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Tetramaleimide connexin and application thereof

A linker and alkylene technology, applied in the field of antibody drug conjugates, can solve the problems of reducing interchain disulfide bonds, pharmacokinetic properties, potency and toxicity heterogeneity

Active Publication Date: 2018-02-02
NEWBIO THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Since the existing reducing agents (DTT, TCEP, etc.) cannot selectively reduce the interchain disulfide bonds, the resulting conjugates are not uniform products, but are composed of multiple components, the main component of which is DAR Values ​​are 0, 2, 4, 6, 8
At the same time, for each component with a specific DAR value, there are isomers formed due to different connection sites, resulting in certain heterogeneity
The heterogeneity of antibody drug conjugate products can lead to the heterogeneity of pharmacokinetic properties, potency and toxicity among the member components

Method used

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  • Tetramaleimide connexin and application thereof

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Embodiment Construction

[0099] The tetramaleimide linker provided by the present invention comprises four maleimide units and a fifth coupling group. Four maleimide units are used to cross-link cysteine ​​residues (after reduction) or other amino acid residues between antibody chains, while the fifth coupling group is used for small molecule drugs or drug-linkages The subunits are coupled as shown in Scheme 1 below:

[0100]

[0101] plan 1

[0102] The resulting antibody drug conjugates can be used for targeted delivery of drugs to target cell populations, such as tumor cells. Antibody-drug conjugates can specifically bind to cell surface proteins, and the resulting conjugates are then endocytosed by cells. Inside the cell, the drug is released in active drug form to produce its effect.

[0103] The antibodies of the present invention include chimeric antibodies, humanized antibodies, human antibodies; antibody fragments that can bind to antigens; or antibody Fc fusion proteins; or proteins. ...

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Abstract

The invention relates to tetramaleimide connexin and application thereof. Particularly, the invention relates to a compound shown as a formula I and application of the compound serving as connexin inpreparing antibody drug conjugate. The antibody drug conjugate prepared through the connexin has high uniformity and stability and can be effectively used for treating various diseases like tumor. Definitions of groups in the formula I are identical with that in the description.

Description

technical field [0001] The invention relates to a novel tetramaleimide linker, an antibody-drug conjugate prepared from the linker, and the use of the antibody-drug conjugate in treating tumors or other diseases. Background technique [0002] Antibody-Drug Conjugates (ADCs) are a new type of targeted therapy drugs, which are mainly used in the treatment of cancer and autoimmune diseases. Its basic design idea originated from the "magic bullet" and the concept of drug targeting first proposed by Paul Ehrlich in 1913, that is, to target the delivery of drugs through appropriate carriers to the site of disease. 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 not released until 2000. TM ) was approved by the FDA. Recently, Adcetris, a new drug developed by Seattle Genetics for the treatment of Hodgkin's lymphoma (HL) / relapsed anaplast...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/452C07K7/06A61K47/68A61K45/00A61P35/00A61P37/00A61P29/00
CPCA61K45/00C07D207/452C07K7/06A61K47/68031A61K47/6889A61P29/00A61P35/00A61P37/00A61K47/545A61K47/65A61K47/6849A61K38/07C07D403/14
Inventor 安德强韩念和朱鹏曾迪王宝祥李花丽杨春
Owner NEWBIO THERAPEUTICS
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