Methods for dosing an actriib antagonist and monitoring of treated patients

a technology of actriib and tgfbeta, which is applied in the field of superfamily of transforming growth factorbeta, can solve the problems of increasing blood pressure or other undesirable side effects, and achieve the effects of increasing red blood cell and hemoglobin levels, promoting muscle growth or bone growth, and increasing reticulocyte levels

Inactive Publication Date: 2010-01-14
ACCELERON PHARMA INC
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Benefits of technology

[0004]In part, the disclosure related to methods for administering ActRIIB antagonists to patients in a manner that is appropriate given the effects that such antagonists can have on a variety of tissues, including red blood cells. In some embodiments, the disclosure provides ActRIIb antagonists can increase red blood cell and hemoglobin levels and also promote muscle growth or bone growth. This dual effect has particular advantages in patients that have both anemia and muscle or bone loss, such as many cancer patients (where anemia and muscle loss can be a consequence of the tumor or a consequence of irradiation or chemotherapy), many forms of cachexia, sarcopenia (muscle loss associated with aging). In particular, the disclosure demonstrates that a soluble form of ActRIIb is effective to increase reticulocyte levels in vivo, an effect which over a longer time period is expected to cause increased hematocrit levels. While soluble ActRIIb may affect reticulocyte levels through a mechanism other than ActRIIb antagonism, the disclosure nonetheless demonstrates that desirable therapeutic agents may be selected on the basis of ActRIIb antagonism. The term ActRIIb antagonist is used herein to indicate soluble ActRIIb polypeptides (e.g., ActR

Problems solved by technology

For example, excessive increases in red blood cell levels, hemoglobin levels, or hema

Method used

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  • Methods for dosing an actriib antagonist and monitoring of treated patients
  • Methods for dosing an actriib antagonist and monitoring of treated patients

Examples

Experimental program
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Effect test

example 1

Generation of ActRIIb-Fc Fusion Proteins

[0126]Applicants constructed a soluble ActRIIb fusion protein that has the extracellular domain of human ActRIIb fused to a human or mouse Fc domain with a minimal linker (three glycine amino acids) in between. The constructs are referred to as ActRIIb-hFc and ActRIIb-mFc, respectively.

[0127]ActRIIb-hFc is shown below as purified from CHO cell lines (SEQ ID NO: 8):

GRGEAETRECIYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCWLDDFNCYDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPTAPTGGGTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR

[0128]The ActRIIb-hFc and ActRIIb-mFc proteins were expressed in CHO cell lines. Three different leader sequences were considered:

(i) Honey bee mellitin (HBML):MKFLVNVALVFMVVYISYIYA;(SEQ ID NO: 11)(ii) Tissue Plasminogen Activator (TPA):MDAMKRGLCCVLLLCGAVFVSP;(SEQ ID NO: 12)and(iii) Native:MGAAAKLAFAVFLISCSSGA.(SEQ ID NO: 13)

[0129]The selected form employs the TPA leader and has the following unprocessed amino acid sequence (SEQ ID NO: ...

example 2

ActRIIb-hFc Stimulates Erythropoiesis in Non-Human Primates

[0139]ActRIIb-hFc (IgG1) was administered once a week for 1-month to male and female cynomolgus monkeys by subcutaneous injection. Forty-eight cynomolgus monkeys (24 / sex) were assigned to one of four treatment groups (6 animals / sex / group) and were administered subcutaneous injections of either vehicle or ActRIIb-hFc at 3, 10, or 30 mg / kg once weekly for 4 weeks (total of 5 doses). Parameters evaluated included general clinical pathology (hematology, clinical chemistry, coagulation, and urinalysis). ActRIIb-hFc caused statistically significant elevated mean absolute reticulocyte values by day 15 in treated animals. By day 36, ActRIIb-hFc caused several hematological changes, including elevated mean absolute reticulocyte and red blood cell distribution width values and lower mean corpuscular hemoglobin concentration. All treated groups and both sexes were affected. These effects are consistent with a positive effect of ActRIIb...

example 3

ActRIIb-mFc Promotes Aspects of Erythropoiesis in Mice by Stimulation of Splenic Erythropoietic Activities

[0140]In this study the effects of the in vivo administration of ActRIIb-mFc on the frequency of hematopoietic progenitors in bone marrow and spleen was analyzed. One group of Black6 mice was injected with PBS as a control and a second group of mice administered two doses of ActRIIb-mFc at 10 mg / kg and both groups sacrificed after 8 days. Peripheral blood was used to perform complete blood counts and femurs and spleens were used to perform in vitro clonogenic assays to assess the lymphoid, erythroid and myeloid progenitor cell content in each organ. In the brief time frame of this study, no significant changes were seen in red blood cell, hemoglobin or white blood cell levels in treated mice. In the femurs there was no difference in the nucleated cell numbers or progenitor content between the control and treated groups. In the spleens, the compound treated group experienced a st...

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Abstract

In certain aspects, the present invention provides methods for dosing a patient with an ActRIIb antagonist and methods for managing patients treated with an ActRIIb 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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IPC IPC(8): A61K39/395C12Q1/02G01N33/20A61K38/16A61P21/00A61P19/00
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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