a gdf15 modulator
  • Treatment of chronic kidney disease and other renal dysfunction using a gdf15 modulator

Examples

Experimental program
Comparison scheme
Effect test

example 1

Administration of Recombinant mFc-GDF15 Increases Blood Urea Levels

[0144]ICR SCID (spontaneous mutant T&B cell deficient) mice were injected intraperitoneally with a PBS solution (control) or 40 μg of a murine, recombinant Fc-GDF15 protein. Body weight, and molecular markers for muscle degradation (Atrogin, MurF1), adipogenesis (Glut4, Leptin, C / EPBβ) and lipid accumulation (Stearoyl-CoA desaturase, Fatty acid synthase) were measured after injection.

[0145]FIG. 1 shows that mice injected with Fc-GDF15 exhibited significant body weight loss. Similarly, mice injected with Fc-GDF15 exhibited significant loss of gonadal mass (FIG. 2A) and gastroc mass (FIG. 2B). The treated mice also exhibited upregulation of markers for muscle degradation (Atrogin, MurF1) and downregulation of markers of adipogenesis (Glut4, leptin) and lipid accumulation (stearoyl-CoA desaturase; fatty acid synthase).

[0146]Mice treated with Fc-GDF15 also exhibited lower levels of liver enzymes (alanine aminotransferase...

example 2

Treatment of Renal Hypotrophy in an HT-1080 Xenograft Tumor Model

[0147]This Example demonstrates the treatment of renal hypotrophy (as indicated by kidney weight loss) by an anti-GDF15 antibody (01G06) in an HT-1080 fibrosarcoma xenograft model. HT-1080 cells were grown in culture at 37° C. in an atmosphere containing 5% CO2, using Eagle's Minimum Essential Medium (ATCC, Catalog No. 30-2003) containing 10% FBS. Cells were inoculated subcutaneously into the flank of 8-week old female ICR SCID mice with 5×106 cells per mouse in 50% matrigel. Body weight was measured daily. When body weight reached 80%, the mice were randomized into two groups of five mice each. Each group received one of the following treatments via intraperitoneal injection: murine IgG control, murine 01G06 dosed at 2 mg / kg on day 1 and day 7. In this experiment, a group of five mice were sacrificed at the time of dosing (baseline or 80% body weight loss, without treatment) and at the end of study (seven days post do...

example 3

Treatment with Anti-GDF15 Antibody Reverses Elevated Levels of Urea Seen in Mice Bearing HT-1080 Human Tumor Xenographs

[0150]ICR SCID (spontaneous mutant T&B cell deficient) mice bearing HT-1080 human tumor xenografts, as in Example 2, exhibit cachexia. Systemic administration of 10 mg / kg of an anti-GDF15 antibody (Hu01G06-127) but not human IgG reversed the body weight loss observed in mice bearing HT-1080 human tumor xenografts (FIG. 5A), as well gonadal weight loss (FIG. 5B). Administration of the anti-GDF15 antibody also reversed elevated levels of urea observed in mice bearing HT-1080 human tumor xenografts (FIG. 6).

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Abstract

The invention provides methods and compositions for treating a subject having a renal-related disorder, such as chronic kidney disease (CKD), end stage renal failure, diabetes, insulin resistance, kidney hypertrophy, kidney hypotrophy, polycystic kidney disease, proteinuria, hyperglycemia, hyperuricemia, gout, kidney stones, hypertension or hypertensive nephropathy, dyslipidemia, anemia and / or reduced erythropoietin production, iron deficiency or hyperfiltration. The methods and compositions use or contain a composition that reduces or inhibits GDF15 activity.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Patent Application No. 62 / 015,242, filed Jun. 20, 2014, incorporated by reference herein in its entirety.FIELD OF THE INVENTION[0002]The present invention relates to methods of using, and compositions containing, a GDF15 modulator for treating a subject having a renal disorder or renal dysfunction, particularly chronic kidney disease, acute, chronic or end stage renal failure, glomerulonephritis, anemia, diabetic nephropathy and insulin resistance.BACKGROUND OF THE INVENTION[0003]Kidney disease is a common and expensive condition that is a major source of morbidity and mortality in humans. From a clinical perspective, kidney diseases can be classified as acute kidney injury (AM) and chronic kidney disease (CKD). AKI, also termed acute kidney failure or acute renal failure, is a rapid loss of renal function, and may end up with full, partial or no recovery of normal renal function. AKI i...

Claims

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Application Information

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IPC IPC(8): C07K16/22
CPCC07K16/22A61K2039/505C07K2317/76C07K14/475C07K2319/30A61P13/12A61P43/00
Inventor GYURIS, JENOLERNER, LORENA
Owner AVEO PHARM INC
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