Stable antibody-drug conjugate, preparation method therefor, and use thereof
The present invention provides a conjugate and preparation method thereof, a pharmaceutical composition comprising the conjugate and use of the pharmaceutical composition in the manufacture of a medicament for the treatment or prevention of a disease.
1. A compound of Formula (I) or (II):
or a pharmaceutically acceptable salt thereof, wherein
PCA is a specific substrate recognition sequence of a ligase;
LA1 and LA2 are linker moieties;
a and p are independently 0 or 1, that is, LA1 and LA2 are independently present or absent;
CCA′ is a chemical conjugation moiety;
represents a single or double bond;
Y is a radioactive label, a fluorescent label, an affinity purification tag, a tracer molecule, an anticancer drug or a cytotoxic molecule;
z is any of the integers between 1 and 1000.
2. The compound according to claim 1 , wherein Y is maytansine, DM1, DM4, paclitaxel, Auristatin, monomethyl auristatin E(MMAE), monomethyl auristatin F (MMAF), monomethyl auristatin D (MMAD), epothilone, or a vinca alkaloid compound.
3. A compound wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof, wherein n represents any of the integers between 1 and 100, m is 0 or any of the integers between 1 and 1000, and x is —OH or —NH 2 group.
4. The compound according to claim 1 , which is prepared by the following steps:
A) a solution of Y and a solution of
are mixed and incubated to obtain a solution of the conjugate:
or
a solution of Y and a solution of
are mixed and incubated to obtain a solution of the conjugate
in this case, a —S-(LA2) p group is connected to Y;
B) to a solution of the conjugate
prepared in A) is added a Tris base solution or other solution which facilitates ring-opening.
5. The compound according to claim 4 , wherein the preparation further comprises purifying the obtained product by HPLC.
6. The compound according to claim 5 , wherein the total molar content of the compounds of Formula (I) or (II) is more than 50%.
7. The compound according to claim 1 , wherein the PCA is 3 series-connected structure units which are selected from the group consisting of one or more glycine and alanine.
8. A compound, wherein the compound is:
wherein n is 3 and x is —OH or —NH 2 .