Antibody-drug conjugate having acidic self-stabilization junction
The present invention provides a special drug conjugate having a hydrophilic acidic stabilization junction. Compared with a conjugate having a lower drug loading, due to the introduction of the acidic stabilization junction, the conjugate in the present invention can also have a higher drug loading (that is, each targeted reagent has more hydrophilic drug junctions), keeps a desired PK property and has a same or better activity in a body.
1 . An antibody-drug conjugate or its pharmaceutically acceptable salt thereof as shown in Formula I:
wherein:
the circle represents a scaffold, wherein the scaffold comprises a C 1-8 alkylidene group, a C 1-8 heteroalkylidene group, a C 6-10 arylidene group, or a C 4-10 heteroarylidene group;
L comprises an antibody, an antibody fragment or a protein;
M comprises a succinimide group;
Ac is connected to the scaffold through an amino group, wherein Ac comprises an acidic unit that serves to stabilize the antibody-drug conjugate, and wherein Ac comprises a fragment consisting of at least one amino group and at least one acidic group or an oligopeptide group consisting of a plurality of amino acid units;
D comprises a drug unit;
A comprises a linker;
m is an integer selected from 1 to 20; and
n is 1 or 2.
2 . The antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in claim 1 , wherein M comprises a succinimide group, and wherein said antibody corresponds to an antibody for a cell surface receptor and tumor-associated antigen.
3 . The antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in claim 1 , wherein the acidic unit of Ac is selected from a group consisting of carboxylic acid, phosphoric acid, phosphite, and sulfonic acid groups, and wherein the drug unit D is selected from a group consisting of auristatins, amantins, camptothecins, maytansinoids, analogs of dolastatin 10, cachymycins, calicheamicins, doxorubicins, duocarmycins, rachelmycin (CC-1065), goitrogens, icticam, irinotecan, ixitecan, their pharmaceutically acceptable salts or derivatives thereof.
4 . The antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in claim 1 , wherein Ac comprises an acidic amino acid group or an acidic oligopeptide group, and wherein the drug unit D comprises autistatins, amantins, camptothecins, or their pharmaceutically acceptable salts or derivatives thereof.
5 . The antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in claim 1 , wherein the heteroalkylidene group comprises one or more heteroatoms selected from a group consisting of O, S, N or P atoms; wherein the arylidene group is selected from a group consisting of phenyl, naphthyl or diphenyl; wherein the heteroarylidene group is selected from a group consisting of pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrole, thiazolyl, furanyl and thiophene.
6 . The antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in claim 1 , wherein A comprises a cleavable linker or a non-cleavable linker.
7 . The antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in claim 1 , wherein said drug unit D comprises a cytotoxic drug, a drug for treating autoimmune disease, or an anti-inflammatory drug.
8 . The antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in claim 7 , wherein the drug unit D is selected from a group consisting of maitansine drugs, australin drugs, benzodipyrrole drugs, pyrrolozodiazole drugs, amantin and camptothecine compounds, their pharmaceutically acceptable salts or derivatives thereof.
9 . The antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in claim 6 , wherein A has a structure as shown in the following formula:
wherein C represents an extensible unit at the end, E represents a cleavable unit, F represents a spacer unit, subscripts e and f each is independently 0 or 1, the wavy line on the left represents a connection site to the scaffold and the wavy line on the right represents a connection site to the drug unit.
10 . The antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in claim 9 , wherein E is configured to be cleaved off from the drug unit D or the spacer unit F by a tumor-associated protease or under an acidic pH.
11 . The antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in claim 9 , wherein F is selected from a group consisting of p-aminobenzyl alcohol, ethylenediamine units, and their derivatives thereof.
12 . The antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in claim 5 , wherein the scaffold comprises C 1-8 alkylidene or C 1-8 heteroalkylidene.
13 . The antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in claim 12 , wherein the scaffold comprises a C 1-3 alkylidene.
14 . The antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in claim 1 , wherein Ac is (D/L) glycine.
15 . A method of making a pharmaceutical composition for treating cancer, immune disease or inflammation using the antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in claim 1 , comprising combining the antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in claim 1 with a pharmaceutically acceptable carrier.
16 . A pharmaceutical composition, comprising the antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in claim 1 and a pharmaceutically acceptable carrier.
17 . A method of treating cancer, immune disease or inflammation in a subject in need thereof, comprising administering to the subject an effective amount of the antibody-drug conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 16 .
18 . The antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in claim 1 , wherein
is
wherein q is an integer ranging from 1 to 8, and wherein the drug unit D comprises auristatins, amantins, camptothecins, or its pharmaceutically acceptable salts or derivatives thereof.