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Methods for dosing an activin-actriia antagonist and monitoring of treated patients

a technology of activin-actriia and activin-actriia, which is applied in the field of monitoring of treated patients, can solve problems such as increased blood pressure or other undesirable side effects, and achieve the effects of increasing red blood cell and hemoglobin levels, increasing bone density, and increasing red blood cell levels

Inactive Publication Date: 2010-01-21
ACCELERON PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes methods for administering activin antagonists to patients to treat anemia and bone loss. These antagonists can increase red blood cell levels and bone density, but they can also have negative effects on red blood cells and hemoglobin levels. The disclosure provides methods for managing patients who have been treated with activin antagonists by monitoring hematologic parameters that correlate with an increase in red blood cell levels, such as blood pressure and iron stores. The patent also describes a soluble ActRIIa polypeptide that can be used as a pharmaceutical preparation to treat anemia and bone loss. The ActRIIa polypeptide has been shown to have a high degree of selectivity for activin inhibition over other proteins.

Problems solved by technology

For example, excessive increases in red blood cell levels, hemoglobin levels, or hematocrit levels may cause increases in blood pressure or other undesirable side effects.

Method used

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  • Methods for dosing an activin-actriia antagonist and monitoring of treated patients
  • Methods for dosing an activin-actriia antagonist and monitoring of treated patients
  • Methods for dosing an activin-actriia antagonist and monitoring of treated patients

Examples

Experimental program
Comparison scheme
Effect test

example 1

ActRIIa-Fc Fusion Proteins

[0142]Applicants constructed a soluble ActRIIa fusion protein that has the extracellular domain of human ActRIIa fused to a human or mouse Fc domain with a minimal linker in between. The constructs are referred to as ActRIIa-hFc and ActRIIa-mFc, respectively.

[0143]ActRIIa-hFc is shown below as purified from CHO cell lines (SEQ ID NO: 7):

ILGRSETQECLFFNANWEKDRTNQTGVEPCYGDKDKRRHCFATWKNISGSIEIVKQGCWLDDINCYDRTDCVEKKDSPEVYFCCCEGNMCNEKFSYFPEMEVTQPTSNPVTPKPPTGGGTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI

[0144]The ActRIIa-hFc and ActRIIa-mFc proteins were expressed in CHO cell lines. Three different leader sequences were considered:

(i) Honey bee mellitin (HBML):MKFLVNVALVFMVVYISYLYA(SEQ ID NO: 8)(ii) Tissue Plasminogen Activator (TPA):MDAMKRGLCCVLLLCGAVFVSP(SEQ ID NO: 9)(iii) Native:MGAAAKLAFAVFLISCSSGA.(SEQ ID NO: 10)

[0145]The selected form employs the TPA leader and has the following unprocessed amino acid sequence:

(SEQ ID NO:13)MDAMKRGLCCVLLLCGAVFVSPGAAILGRSETQECLFFNANWEKDRT...

example 2

Characterization of an ActRIIa-hFc Protein

[0150]ActRIIa-hFc fusion protein was expressed in stably transfected CHO-DUKX B11 cells from a pAID4 vector (SV40 ori / enhancer, CMV promoter), using a tissue plasminogen leader sequence of SEQ ID NO:9. The protein, purified as described above in Example 1, had a sequence of SEQ ID NO:7. The Fc portion is a human IgG1 Fc sequence, as shown in SEQ ID NO:7. Sialic acid analysis showed that the protein contained, on average, between about 1.5 and 2.5 moles of sialic acid per molecule of ActRIIa-hFc fusion protein.

[0151]This purified protein showed a remarkably long serum half-life in all animals tested, including a half-life of 25-32 days in human patients (see Example 6, below). Additionally, the CHO cell expressed material has a higher affinity for activin B ligand than that reported for an ActRIIa-hFc fusion protein expressed in human 293 cells (del Re et al., J Biol Chem. Dec. 17, 2004;279(51):53126-35.) Additionally, the use of the tPa lead...

example 3

ActRIIa-hFc Increases Red Blood Cell Levels in Non-Human Primates

[0152]The study employed four groups of five male and five female cynomolgus monkeys each, with three per sex per group scheduled for termination on Day 29, and two per sex per group scheduled for termination on Day 57. Each animal was administered the vehicle (Group I) or ActRIIa-Fc at doses of 1, 10, or 30 mg / kg (Groups 2, 3 and 4, respectively) via intravenous (IV) injection on Days 1, 8, 15 and 22. The dose volume was maintained at 3 mL / kg. Various measures of red blood cell levels were assessed two days prior to the first administration and at days 15, 29 and 57 (for the remaining two animals) after the first administration.

[0153]The ActRIIa-hFc caused statistically significant increases in mean red blood cell parameters (red blood cell count [RBC], hemoglobin [HGB], and hematocrit [HCT]) for males and females, at all dose levels and time points throughout the study, with accompanying elevations in absolute and re...

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Abstract

In certain aspects, the present invention provides methods for dosing a patient with an activin-ActRIIa antagonist and methods for managing patients treated with an activin-ActRIIa anatagonist. In certain aspects, the methods involve measuring one or more hematologic parameters in a patient.

Description

RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 133,354, filed on Jun. 26, 2008, the specification of which is incorporated by reference herein in its entirety.BACKGROUND OF THE INVENTION[0002]The transforming growth factor-beta (TGF-beta) superfamily contains a variety of growth factors that share common sequence elements and structural motifs. These proteins are known to exert biological effects on a large variety of cell types in both vertebrates and invertebrates. Members of the superfamily perform important functions during embryonic development in pattern formation and tissue specification and can influence a variety of differentiation processes, including adipogenesis, myogenesis, chondrogenesis, cardiogenesis, hematopoiesis, neurogenesis, and epithelial cell differentiation. The family is divided into two general branches: the BMP / GDF and the TGF-beta / Activin / BMP10 branches, whose members have diverse, often complementary ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395C12Q1/02G01N33/20A61K38/16G01N33/72G01N33/68A61P19/08A61P35/00A61B5/021
CPCA61K38/1796C07K14/72C07K2319/30G01N2800/52G01N33/80G01N33/90G01N33/721A61P19/00A61P7/06A61K38/22G01N2333/79G01N2333/47C07K14/475
Inventor SHERMAN, MATTHEW L.BORGSTEIN, NIELS
Owner ACCELERON PHARMA INC
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