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

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 ...

AI Technical Summary

Benefits of technology

[0004]In part, the disclosure relates to methods for administering activin antagonists, as well as ActRIIa antagonists (collectively, “activin-ActRIIa 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 part, the disclosure demonstrates that activin-ActRIIa antagonists can increase red blood cell and hemoglobin levels and also increase bone density. This dual effect has particular advantages in patients that have both anemia and bone loss, such as many cancer patients (where anemia and bone loss can be a consequence of the tumor or a consequence of irradiation or chemotherapy), patients with osteoporosis and patients with renal failure. In particular, the disclosure demonstrates that a soluble form of ActRIIa acts as an inhibitor of activin and, when administered in vivo, increases red blood cell levels. While soluble ActRIIa may affect red blood cell levels through a mechanism other than activin antagonism, the disclosure nonetheless demonstrates that desirable therapeutic agents may be selected on the basis of activin antagonism or ActRIIa antagonism or both. Such agents are referred to collectively as activin-ActRIIa antagonists. As described herein, and in published patent applications WO / 2009 / 038745, WO / 2008 / 100384, WO / 2008 / 094708, WO / 2008 / 076437, WO / 2007 / 062188 and WO / 2006 / 012627, activin-ActRIIa antagonists also have a variety of other therapeutic uses including, for example, promoting bone growth, decreasing FSH levels, treating multiple myeloma and treating breast cancer. In certain instances, when administering an activin-ActRIIa antagonists for promoting bone growth or treating breast cancer, it may be desirable to monitor the effects on red blood cells during administration of an activin-ActRIIa antagonists, or to determine or adjust the dosing of an activin-ActRIIa antagonists, in order to reduce undesired effects on red blood cells. 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. It may also be desirable to restrict dosing of activin-ActRIIa antagonists to patients who have appropriate hematologic parameters. For example, it may be desirable to limit dosing to only those patients who have a hemoglobin level below normal (e.g., below 12 g / dL, below 11 g / dL, below 10 g / dL or below 9 g / dL or lower).

[0008]An activin-binding ActRIIa polypeptide may be a fusion protein that has, as one domain, an ActRIIa polypeptide, (e.g., a ligand-binding portion of an ActRIIa) and one or more additional domains that provide a desirable property, such as improved pharmacokinetics, easier purification, targeting to particular tissues, etc. For example, a domain of a fusion protein may enhance one or more of in vivo stability, in vivo half life, uptake / administration, tissue localization or distribution, formation of protein complexes, multimerization of the fusion protein, and / or purification. An activin-binding ActRIIa fusion protein may include an immunoglobulin Fc domain (wild-type or mutant) or a serum albumin or other polypeptide portion that provides desirable properties such as improved pharmacokinetics, improved solubility or improved stability. In a preferred embodiment, an ActRIIa-Fc fusion comprises a relatively unstructured linker positioned between the Fc domain and the extracellular ActRIIa domain. This unstructured linker may be an artificial sequence of 1, 2, 3, 4 or 5 amino acids or a length of between 5 and 15, 20, 30, 50 or more amino acids that are relatively free of secondary structure, or a mixture of both. A linker may be rich in glycine and proline residues and may, for example, contain a single sequence of threonine / serine and glycines or repeating sequences of threonine / serine and glycines (e.g., TG4 (SEQ ID NO: 15) or SG4 (SEQ ID NO: 16) singlets or repeats). A fusion protein may include a purification subsequence, such as an epitope tag, a FLAG tag, a polyhistidine sequence, and a GST fusion. Optionally, a soluble ActRIIa polypeptide includes one or more modified amino acid residues selected from: a glycosylated amino acid, a PEGylated amino acid, a famesylated amino acid, an acetylated amino acid, a biotinylated amino acid, an amino acid conjugated to a lipid moiety, and an amino acid conjugated to an organic derivatizing agent. A pharmaceutical preparation may also include one or more additional compounds such as a compound that is used to treat a bone disorder or a compound that is used to treat anemia. Preferably, a pharmaceutical preparation is substantially pyrogen free. In general, it is preferable that an ActRIIa protein be expressed in a mammalian cell line that mediates suitably natural glycosylation of the ActRIIa protein so as to diminish the likelihood of an unfavorable immune response in a patient. Human and CHO cell lines have been used successfully, and it is expected that other common mammalian expression systems will be useful.

[0012]In certain aspects, the disclosure provides a method for dosing a patient with an activin-ActRIIa antagonist, comprising dosing the patient in amounts and at intervals selected so as to reduce the risk of causing a rise in hemoglobin levels greater than 0.5 g / dL, 1 g / dl or 1.5 g / dL in two weeks.

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.

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