Patent RU-2752671-C2 (RU)
Title: Linker links and molecular structures containing them
Inventor: CHANG TSE-WEN
IPC: C07K16/30
Filed: 2018-03-16
Granted: 2021-07-29
Abstract: FIELD: pharmaceutics. 
     SUBSTANCE: invention relates to a linker link containing: a core containing 2-20 lysine (hereinafter – K) residues, one or several spacers and the first conjugating fragment, while any two of K residues are adjacent to each other or separated by one of spacers; each of spacers independently contains (1) one or several non-K-amino acid residues or (2) pegylated amino acid containing from 2 to 12 links of ethylene glycol (hereinafter – EG); at least one spacer is connected to N-end of the first K residue, starting from N-end, or to C-end of the last K residue, starting from N-end; and the first conjugating fragment contains a carboxyl group or amino group and conjugating group selected from azide, alkyne, tetrazine, cyclooctene and cyclooctyne groups, wherein, if the spacer is connected to N-end of the first K residue, then the first conjugating fragment contains a carboxyl group, and it is connected to the spacer by means of formation of amide connection to an alpha-amino group of the spacer; or, if the spacer is connected to C-end of the last K residue, then the first conjugating fragment contains an amino group, and it is connected to the spacer by means of formation of amide connection to a carboxyl group of the spacer; a set of binding branches, while each of binding branches is peptide containing from 2 to 12 non-K-amino acid residues or a polyethylene glycol (PEG) chain containing from 2 to 24 links of EG, each of binding branches contains a reactive group at one end and a functional group at the other end, and it is connected to core K residues by means of formation of amide connection between the reactive group of the binding branch and the amino group of the core K residue, and the functional group is selected from amine, carboxyl, hydroxyl, tert-butyldimethylsilyl (TBDMS), N-hydroxysuccinimidyl (NHS), maleimide, vinyl sulfone, monosulfone, methylsulfonylbenzothiazole, iodine, iodoacetamide, azide, alkyne, cyclooctyne, tetrazine and cyclooctene groups under the condition that, if the conjugating group is an azide, alkyne or cyclooctyne group, then the functional group is a tetrazine or cyclooctene group, and if the conjugating group is a tetrazine or cyclooctene group, then the functional group is an azide, alkyne or cyclooctyne group; a set of the first elements that are, respectively, connected to the set of binding branches by means of formation of amide or complex ether connection between them or by means of thiol-maleimide reaction, S N 2 reaction, copper-catalyzed azide-alkyne cycloaddition (hereinafter – CuAAC) reaction, stress-promoted azide-alkyne click (hereinafter – SPAAC) reaction or inverse electron-demand Diels–Alder (hereinafter – iEDDA) reaction, where each of the first set of elements is cholecystokinin octapeptide (CCK8); and the second element that is connected to the conjugating group by means of CuAAC reaction, SPAAC reaction or iEDDA reaction, where the second element is an antibody fragment specifical to CD3. The invention also relates to a molecular structure. 
     EFFECT: linker has more required stability and efficiency of conjugation with functional elements. 
     8 cl, 27 dwg, 25 ex