PEGylated interferon-beta variant
Inventors
Shin, Young-Kee • Kim, Young-Deug • Song, Kyoung • Na, Dong Hee • JEONG, Seong Hoon • KIM, Dae Duk • YOON, In Soo • Lee, Hee Jung • LEE, Sae Hyung
Assignees
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Publication Number
US-11759500-B2
Publication Date
2023-09-19
Expiration Date
Abstract
The present invention provides a PEGylated IFN-β variant and a composition for preventing or treating hyperproliferative diseases, inflammatory diseases, autoimmune diseases or viral infectious diseases, the composition comprising the PEGylated IFN-β variant as an effective ingredient. The PEGylated IFN-β variant of the present invention has an excellent anti-viral efficacy, immune regulatory function and anti-cell growth efficacy by virtue of better pharmacokinetic properties compared to native IFN-β and non-PEGylated IFN-β variants, and therefore can be used usefully against various diseases. The present invention provides good patient convenience in terms of administration due to exhibition of an excellent pharmacological activity effect upon administration and a significant increase of half-life in blood over existing interferon formulations.
Core Innovation
The invention relates to a PEGylated interferon-b2 (IFN-b2) variant in which an IFN-b2 variant is PEGylated by covalently binding CH3O(CH2CH2O)n (n is an integer of 2-4000) to an amine group or a carboxyl group via carbonyl, amide, urethane, secondary amine, thioether, disulfide, or hydrazone. The PEGylated IFN-b2 variant is formed by PEGylation with a polyethylene glycol derivative having a methoxy group at C-terminal and specified functional groups at N-terminal.
The IFN-b2 variant consists of an amino acid sequence in which Arg is substituted with Thr at the 27th amino acid residue of SEQ ID NO: 1, and the PEGylated IFN-b2 variant is mono-mPEG-20K-R27T or mono-mPEG-40K-R27T. The N-terminal PEG functional groups are selected from aldehyde, hydrazide, maleimide, succinimide, or ortho-pyridyl disulfide.
The PEGylated IFN-b2 variant is positioned to address hyperproliferative, inflammatory, autoimmune, and viral infectious diseases. The documented embodiments describe mono-PEGylated IFN-b2 conjugates and pharmaceutical composition formulations, along with measurements and biological/functional evaluations including antiviral efficacy, immune regulatory function, and anti-cell growth activity.
Claims Coverage
The independent claim covers a specifically defined PEGylated IFN-b2 variant with a defined amino acid substitution, mono-mPEG attachments, and specified covalent linker chemistries, including at least 3 core inventive features. In the partial content provided, only one independent claim (clm-00001) is explicitly identified.
Arg27 substitution to form PEGylated IFN-b2 variants
An IFN-b2 variant consisting of the amino acid sequence in which Arg is substituted with Thr at the 27th amino acid residue of SEQ ID NO: 1.
Mono-mPEG-20K or mono-mPEG-40K with specified PEG end groups
A PEGylated IFN-b2 variant formed by PEGylation with a polyethylene glycol derivative having a methoxy group at C-terminal, wherein the PEGylated IFN-b2 variant is mono-mPEG-20K-R27T or mono-mPEG-40K-R27T.
Covalent PEG attachment via selected linker chemistries and N-terminal functional groups
PEGylation by allowing CH3O(CH2CH2O)n (n is an integer of 2-4000) to be covalently bound to an amine group or a carboxyl group via carbonyl, amide, urethane, secondary amine, thioether, disulfide, or hydrazone, and wherein aldehyde, hydrazide, maleimide, succinimide or ortho-pyridyl disulfide are present at the N-terminal.
Across the independent claim coverage provided, the invention centers on a PEGylated IFN-b2 variant with an Arg27 Thr substitution (SEQ ID NO: 1), mono-mPEG-20K or mono-mPEG-40K conjugation via methoxy-terminated PEG with specified N-terminal PEG functional groups, and covalent attachment through selected carbonyl/amide/urethane/secondary-amine/thioether/disulfide/hydrazone chemistries.
Stated Advantages
Improved pharmacokinetic properties versus natural IFN-b2 and non-PEGylated IFN-b2, including an increased AUC versus Rebif R for SC dosing.
Antiviral efficacy and biological activity, including comparative activity for the mono-mPEG conjugates in an EMCV in vitro evaluation.
Maintenance of immune regulatory function compared to an unmodified IFN-b2 variant.
Anti-cell growth activity.
Documented Applications
Preventing or treating hyperproliferative, inflammatory, autoimmune, or viral infectious diseases using a pharmaceutical composition containing the PEGylated IFN-b2 variant.
Administration of the pharmaceutical composition by intravenous, subcutaneous, or intramuscular injection.
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