Methods and compositions for treating myelofibrosis

a technology of compositions and myelofibrosis, applied in the field of methods and compositions for treating myelofibrosis, can solve the problems of unmet needs for effective therapies, high treatment-related mortality, and many other currently available treatments that are not effective in reversing the process of myelofibrosis, and achieve the effects of reducing splenomegaly, fibrosis, and extramedullary hematopoiesis

Inactive Publication Date: 2018-02-22
ACCELERON PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0005]In part, the present disclosure relates to the discovery that an ActRIIB antagonist (inhibitor) can be used to treat myelofibrosis, particularly ameliorating various complications of the disease including, for example, splenomegaly, extramedullary hematopoiesis, and fibrosis. In particular, the data presented herein show that a GDF trap polypeptide decrease splenomegaly, extramedullary hematopoiesis, and fibrosis in a JAK2V617F model of myelofibrosis. Accordingly, in certain aspects, the disclosure relates to compositions and methods for treating myelofibrosis, particularly treating or preventing one or more complications of myelofibrosis (e.g., splenomegaly, extramedullary hematopoiesis, anemia, and fibrosis), by administering to a patient in need thereof an effective amount of one or more ActRIIB antagonists, optionally in combination of one or more other supportive therapies or active agents for treating myelofibrosis. While GDF trap polypeptides may affect myelofibrosis through a mechanism other than ActRIIB antagonism [e.g., inhibition of one or more of GDF11, GDF8, activin B, BMP6, GDF3, and BMP10 may be an indicator of the tende...

Problems solved by technology

However, treatment-related mortality is high, and only a minority of patients qualify for transplantation.
Many of other currently available treatments are not effe...

Method used

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  • Methods and compositions for treating myelofibrosis
  • Methods and compositions for treating myelofibrosis
  • Methods and compositions for treating myelofibrosis

Examples

Experimental program
Comparison scheme
Effect test

example 1

n of ActRIIB-Fc Fusion Proteins

[0275]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-Fc, respectively.

[0276]ActRIIB-hFc is shown below as purified from CHO cell lines (SEQ ID NO: 24):

GRGEAETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCWLDDENCYDRQECVATEENPQVYFCCCEGNECNERFTHLPEAGGPEVTYEPPPTAPTGGGTHTCPPCPAPELLGGPSVFLEPPKPKDTLMIS

[0277]The ActRIIB-hFc and ActRIIB-Fc proteins were expressed in CHO cell lines. Three different leader sequences were considered: (i) Honey bee mellitin (HBML):

(SEQ ID NO: 21)MKFLVNVALVFMVVYISYIYA,

ii) Tissue plasminogen activator (TPA):

(SEQ ID NO: 22)MDAMKRGLCCVLLLCGAVFVSP,

and (iii) Native:

(SEQ ID NO: 23)MGAAAKLAFAVFLISCSSGA.

[0278]The selected form employs the TPA leader and has the following unprocessed amino acid sequence (SEQ ID NO: 25):

MDAMK...

example 2

n of a GDF Trap

[0292]Applicants constructed a GDF trap as follows. A polypeptide having a modified extracellular domain of ActRIIB (amino acids 20-134 of SEQ ID NO: 1 with an L79D substitution) with greatly reduced activin A binding relative to GDF11 and / or myostatin (as a consequence of a leucine-to-aspartate substitution at position 79 in SEQ ID NO:1) was 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(L79D 20-134)-hFc and ActRIIB(L79D 20-134)-Fc, respectively. Alternative forms with a glutamate rather than an aspartate at position 79 performed similarly (L79E). Alternative forms with an alanine rather than a valine at position 226 with respect to SEQ ID NO: 44, below were also generated and performed equivalently in all respects tested. The aspartate at position 79 (relative to SEQ ID NO: 1, or position 60 relative to SEQ ID NO: 29) is indicated with double underlining below. The valine at...

example 3

for GDF-11- and Activin-Mediated Signaling

[0300]An A-204 reporter gene assay was used to evaluate the effects of ActRIIB-Fc proteins and GDF traps on signaling by GDF-11 and activin A. Cell line: human rhabdomyosarcoma (derived from muscle). Reporter vector: pGL3(CAGA)12 (described in Dennler et al, 1998, EMBO 17: 3091-3100). The CAGA12 motif is present in TGF-beta responsive genes (e.g., PAI-1 gene), so this vector is of general use for factors signaling through SMAD2 and 3.

[0301]Day 1: Split A-204 cells into 48-well plate.

[0302]Day 2: A-204 cells transfected with 10 ug pGL3(CAGA)12 or pGL3(CAGA)12(10 ug)+pRLCMV (1 μg) and Fugene.

[0303]Day 3: Add factors (diluted into medium+0.1% BSA). Inhibitors need to be preincubated with factors for 1 hr before adding to cells. Six hrs later, cells were rinsed with PBS and lysed.

[0304]This is followed by a luciferase assay. In the absence of any inhibitors, activin A showed 10-fold stimulation of reporter gene expression and an ED50˜2 ng / ml. GD...

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Abstract

In part, the present disclosure relates methods for treating, preventing, or reducing the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis (extramedullary hematopoiesis, splenomegaly, anemia, and fibrosis). In certain aspects, the disclosure provides ActRIIB antagonists for use in treating, preventing, or reducing the progression rate and/or severity of one or more complications associated with Janus kinase inhibitor therapy in a patient (e.g., anemia).

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of priority to U.S. provisional application Ser. No. 62 / 367,289, filed on Jul. 27, 2016. The disclosure of the foregoing application is hereby incorporated by reference in its entirety.BACKGROUND OF THE INVENTION[0002]Myelofibrosis is a rare disease mainly affecting people of older age. Myelofibrosis is a BCR-ABL1-negative myeloproliferative neoplasm that presents de novo (primary) or may be preceded by polycythemia vera (post-polycythemia vera) or essential thrombocythemia (post-essential thrombocythemia). Clinical features include progressive anemia, marked splenomegaly, fibrosis (e.g., bone marrow fibrosis), constitutional symptoms (e.g., fatigue, night sweats, bone pain, pruritus, and cough), and weight loss [Tefferi A (2000) N Engl J Med 342:1255-1265]. Median survival ranges from less than 2 years to over 15 years based on currently identified prognostic factors. Mutations involving JAK2, MPL, TET...

Claims

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Application Information

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IPC IPC(8): A61K38/17A61K31/519
CPCA61K38/179A61K31/519C07K2319/30A61P7/06A61P7/00C07K14/71A61K38/1796A61K45/06A61K2300/00A61K31/155A61K38/17A61K39/3955A61K2039/505
Inventor KUMAR, RAVINDRAVENKATA SAI RAJASEKHAR SURAGANI, NAGA
Owner ACCELERON PHARMA INC
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