US 11,903,948 B2
Anti-ErbB2 antibody-drug conjugate and composition thereof, preparation method therefor, and use thereof
Tongtong Xue, Sichuan (CN); Zhenwei Miao, San Diego, CA (US); Jing Wang, Sichuan (CN); Gang Chen, San Diego, CA (US); Yan Qing, Sichuan (CN); Tong Zhu, San Diego, CA (US); Liang Xiao, Sichuan (CN); Hong Zhang, San Diego, CA (US); Qiuyan Yang, Sichuan (CN); Dylan Dalun Deng, San Diego, CA (US); Liping Liu, Sichuan (CN); Hong Zeng, Sichuan (CN); Li Yin, Sichuan (CN); Qifeng Shi, Sichuan (CN); Hongmei Song, Sichuan (CN); Xi Zhao, Sichuan (CN); Lichun Wang, Sichuan (CN); and Jingyi Wang, Sichuan (CN)
Assigned to SICHUAN KELUN-BIOTECH BIOPHARMACEUTICAL CO., LTD., Sichuan (CN)
Filed by SICHUAN KELUN-BIOTECH BIOPHARMACEUTICAL CO., LTD., Sichuan (CN)
Filed on Feb. 5, 2021, as Appl. No. 17/169,087.
Application 17/169,087 is a division of application No. 15/765,685, filed on Apr. 3, 2018.
Claims priority of application No. 201510824064.8 (CN), filed on Nov. 23, 2015.
Prior Publication US 2021/0252006 A1, Aug. 19, 2021
Int. Cl. A61K 31/536 (2006.01); A61K 47/68 (2017.01); A61K 47/65 (2017.01); A61K 47/64 (2017.01); A61P 35/00 (2006.01); C07K 16/32 (2006.01)
CPC A61K 31/536 (2013.01) [A61K 47/64 (2017.08); A61K 47/65 (2017.08); A61K 47/6803 (2017.08); A61K 47/6869 (2017.08); A61P 35/00 (2018.01); C07K 16/32 (2013.01); C07K 2317/24 (2013.01)] 7 Claims
OG exemplary drawing
 
1. A preparation method of an antibody-drug conjugate represented by Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, or a solvate of the foregoing,

OG Complex Work Unit Chemistry
wherein:
A is an anti-ErbB2 antibody, wherein the anti-ErbB2 antibody is Trastuzumab;
X is N;
Y is N or CR1, and R1 is H or C1-C10 alkyl;
L is

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D is a cytotoxic agent group of Formula (D1) or a stereoisomer thereof,

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wherein R2 is —CH2N3, R3 is selected from the group consisting of H and —OH, and R4 is selected from the group consisting of H, —NH2, Cl, Br, I and —OS(O)2R6, wherein R6 is H, C1-C8 alkyl, C3-C8 cycloalkyl or C6-C14 aryl, and the alkyl, cycloalkyl and aryl are each optionally substituted with one or more halogen substituents;
a is an integer selected from the group consisting of 2-10; and
all the cytotoxic agent groups are conjugated to the lysine residues of the same peptide segment of the light chain of the antibody;
the method comprising the steps of:
(1) preparing a compound of Formula (I-A):

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(2) obtaining a compound of Formula (I-B) by reacting the compound of Formula (I-A) with pentafluorophenol using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N-hydroxysuccinimide and/or dichloromethane

OG Complex Work Unit Chemistry
(3) obtaining a mixture of a variety of antibody-drug conjugates having different a values by conjugating the compound of Formula (I-B) from step (2) with the anti-ErbB2 antibody; and
(4) obtaining the antibody-drug conjugate represented by Formula (I) by purifying the mixture from step (3) with hydrophobic interaction chromatography (HIC) method, said method utilizing a stationary phase that comprises a phenyl resin;
wherein a mobile phase A of the HIC method comprises ammonia sulfate and disodium hydrogen phosphate; and a mobile phase B of the HIC method comprises disodium hydrogen phosphate and isopropanol.