N-terminal modified PEG-TRAIL
Inventors
Lee, Kang Choon • Chae, Su Young • Youn, Yu Seok • Kim, Won Bae • Lee, Sung Kwon
Assignees
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Publication Number
US-9321825-B2
Publication Date
2016-04-26
Expiration Date
Abstract
Disclosed herein are an N-terminal modified PEG-TRAIL conjugate and a preparation method and use thereof. The PEG-TAIL conjugate has pharmaceutical activity identical or similar to that of native TRAIL (TNF-related apoptosis-inducing ligand) with extended in vivo half-life and enhanced stability. Compared to native TRAIL, the PEG-TAIL conjugate exhibits high solubility and solution stability, with highly improved pharmacokinetic profiles. Thus, the PEG-TAIL conjugate may be very useful for preventing and treating proliferative diseases and autoimmune diseases.
Core Innovation
The invention relates to an N-terminal modified PEG-TRAIL conjugate in which a trimeric TRAIL comprising SEQ ID NO:2 amino acids 114 to 281 is modified by attaching a zipper amino acid motif at the N-terminus of each TRAIL monomer. The PEG or a PEG derivative is bound via a linker to an amino acid residue in SEQ ID NO:2 amino acids 114 to 281 or to the zipper motif in the N-terminal domain of at least one monomer of the trimeric TRAIL. The conjugate is defined using linker and overall molecular weight ranges verified by SDS-PAGE.
The N-terminal PEG-TRAIL conjugate is directed to improved pharmaceutical properties compared to native TRAIL. The stated improvements include increased solubility and solution stability, reduced hepatotoxicity associated with reduced hepatic uptake or removal, and markedly improved pharmacokinetics characterized by longer blood residence and reduced renal excretion and hepatic metabolism, while maintaining comparable apoptosis bioactivity in cancer cell assays.
The document also describes therapeutic uses for proliferative and autoimmune diseases using the N-terminal modified PEG-TRAIL conjugate. Biological evaluations described include apoptosis assays and solubility and solution stability assays, together with rat pharmacokinetics measurements reported using parameters such as AUC, Cmax, Tmax, and T1/2.
Claims Coverage
The document includes one independent claim directed to an N-terminal modified PEG-TRAIL conjugate with defined TRAIL structure, N-terminal zipper motif, PEG/derivative selection, and molecular weight constraints verified by SDS-PAGE.
N-terminal zipper-motif trimeric TRAIL conjugated to PEG
A trimeric TRAIL comprising SEQ ID NO:2 amino acids 114 to 281 and a zipper amino acid motif present at the N-terminus of each TRAIL monomer.
PEG selected from specified PEG derivatives bound via linker
A PEG or a derivative thereof selected from methoxypolyethylene glycol succinimidyl propionate, methoxypolyethylene glycol N-hydroxysuccinimide, methoxypolyethylene glycol aldehyde, methoxypolyethylene glycol maleimide and multiple-branched polyethylene glycol, bound via a linker having an average molecular weight between one and 30,000 daltons to an amino acid residue in SEQ ID NO:2 amino acids 114 to 281 or the zipper motif in the N-terminal domain of at least one monomer of the trimeric TRAIL.
SDS-PAGE-defined PEG/linker molecular weight range
The PEG or the derivative thereof and linker has a molecular weight of between 5,000 and 100,000 daltons as determined by SDS-PAGE.
Overall, the claim coverage focuses on an N-terminal modified PEG-TRAIL conjugate defined by a trimeric TRAIL segment with an N-terminal zipper motif, attachment of selected PEG/PEG derivatives to a specified N-terminal region via a linker within defined average molecular weight limits, and an overall PEG/derivative-plus-linker molecular weight range confirmed by SDS-PAGE.
Stated Advantages
Increased solubility.
Increased solution stability.
Reduced hepatotoxicity via reduced hepatic uptake/removal.
Markedly improved pharmacokinetics with longer blood residence.
Reduced renal excretion and reduced hepatic metabolism.
Comparable apoptosis bioactivity in cancer cell assays.
Documented Applications
Therapeutic use for proliferative diseases, including various carcinomas, glioma, brain tumor, and multiple myeloma.
Therapeutic use for autoimmune diseases, including experimental autoimmune encephalomyelitis, rheumatoid arthritis, and type I diabetes.
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