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A disubstituted maleamide linker for antibody-drug conjugation and its preparation method and use

A maleamide and linker technology, which is applied in the field of novel disulfide chain bridging cross-linking reagents, can solve the problems of poor chemical stability of coupling reagents, cluttered electrophoresis of antibody conjugates, and long synthesis routes of coupling reagents. , to achieve the effect of high uniformity, improved safety and fast cross-linking speed

Active Publication Date: 2021-11-12
MABWELL (SHANGHAI) BIOSCIENCE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the above-mentioned technology has a long synthetic route of the coupling reagent, poor chemical stability of the coupling reagent, and messy electrophoresis of the antibody conjugate, suggesting that there may be side reactions in the coupling process, and the existing scheme does not solve the problem of in vivo circulation. Sulfhydryl exchange (reverse Michael addition reaction) and other issues

Method used

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  • A disubstituted maleamide linker for antibody-drug conjugation and its preparation method and use
  • A disubstituted maleamide linker for antibody-drug conjugation and its preparation method and use
  • A disubstituted maleamide linker for antibody-drug conjugation and its preparation method and use

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Embodiment Construction

[0223] Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Percentages and parts are by weight unless otherwise indicated.

[0224] Embodiment group one, compound synthesis and preparation method

[0225] 1.1 Synthesis of Compound E-1 (Formula Ia-1)

[0226] 1.1.1 Intermediate A-1 (step a)

[0227]

[0228] Triethylene glycol (92 g, 613 mmol) was dissolved in tBuOH (200 ml). KOtBu (22.91g, 204mmol) was added under ice-cooling and stirred for half an hour. Under argon protection, a solution of tert-butyl bromoacetate (39.8g, 204mmol) in tBuOH (40ml) was added dropwise, and stirred overnigh...

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Abstract

The invention provides a double-substituted maleamide linker coupled with an antibody and its preparation method and application. Specifically, the invention couples strong cytotoxic active substances and biological macromolecules through a new type of linker couplet. This type of linker can selectively act on the disulfide chain at the same time, thereby greatly improving the material uniformity and stability of the conjugate. The conjugate prepared by the linker of the present invention has high inhibitory activity on cell lines expressing corresponding antigens. The present invention also provides the preparation method and application of the above-mentioned conjugate.

Description

technical field [0001] The invention relates to a novel disulfide chain bridging and crosslinking reagent, a macromolecule, a therapeutic conjugate and a synthesis method thereof. More specifically, the present invention relates to a conjugate obtained by cross-linking cytotoxic drugs and macromolecules with a maleamide-based disulfide chain bridging cross-linking reagent, and a preparation method and use thereof. Background technique [0002] As a new type of targeted therapy drug, antibody-drug conjugate (Antibody Drug Conjguate, ADC) ushered in a new era of tumor treatment, and its basic design idea originated from Paul Ehrlich's first The concept of "Magic bullet" and drug targeting is put forward, that is, to deliver the drug to the disease site through an appropriate carrier. However, subject to the constraints of antibody and highly active cytotoxic drug technology, the first antibody-drug conjugate (Mylotarg) for the treatment of acute myeloid leukemia (AML) was rel...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/456C07D401/14A61K31/537A61P35/00C07K5/027C07K5/06
Inventor 沈竞康孟韬马兰萍王昕张永良于霆陈驎彭红丽杜志彦王英
Owner MABWELL (SHANGHAI) BIOSCIENCE CO LTD
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