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Bridge linkers for conjugate coupling of cell-binding molecules

A linker and cell technology, applied in the field of preparing cell-binding agent-drug conjugates, can solve the problem that the DAR value is lower than 2

Pending Publication Date: 2021-09-07
HANGZHOU DAC BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the design of the above-mentioned bridge linker is to couple a cytotoxic molecule with a pair of disulfide bonds. Due to the limited number of disulfide bonds available for conjugation on the antibody (about 2 pairs), most Under the circumstances, the DAR value of the ADCs produced is lower than 2

Method used

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  • Bridge linkers for conjugate coupling of cell-binding molecules
  • Bridge linkers for conjugate coupling of cell-binding molecules
  • Bridge linkers for conjugate coupling of cell-binding molecules

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach 1

[0204] Embodiment 1. A bridging body with a structure as shown in (I), used to prepare a conjugate of a cell-binding agent and a cytotoxic agent:

[0205]

[0206] in:

[0207] Y 1 and Y 2 are the same or different functional groups that can react with a pair of sulfur atoms on the cell-binding agent to form disulfide, thioether or thioester linkages. preferred Y 1 and Y 2 For, but not limited to, N-hydroxysuccinimidyl ester, maleimide, disulfide, haloacetyl, acid halide, vinylsulfonyl, acryloyl, 2-(p-toluenesulfonyloxy) Acetyl, 2-(methylsulfonyloxy)acetyl, 2-(nitrophenoxy)acetyl, 2-(dinitrophenoxy)acetyl, 2-(fluorophenoxy)acetyl , 2-(difluorophenoxy)acetyl, 2-(pentafluorophenoxy)acetyl, 2-(trifluoromethanesulfonic acid oxy)acetyl, and / or anhydride groups, the structure of which is as follows:

[0208] N-hydroxysuccinimide ester; Maleimide group; disulfide; Haloacetyl; acid halides or esters; Vinylsulfonyl; Acryloyl; 2-(p-toluenesulfonyloxy)acetyl; 2...

Embodiment approach 2

[0213] Embodiment 2. A cell-binding agent-drug conjugate having a structure such as formula (II):

[0214]

[0215] in:

[0216] Cb is a cell binding agent, most preferably an antibody.

[0217] Drug1 and Drug2 are the same or different cytotoxic agents, which are linked by bridges in the form of alkyl, alkylene, alkenylene, alkynylene, ether, polyalkoxy, ester, amine, imine, polyamine , hydrazine, hydrazone, amide, urea, semicarbazide, carbazide, alkoxyamine, carbamate, amino acid, peptide, acyloxyamide, hydroxamic acid, disulfide bond, thioether, thioester, carbamate Ester, carbonate, heterocyclic, heteroalkyl, heteroaryl, or alkhydroxime linkages and combinations thereof are linked to the cell-binding agent.

[0218] In parentheses is the linker-drug component, which is coupled to the cell-binding agent via a pair of sulfur atoms (thiols). Sulfur atom pairs that can undergo coupling reactions are usually generated by the reduction of disulfide bonds on cell-binding agen...

Embodiment approach 3

[0220] Embodiment 3. Compounds of formula (III):

[0221]

[0222] where Cb, Z 1 ,Z 2 ,n,R 1 , R 2 , R 3 and R 4 The definition is the same as embodiment 1 and 2.

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Abstract

The present invention relates to bridge linkers for conjugate coupling of cell-binding molecules. More specifically, the present invention relates to the preparation of a novel class of bridge linkers that specifically conjugates cell-binding molecules with small molecule drugs, in particular cytotoxic agents, by reacting with sulfydryl pairs on the cell-binding molecules. The invention also relates to a method for preparing the cell-binding agent-drug (cytotoxic agent) conjugate, which comprises the steps of: one is to modify a small drug molecule by using the bridge linker and then react with a cell-binding agent; and the other is to modify a cell-binding agent by using the bridge linker and then react with the small drug molecule. The invention also relates to the use of the conjugates in the treatment of cancer, infections and autoimmune diseases.

Description

[0001] This application is a divisional application of an application with an application date of July 12, 2015, an application number of 201580082279.5, and an invention titled "Conjugate-coupled bridge linker with cell-binding molecules". technical field [0002] The invention relates to the preparation of a new type of bridge linker, which specifically conjugates the cell-binding molecule with small molecule drugs, especially cytotoxic agents, through the interaction with the sulfhydryl group on the cell-binding molecule. The present invention also relates to a method for preparing a cell-binding agent-drug (cytotoxic agent) conjugate: one is to modify the drug small molecule with this type of linker, and then react with the cell-binding agent; This type of linker modifies the cell-binding agent and then reacts with the drug small molecule. [0003] technical background [0004] Traditional cancer chemotherapy is often accompanied by systemic toxicity in patients. Monoclo...

Claims

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Application Information

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IPC IPC(8): A61K47/68A61K31/337A61K31/537A61K31/704A61K38/07A61K45/06A61P31/00A61P35/00A61P37/00C07D207/448C07D519/00
CPCC07D213/71C07D403/14C07D417/14C07D207/448C07D519/00A61K47/6889A61K47/6803A61K47/6817A61K47/6851A61P31/00A61P31/04A61P31/12A61P33/00A61P35/00A61P37/02A61P43/00A61K47/68031A61K47/68033
Inventor 赵珞博永新
Owner HANGZHOU DAC BIOTECH
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