37 results about "Tgf β superfamily" patented technology

The invention provides hetero-multivalent ligand binging agents (traps) for members of the TGF-β superfamily, as well as methods for making and using such constructs. In an embodiment of the invention there is provided a hetero-multivalent binding agent with affinity for a member of the TGF-β superfamily, said agent comprising the general structure (I): (<bd1>-linker1)_k-[{<bd1>-linker2-<bd2>-linker3_r-}_n-(<bd3>)_m-(linker4-<bd4>)_d]_h, where bd1, bd2, bd3 and bd4 are polypeptide binding domains having an affinity for different sites on the same member or for different members of the TGF-β superfamily, wherein at least two of bd1, bd2, bd3, and bd4 are different from each other.

In accordance with the present invention, there are provided novel receptor proteins characterized by having the following domains, reading from the N-terminal end of said protein: an extracellular, ligand-binding domain, a hydrophobic, trans-membrane domain, and an intracellular, receptor domain having serine kinase-like activity. The invention receptors optionally further comprise a second hydrophobic domain at the amino terminus thereof. The invention receptor proteins are further characterized by having sufficient binding affinity for at least one member of the activin/TGF-β superfamily of polypeptide growth factors such that concentrations of ≦10 nM of said polypeptide growth factor occupy ≦50% of the binding sites of said receptor protein. A presently preferred member of the invention superfamily of receptors binds specifically to activins, in preference to inhibins, transforming growth factor-β, and other non-activin-like proteins. DNA sequences encoding such receptors, assays employing same, as well as antibodies derived therefrom, are also disclosed.

The present invention provides methods for the treatment, and pharmaceuticals for use in the treatment, of mammalian subjects in, or at risk of chronic renal failure, or at risk of a need for renal replacement therapy. The methods involve the administration of certain proteins of, or based upon, the osteogenic protein/bone morphogenetic protein (OP/BMP) family within the TGF-β superfamily of proteins.

The present invention provides methods for the treatment, and pharmaceuticals for use in the treatment, of mammalian subjects in, or at risk of, acute renal failure, or subject to, or at risk of, inflammation, neutrophil-mediated cell damage, and apoptosis resulting from tissue damage or injury. The methods involve the administration of certain proteins of the osteogenic protein/bone morphogenetic protein (OP/BMP) family within the TGF-β superfamily of proteins.

In certain aspects, the present disclosure provides compositions and methods for inhibiting activity of TGFβ superfamily ligands, particularly ligands such as GDF8, GDF11, activin A, activin B, activin C and activin E, in vertebrates, including rodents and primates, and particularly in humans. In some embodiments, the compositions of the disclosure may be used to treat or prevent diseases or disorders that are associated with abnormal activity of a follistatin-related polypeptide and/or a follistatin ligand.

The present invention provides formulations of cysteine knot proteins, including TGF-β superfamily proteins and bone morphogenic proteins that are pH stabilized. In particular, the present invention relates to the observation that certain buffers enhance the stability of cysteine knot proteins, including TGF-β superfamily proteins and bone morphogenic proteins. In particular, disclosed herein are liquid and lyophilized formulations prepared with a glycylglycine and tartaric acid buffers to stabilize the pH of the formulation.

The invention provides modified proteins and DNAs of the TGF-β superfamily including modified morphogenic proteins. The proteins of the present invention display altered biological or biochemical attributes. Specifically, the modified proteins are designed through manipulation or exchange of subdomains among two or more members of the superfamily such that certain desired attributes are mixed-and-matched and then exploited therapeutically.

Members of the TGF-β superfamily and peptide fragments based on member proteins are employed to purify solutions containing member proteins or as therapeutics.

Fish sexual characteristics are determined by measuring the concentration in fish serum, plasma or whole blood of one or more peptide hormones of the transforming growth factor-beta superfamily (TGF-β superfamily). The disclosed method and an accompanying field test kit may be used in sturgeon aquaculture to cull out young male fish so that increased time and resources may be devoted to the further rearing of female fish for caviar production. The method and test kit may also be used for wild fish life history studies.

Disclosed are aryl pyrimidine compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structure (I) and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein A, Z, R and R′ are as described herein. In certain embodiments, a compound disclosed herein inhibits the activity of one or more members of the TGF-β superfamily, and can be used to treat disease by blocking such activity.

The invention provides multivalent ligand binging agents (traps) for members of the TGF-β superfamily and polypeptide linkers and methods for making and using such constructs. In an embodiment of the invention there is provided a multivalent binding agent with affinity for a member of the TGF-β superfamily, said agent comprising the general structure I: (<bd1>-linker1)_k-[{bd1>-linker2-<bd2>-linker3_f-}_n-(<bd3>)_m-(linker4-<bd4>)_d]_h, where: -n and h are independently greater than or equal to 1; -d, f, m and k arc independently equal to or greater than zero; -bd1, bd2, bd3 and bd4 are polypeptide binding domains having an affinity for the same member of the TGF-β superfamily, with bd1, bd2, bd3, and bd4 being independently the same or different from each other; and, -linkeri, linker2, linker3 and linker4 are unstructured polypeptide sequences; wherein the number of amino acids in each linker is determined independently and is greater than or equal to X/2.5; where, X equals the shortest linear distance between: (a) the C-terminus of an isolated form of the binding domain that is located at the N-terminus of the linker and that is specifically bound to its ligand; and, (b) the N-terminus of an isolated form of the binding domain that is located at the C-terminus of the linker and that is specifically bound to its ligand.

The present invention is directed to methods and compositions for accomplishing systemic delivery of minimally-soluble bioactive agents such as, but not limited to, proteins of the TGF-β superfamily via a peripheral mode of administration. According to the invention, an exemplary bioactive agent is BMP-7. The invention further provides for minimally-invasive systemic treatment of skeletal disorders such as osteoporosis as well as minimally-invasive systemic treatment of injured or diseased non-mineralized tissues and organs such kidneys. Practice of the invention eliminates adverse side effects at the peripheral site of intravenous administration of the bioactive agent.

Disclosed are pyrazole compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structure and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein A, X, Z, m, p, and R² are as described herein. In certain embodiments, a compound disclosed herein inhibits the activity of one or more members of the TGF-β superfamily, and can be used to treat disease by blocking such activity.

The invention provides novel compositions comprising a Smad protein and an isolated protein component of the proteasome-mediated degradation pathway. The invention also provides novel compositions comprising a Smad1 protein and a substrate for proteasome-mediated degradation. The invention also provides methods of screening for compounds that modulate the interaction between the proteins comprising these compositions. The invention also provides methods of screening for compounds that modulate the activity of the proteins comprising these compositions. The invention also provides methods of detecting proteasome-mediated degradation of novel Smad interacting proteins. A further aspect of the invention is a kit for detecting proteasome-mediated degradation of novel Smad interacting proteins. The invention also provides methods of treating diseases which are associated with aberrant levels of activity of a TGF-β superfamily member.