US2003195154A1PendingUtilityA1

Use of transthyretin peptide/protein fusions to increase the serum half-life of pharmacologically active peptides/proteins

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Priority: Apr 4, 2002Filed: Apr 3, 2003Published: Oct 16, 2003
Est. expiryApr 4, 2022(expired)· nominal 20-yr term from priority
Inventors:Kenneth W. WalkerFei Xiong
A61K 38/20A61K 47/61A61P 7/04A61K 38/29A61P 5/18A61P 3/10C07K 14/47A61P 9/12A61K 47/58A61K 47/60A61K 47/643A61K 38/10C07K 2319/31A61K 38/043
59
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Claims

Abstract

The present invention provides a means for increasing the serum half-life of a selected biologically active agent by utilizing transthyretin (TTR) as a fusion partner with a biologically active agent. Specifically, the present invention provides substantially homogenous preparations of TTR (or a TTR variant)-biologically active agent fusions and PEG-TTR (PEG-TTR variant)-biologically active agent fusions. As compared to the biologically active agent alone, the TTR-biologically active agent fusion and/or PEG-TTR-biologically active agent fusion has substantially increased serum half-life.

Claims

exact text as granted — not AI-modified
What is claimed is:  
     
         1 . A method for increasing the serum half-life of a biologically active agent comprising fusing the biologically active agent to transthyretin (TTR) or a TTR variant.  
     
     
         2 . The method of  claim 1  where said TTR or TTR variant is chemically modified with a chemical selected from the group consisting of dextran, poly(n-vinyl pyurrolidone), polyethylene glycols, propropylene glycol homopolymers, polypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols and polyvinyl alcohols.  
     
     
         3 . The method of  claim 2  where said TTR or TTR variant is chemically modified with polyethylene glycol.  
     
     
         4 . The method of  claim 3  wherein said polyethylene glycol has a molecular weight of between about 1 kD and 100 kD.  
     
     
         5 . The method of  claim 4  wherein said polyethylene glycol has a molecular weight of between about 5 kD and 30 kD.  
     
     
         6 . The method of  claim 1  wherein said TTR is encoded by the nucleic acid of SEQ ID NO:2.  
     
     
         7 . The method of  claim 1  wherein the TTR variant is encoded by the nucleic acid of SEQ ID NO:8.  
     
     
         8 . The method of  claim 1  wherein the biologically active agent is a protein.  
     
     
         9 . The method of  claim 1  wherein the biologically active agent is a peptide.  
     
     
         10 . The method of  claim 9  wherein the peptide is a TPO mimetic peptide (TMP).  
     
     
         11 . The method of  claim 9  wherein the biologically active agent is a Glucagon-like Peptide-1 (GLP-1).  
     
     
         12 . A substantially homogenous preparation of a TTR-biologically active agent fusion, optionally in a pharmaceutically acceptable diluent, carrier or adjuvant.  
     
     
         13 . A substantially homogenous preparation of a PEG-TTR-biologically active agent fusion, optionally in a pharmaceutically acceptable diluent, carrier or adjuvant.  
     
     
         14 . The preparation of  claim 13  wherein the biologically active agent is a protein.  
     
     
         15 . The preparation of  claim 13  wherein the biologically active agent is a peptide.  
     
     
         16 . The preparation of  claim 15  wherein the peptide is a TMP.  
     
     
         17 . The preparation of  claim 15  wherein the peptide is a GLP-1.  
     
     
         18 . A substantially homogenous preparation of a TTR variant-biologically active agent fusion, optionally in a pharmaceutically acceptable diluent, carrier or adjuvant.  
     
     
         19 . A substantially homogenous preparation of a PEG-TTR variant-biologically active agent fusion, optionally in a pharmaceutically acceptable diluent, carrier or adjuvant.  
     
     
         20 . The preparation of  claim 19  wherein the biologically active agent is a protein.  
     
     
         21 . The preparation of  claim 19  wherein the biologically active agent is a peptide.  
     
     
         22 . The preparation of  claim 21  wherein the peptide is a TMP.  
     
     
         23 . The preparation of  claim 21 , wherein the peptide is GLP-1.  
     
     
         24 . The preparation of any of claims  10 - 23  wherein the fusion contains a linker peptide.  
     
     
         25 . A process for preparing a substantially homogenous preparation of a TTR-biologically active agent fusion comprising: (a) fusing said TTR to a biologically active agent to provide a TTR-biologically active agent fusion; and (b) isolating said TTR-biologically active agent fusion.  
     
     
         26 . A process for preparing a substantially homogenous preparation of a TTR variant-biologically active agent fusion comprising: (a) engineering a cysteine residue into a specific amino acid position within the amino acid sequence of said TTR to provide a variant of said TTR; (b) fusing said TTR variant to a biologically active agent to provide a TTR variant-biologically active agent fusion; and (c) isolating said TTR variant-biologically active agent fusion.  
     
     
         27 . A process for preparing a substantially homogenous preparation of a PEG-TTR-biologically active agent fusion comprising: (a) conjugating a polyethylene glycol to said TTR to provide a PEG-TTR; (b) fusing said PEG-TTR to a biologically active agent to provide a PEG-TTR-biologically active agent fusion; and (c) isolating said PEG-TTR-biologically active agent fusion.  
     
     
         28 . A process for preparing a substantially homogenous preparation of a PEG-TTR variant-biologically active agent fusion comprising: (a) engineering a cysteine residue into a specific amino acid position within the amino acid sequence of said TTR to provide a variant of said TTR; (b) conjugating a polyethylene glycol to said TTR variant at said cysteine residue to provide a PEG-TTR variant; (c) fusing said PEG-TTR variant to a biologically active agent to provide a PEG-TTR-biologically active agent fusion; and (d) isolating said PEG-TTR-biologically active agent fusion.  
     
     
         29 . A method of treating thrombocytopenia comprising administering a therapeutically effective dose of a preparation of  claim 16 .  
     
     
         30 . A method of treating thrombocytopenia comprising administering a therapeutically effective dose of a preparation of  claim 22 .  
     
     
         31 . A method of treating non-insulin dependent diabetes comprising administering a therapeutically effective dose of a preparation of  claim 17 .  
     
     
         32 . A method of treating non-insulin dependent diabetes comprising administering a therapeutically effective dose of a preparation of  claim 23 .  
     
     
         33 . A fusion protein comprising a TTR protein fused to a heterologous sequence.  
     
     
         34 . A fusion protein of  claim 33  wherein the heterologous sequence is a TMP.  
     
     
         35 . A fusion protein of  claim 33  wherein the heterologous sequence is a GLP-1.  
     
     
         36 . A fusion protein of any one of claims  33 ,  34  or  35  further comprising a linker sequence between the TTR protein and the heterologous sequence.  
     
     
         37 . A nucleic acid encoding the fusion protein of any one of claims  33 ,  34  or  35 .

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