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Modified transferrin fusion proteins

A technology of fusion protein and transferrin, which is applied in the direction of hybrid peptides, non-active ingredients of polymer compounds, peptides, etc., and can solve problems such as unmodified or modified

Inactive Publication Date: 2009-09-02
BIOREXIS PHARMA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] However, transferrin fusion proteins have not been modified or engineered to extend the serum half-life of therapeutic proteins or peptides, or to increase bioavailability by reducing or inhibiting glycosylation of Tf components, or to reduce or prevent iron and / or or Tf receptor binding

Method used

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  • Modified transferrin fusion proteins
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  • Modified transferrin fusion proteins

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0600] By fusing one or more copies of the nucleotide sequence encoding the anti-fusion HIV-1 peptide (T-20) with the nucleotide sequence of TF, a fusion protein containing the modified Tf of the sequence and the peptide is prepared, The resulting fusion protein has a peptide fused to the N- or C-terminus of Tf.

[0601] In one embodiment, the Tf portion of the fusion protein is engineered so that it is not glycosylated when produced in yeast. As mentioned above, human transferrin has two N-linked glycosylation sites at approximately N413 and approximately N611. N-linked glycosylation sites contain the sequence N-X-S / T. In one embodiment, N(Asn) is changed to Q(Gln); other changes can also be made, such as Asn to Ala or Ser to any other amino acid.

[0602] Specifically, N413 and N611 codons were converted to GAT and GAC by oligonucleotide-directed mutagenesis using the dut- and ung-method. See Kunkel et al. (1985) Proc. Natl. Acad. Sci. 82:488-492. Mutagenic oligonucleoti...

Embodiment 2

[0645] INGAP fusions were prepared using the reverse translated human INGAP amino acid sequence. 蛋白质序列如下:sp|Q92778|PBCG_HUMAN Human INGAPMMLPMTLCRMSWMLLSCLMFLSWVEGEESQKKLPSSRITCPQGSVAYGSYCYSLILIPQTWSNAELSCQMHFSGHLAFLLSTGEITFVSSLVKNSLTAYQYIW[IGLHDPSHGTLPNG]GWKWSSSNVLTFYNWERNPSIAADRGYCAVLSQKSGFQKWRDFNCENELPYICKFKV(SEQ ID NO:17)

[0646] Back translation into DNA (codons optimal for yeast) gave the following sequences (SEQ ID NO: 18 and 19).

[0647] 1 atgatgttgc caatgacttt gtgtagaatg tcttggatgt tgttgtcttg tttgatgttt

[0648] m m l p m t l c r m s w m l l s c l m f

[0649] 61 ttgtcttggg ttgaaggtga agaatctcaa aaaaaa ttgc catcttctag aattacttgt

[0650] l s w v e g e e s q k k l p s s r i t c

[0651] 121 ccacaaggtt ctgttgctta tggttcttat tgttattctt tgattttgat tccacaaact

[0652] p q g s v a y g s y c y s l i l i p q t

[0653] 181 tggtctaatg ctgaattgtc ttgtcaaatg catttttctg gtcatttggc ttttttgttg

[0654] w s n a e l s c q m h f s g h l a f l l

[0...

Embodiment 3

[0732] The peptides given below have been shown to mimic EPO activity by causing dimerization of the EPO receptor. The cyclic peptide has no homology to EPO. To be active, the peptide has to act with another peptide (ie as a dimer) so that the two copies of the receptor come close enough to form an active complex. For many peptides, peptide dimers have only a short half-life, which could benefit from an extended half-life by fusion with transferrin. In this example, two peptides were added to the transferrin backbone.

[0733] 1 ggtggtactt actcttgtca ttttggtcca ttgacttggg tttgtaagcc acaaggtggt

[0734] g g t y s c h f g p l t w v c k p q g g g SEQ ID NOS: 24 and 25.

[0735] Peptides could be successfully added between His289 and Gly290 of transferrin as described in detail by Ali et al. The inherent repeat of the transferrin molecule (two domains mirroring each other) means that the peptide can be inserted between Glu625 and Thr626 in the repeat region of the C doma...

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Abstract

Modified fusion proteins of transferrin and therapeutic proteins or peptides with increased serum half-life or serum stability are disclosed. Preferred fusion proteins include those modified so that the transferrin moiety exhibits no or reduced glycosylation, binding to iron and / or binding to the transferrin receptor.

Description

[0001] This case is a divisional application of an invention application with a filing date of August 30, 2002, a Chinese application number of 02821637.7, and an invention title of "modified transferrin fusion protein". [0002] related application [0003] This application claims priority to US Provisional Application 60 / 315,745, filed August 30, 2001, and US Provisional Application 60 / 334,059, filed November 30, 2001, both of which are incorporated herein by reference in their entireties. technical field [0004] The present invention relates to therapeutic proteins or peptides with increased serum stability or increased serum half-life, in particular therapeutic proteins or peptides fused to or inserted into transferrin molecules which are modified so as to reduce or Glycosylation, iron binding and / or transferrin receptor binding are inhibited. Background technique [0005] Therapeutic proteins or peptides in their native state or recombinantly produced are generally un...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K19/00A01KA61KA61K47/42C07HC07KC12NC12P
Inventor 克里斯托弗·P·普赖尔
Owner BIOREXIS PHARMA CORP
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