Methods for increasing red blood cell levels and treating ineffective erythropoiesis by inhibiting activin B and/or GDF11

一种GDF11、激活素的技术，应用在受体/细胞表面抗原/细胞表面决定因子、用于靶向特定细胞融合、有机活性成分等方向，能够解决无法治疗贫血、加重等问题

Pending Publication Date: 2017-05-10
ACCELERON PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because endogenous erythropoietin levels are often high in patients with ineffective erythropoiesis, EPO-based therapeutics will often fail to treat anemia in these patients and / or may exacerbate other aspects of the disease (eg, splenomegaly and iron overload)

Method used

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  • Methods for increasing red blood cell levels and treating ineffective erythropoiesis by inhibiting activin B and/or GDF11
  • Methods for increasing red blood cell levels and treating ineffective erythropoiesis by inhibiting activin B and/or GDF11
  • Methods for increasing red blood cell levels and treating ineffective erythropoiesis by inhibiting activin B and/or GDF11

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0452] Example 1: Characterization of the ligand binding of ActRIIB(L79D 20-134)-Fc and ActRIIB(L79D 25-131)-Fc Specificity

[0453] A variant ActRIIB-Fc fusion protein has been reported previously, which comprises amino acids 20-134 of SEQ ID NO:1 of the present invention, wherein there is an acidic amino acid at position 79 relative to SEQ ID NO:1 [referred to herein as Are "ActRIIB(L79D 20-134)-Fc" fusion proteins, constructs, variants, etc.; see SEQ ID NO: 23 of the present disclosure], which is characterized by unique in vitro and in vivo biological properties (see, for example, the United States Patent No. 8,058,229). Compared to the corresponding sample of the unmodified fusion protein (ActRIIB(20-134)-Fc fusion protein), the ActRIIB(L79D 20-134)-Fc variant is characterized in part by the substantial loss of binding to Activin A The affinity, and therefore the ability to antagonize the activity of Activin A, is significantly reduced, but the binding and inhibition of GD...

Embodiment 2

[0456] Example 2: Bioassay of GDF-11, GDF-8, Activin B, Activin C, and Activin E-mediated signal transduction set

[0457] The A-204 reporter gene assay was used to evaluate the effect of anti-GDF11 / activin B bispecific antibodies on signal transduction via GDF11, activin B, activin A, and / or GDF8. This assay has previously been described in the art (see, for example, US Patent Application No. 2013 / 0243743). In short, the A-204 reporter gene assay uses the human rhabdomyosarcoma cell line (which has been taken from muscle) and the reporter vector pGL3(CAGA)12, as described in Dennler et al. (1998) EMBO 17: 3091-3100 Narrated. The CAGA12 motif is present in TGF-β response genes (for example, PAI-1 gene), so this vector is commonly used for signal transduction through Smad2 and 3 factors (for example, GDF11, activin B, activin A, and GDF8).

[0458] On day 1, transfer A-204 cells to one or more 48-well plates. On the second day, these A-204 cells were transfected with 10 µg pGL3...

Embodiment 3

[0460] Example 3: Treatment with anti-GDF11 / anti-activin B bispecific antibody

[0461] Nineteen-week-old male C57BL / 6NTac mice were randomly assigned to one of two groups. Mice were administered vehicle (10 mM Tris buffered saline, TBS) or anti-GDF11 / anti-activin B bispecific antibody by subcutaneous injection twice a week for three weeks. Blood was collected after the baseline and three weeks of administration. A blood analyzer (for example, HM2, Abaxis, Inc.) will be used to analyze the cell distribution of the blood sample. Specifically, changes in red blood cell parameters of mice will be monitored, including, for example, red blood cell count (RBC), hemoglobin (HGB), and hematocrit (HCT).

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Abstract

In certain aspects, the present disclosure provides compositions and methods for increasing red blood cell and / or hemoglobin levels in a subject in need thereof comprising administering an effective amount of an agent / s that inhibits activin B and / or GDF11. Subjects in need include, for example, subject having an anemia and subjects have an ineffective erythropoiesis disorder.

Description

[0001] Cross references to related applications [0002] This application claims the rights of US provisional patent application serial number 61 / 969,073 filed on March 21, 2014 and US provisional patent application serial number 62 / 021,923 filed on July 8, 2014. The entire teachings of the above-referenced patent applications are incorporated herein by reference. [0003] Background of the invention [0004] Mature red blood cells (erythrocytes) are responsible for oxygen transport in the circulatory system of vertebrates. Red blood cells contain high concentrations of hemoglobin, which is relatively high in oxygen partial pressure (pO 2 ) Combines oxygen and delivers oxygen to the body with relatively low pO 2 Area. [0005] Mature red blood cells are produced by pluripotent hematopoietic stem cells in a process called erythropoiesis. Acquired erythropoiesis is mainly carried out in the bone marrow and red pulp of the spleen. The synergy of various signaling pathways controls the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/18A61K39/395A61K31/7088A61P7/06
CPCA61K45/06C07K16/22A61K2039/505A61K2039/507C07K2317/31C07K2317/75C07K2319/30C07K2319/33A61K39/3955A61P7/06C07K14/71C07K2317/76
Inventor R.库马N.V.S.R.苏拉加尼J.克诺普夫
Owner ACCELERON PHARMA INC
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