Non-peptidic polymeric linker compound, conjugate comprising same linker compound, and methods for preparing same linker compound and conjugate
One aspect of the present invention provides a compound in which a functional group capable of binding to a globulin Fc region or a physiologically active polypeptide is introduced at one end of a non-peptidic polymer and a functional group capable of a click reaction is introduced at the other end; a polypeptide conjugate in which a physiologically active polypeptide binds to one end of the compound; a physiologically active polypeptide conjugate in which a physiologically active polypeptide and an immunoglobulin Fc region bind to both ends thereof by using the compound as a linker; and methods for preparing the same compound, polypeptide conjugate, and physiologically active polypeptide conjugate.
1. A compound selected from a compound of the following Formula 1a, a stereoisomer thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof:
in Formula 1a,
n is an integer of 20 to 1000;
j is an integer of 0 to 6;
R1 is an aliphatic hydrocarbon group comprising an aldehyde group;
R2 is —(R3) k -(Z) l —(R4) m -(CZ) p —Y,
wherein R3 and R4 are each independently C 1 -C 6 alkylene, C 6 -C 20 arylene, or C 5 -C 20 heteroarylene having 1 to 3 heteroatoms selected from N, O, and S,
Z is O or S,
Y is selected from the group consisting of bicyclo[6.1.0]nonyne (BCN), dibenzocyclooctyne (DBCO), difluorinated cyclooctyne (DIFO), DIFO2, DIFO3, dibenzoannulated cyclooctyne (DIBO), biarylazacyclooctynone (BARAC), cyclooctyne (OCT), aryl-less cyclooctyne (ALO), monofluorinated cyclooctyne (MOFO), dimethoxyazacyclooctyne (DIMAC), 2,3,6,7-tetramethoxy-DIBO (TMDIBO), carboxymethylmonobenzocyclooctyne (COMBO), pyrrolocyclooctyne (PYRROC), dibenzo-aza-cyclooctyne (DIBAC), 3,3,6,6-tetramethylthiacycloheptyne (TMTH), Sondheimer diyne, and sulfonylated DIBO (S-DIBO), and
k, 1 , m, and p are each independently an integer of 0 to 3, provided that all of them are not 0 at the same time.
2. The compound of claim 1 , wherein Formula la is any one of the following Formulae 2a to 2n:
in Formulae 2a to 2n,
n is an integer of 20 to 1000;
j is an integer of 0 to 6; and
R1 is a C 1 -C 6 aliphatic hydrocarbon group comprising an aldehyde group.
3. A method of preparing the compound of claim 1 , the method comprising:
introducing an amino group (—NH 2 ) at one end of the polyethylene glycol, and introducing R2 at one end of the polyethylene glycol by an amide bond with the amino group, wherein R2 is the same as defined in claim; and
introducing an aliphatic hydrocarbon group comprising an aldehyde group at the other end of the polyethylene glycol to which R2 is introduced.