Human interferon-beta mutein
Inventors
Shin, Young Kee • So, Moon Kyoung • Lee, Jong Min • Yang, Ji-Hye • Yoo, Ji Uk • Byun, Tae Ho • Kim, Ji Tai • Oh, Han Kyu • Yoon, Ho Chul • Ahn, Ji Soo • Song, Kyung • Jin, Jae Ho
Assignees
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Publication Number
US-8101716-B2
Publication Date
2012-01-24
Expiration Date
Abstract
The present invention relates to a human interferon-beta mutein. In particular, the present invention relates to the human interferon-beta mutein having one or two additional sugar chains compared to natural human interferon-beta.
Core Innovation
The disclosed invention relates to a human interferon-beta mutein engineered by introducing one or two additional N-linked sugar chains relative to natural human IFN-β. The mutein comprises an N-glycosylated polypeptide in which an amino acid sequence is selected using SEQ ID references, including variants in which residue 27 is replaced with Ser or Thr and/or a C-terminal sequence is added that carries an N-linked glycan motif.
The invention specifies introduced N-linked sugar chains at defined positions in the IFN-β mutein sequence, including variants carrying additional glycosylation at named asparagine residues. A representative C-terminal sequence motif is described as a glycine-asparagine-isoleucine-threonine-valine (GNITV) sequence, which is associated with the presence of an N-linked glycan at the C-terminal portion of the mutein.
The disclosed embodiments also include polynucleotide and expression system concepts for producing the IFN-β muteins, including animal-cell expression vector concepts and transformed animal cells. The description characterizes the muteins as intended to improve IFN-β activity-related properties, and experimental evidence associates increased sugar-chain variants with increased molecular weight, increased antiviral activity, stronger inhibition of cell growth, altered immunoregulatory activity, and a prolonged in vivo half-life in rats.
Claims Coverage
The independent claim is directed to an isolated N-glycosylated polypeptide whose sequence is selected from SEQ ID NOs: 18, 19, and 20. The inventive features center on defined N-glycosylation patterns, the C-terminal GNITV sequence, and a residue 27 substitution constraint, with dependent claims also covering expression vector and pharmaceutical composition embodiments.
Isolated N-glycosylated polypeptide selected from defined sequences
An isolated N-glycosylated polypeptide in which the polypeptide has the amino acid sequence selected from the group consisting of SEQ ID NOs: 18, 19 and 20.
Interferon-beta sequence with two N-linked sugar chains and C-terminal GNITV
A human interferon-beta polypeptide of SEQ ID NO:18 containing a C-terminal GNITV sequence and two N-linked sugar chains attached to asparagines at specified amino-acid positions.
Interferon-beta sequence with residue 27 substitution and two N-linked sugar chains
A human interferon-beta polypeptide of SEQ ID NO:19 containing two N-linked sugar chains attached to asparagine residues at specified amino-acid positions, wherein residue 27 is serine or threonine.
Specific interferon-beta variant with GNITV and three N-linked sugar chains
A human interferon-beta sequence (SEQ ID NO:20) defined as a variant that includes the GNITV modification and N-linked sugar chains as specified, together with a residue 27 requirement of serine or threonine.
Expression vector expressing the N-glycosylated polypeptide
An isolated expression vector that expresses the polypeptide recited in the N-glycosylated polypeptide claim.
Pharmaceutical composition for treating Hepatitis C
A pharmaceutical composition whose pharmacological effect is treating Hepatitis C.
Overall, the claim coverage is anchored on an isolated N-glycosylated interferon-beta polypeptide selected from defined SEQ ID NOs, with key inventive structural features centered on defined N-glycosylation patterns, the presence of a C-terminal GNITV sequence, and a residue-27 substitution constraint. Dependent coverage extends to expression vector embodiments and pharmaceutical composition use for treating Hepatitis C.
Stated Advantages
Higher molecular weight for increased sugar-chain variants.
Higher antiviral activity.
Stronger inhibition of cell growth.
Comparable or slightly increased immunoregulatory effects, including MHC class I activation.
Prolonged in vivo half-life in rats.
Potential for reduced dosing frequency.
Documented Applications
A pharmaceutical composition for treating Hepatitis C.
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