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Antibody drug conjugate with alkenylsulphonylamino as connexon and application of antibody drug conjugate

An alkenyl sulfonamide-based, antibody drug technology is applied in the directions of drug combinations, anti-tumor drugs, medical preparations with non-active ingredients, etc., to achieve high stability and improved anti-tumor activity.

Active Publication Date: 2015-06-10
上海中科润达精准医学检验有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Aiming at solving the technical problems of various limitations of linkers used in antibody drug conjugates in the prior art

Method used

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  • Antibody drug conjugate with alkenylsulphonylamino as connexon and application of antibody drug conjugate
  • Antibody drug conjugate with alkenylsulphonylamino as connexon and application of antibody drug conjugate
  • Antibody drug conjugate with alkenylsulphonylamino as connexon and application of antibody drug conjugate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] Because colchicine is too toxic, it cannot be used to treat cancer. In this example, the activity of colchicine derivatives linked with alkenyl sulfonamide groups was tested and linked to herceptin drug molecules, thereby preparing a new antibody-drug conjugate.

[0089] (1) Preparation of Colchicine Derivative 9

[0090] This example provides a method for preparing an antibody-drug conjugate with an alkenylsulfonamide group as a linker. First, a Boc group is attached to the amide bond of colchicine to obtain compound 5, and then the acetyl group is selectively removed with sodium methoxide to obtain compound 6, and finally the Boc group is removed with trifluoroacetic acid, so that the deacetylated compound is obtained. Compound 7, the primary amine in this structure was reacted with 2-chloroethanesulfonyl chloride to obtain colchicine derivative 9 containing alkenylsulfonamide linker.

[0091] The synthetic route is as follows:

[0092]

[0093] The specific pre...

Embodiment 2

[0101] Embodiment 2: ELISA test of colchicine-Herceptin antibody conjugate

[0102] 100uL of 0.05μg / mL human HER2 protein (coating buffer is 0.05M carbonate buffer solution, pH=9.6) was added to the microwells and incubated overnight at 4°C, and washed with 3% skimmed milk in PBS. Add 100uL of Trastuzumab and Trastuzumab-colchicine conjugates of various concentrations to each well and incubate at room temperature for 1 hour, then add HRP-conjugated goat anti-human IgG (1:10,000) and incubate for 1 hour, add 50uL TMB substrate into each well, with an equal volume of H 2 SO 4 Stop the reaction and read the absorbance at 450nm.

[0103] join Figure 19 , the figure shows the ELISA test chart of the binding of Herceptin antibody and colchicine-Herceptin antibody conjugate to the antigen respectively, Her in the figure means Herceptin antibody, and Her-col means colchicine-Herceptin antibody Conjugates. Figure 19 The results of the data show that the antigen-binding ability o...

Embodiment 4

[0104] Example 4: Test of colchicine-Herceptin antibody conjugate against cancer cell SKBR3

[0105] After the cancer cell SKBR3 was inoculated in a 96-well plate and adhered to the wall overnight, the supernatant was discarded, and fresh medium containing different concentrations of antibodies was added. After 72 hours of treatment, MTS reagent (Promega Company) was added to continue incubation for 2 hours, and the absorbance at 490 nm was read with a microplate microplate reader. see Figure 20 , the figure is a schematic diagram of the inhibitory activity of Herceptin antibody and colchicine-Herceptin antibody conjugate on SKBR3 cells, where Herceptin means Herceptin antibody, and Herceptin-Colchincine means colchicine-Herceptin antibody conjugate things. Figure 20 , the abscissa indicates the concentration of Herceptin antibody and colchicine-Herceptin antibody conjugate, and the ordinate indicates the relative activity of SKBR3 cells. From Figure 20 It can be seen t...

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Abstract

The invention discloses an antibody drug conjugate with alkenylsulphonylamino as a connexon and application of the antibody drug conjugate. A preparation method of the antibody drug conjugate comprises the steps of connecting amino and alkenylsulphonyl on the structure of a drug molecule to obtain an alkenylsulphonylamino derivative of the drug molecule; and then, coupling the drug molecule and an antibody compound through carrying out Michael addition reaction on alkenyl on the derivative of the drug molecule and amino on the antibody compound. The alkenylsulphonylamino derivative of the drug molecule can be selectively subjected to coupled reaction with amino on an antibody, conjugates can be selectively and efficiently subjected to coupled reaction with amino acid residues on the surface of the antibody in a water phase, and meanwhile, the activity of the antibody can also be kept. The obtained antibody drug conjugate has high stability in a chemical environment and an in-vivo environment. In addition, the antitumor activity of the antibody drug conjugate is improved as comparison with a single drug molecule.

Description

technical field [0001] The invention belongs to the technical field of antibody-drug conjugates, and in particular relates to antibody-drug conjugates with alkenyl sulfonamide as linkers and applications thereof. Background technique [0002] The advent of Antibody-Drug Conjugates (hereinafter referred to as ADC) has revolutionized the treatment of cancer. Adcetris and Kadcyla, as the only two commercially available ADCs, have achieved good results in the treatment of Hodgkin's lymphoma and breast cancer. ADC connects a biologically active small molecule drug to the monoclonal antibody through a linker, and the monoclonal antibody acts as a carrier to target and transport the small molecule drug to the target cell, which not only improves the anticancer effect of the monoclonal antibody, but also reduces the Molecular Drug Toxicity. [0003] The antibody has fewer chemical sites that can react with the linker, mainly the amino group of lysine and the sulfhydryl group of cy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K31/165A61P35/00
Inventor 姜标曹刚
Owner 上海中科润达精准医学检验有限公司
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