Maytansine antibody drug conjugate and application thereof

Abstract

The invention provides a cleavable maytansine antibody drug conjugate. An innovative structural design is adopted, one end is connected with a maytansine medicine, one end is connected with a connexon, and by using the acetal structure, spontaneous hydrolysis can be achieved in the intracellular acidic environment so as to remove chemical groups introduced on the maytansine and release the free unmodified maytansine, so the cleavable purpose is achieved, thereby the bystander effect is generated, the drug effect is enhanced, and the excellent effect is provided for solid tumor cancers; and themaytansine is more stable in vivo, is not prone to degrading before entering cells, can release maytansine only after entering the cells and being hydrolyzed, and plays an anticancer role, so that non-targeted degradation is difficult, the toxic and side effects of the ADC medicine are reduced, the treatment window of the ADC medicine is truly increased, and the druggability is improved.

Description

technical field [0001] The invention relates to the field of antibody-drug conjugates, in particular to a cleavable maytansinoid antibody-drug conjugate and applications thereof. Background technique [0002] Antibody-drug conjugate (ADC) refers to a type of biological drug that connects a biologically active drug (Drug) and antibody (Antibody) through a chemical linker (Linker). ADC is like a precision-guided weapon system, in which biologically active drugs are used as lethal ammunition, and under the guidance of antibodies, they precisely attack cancerous cells. Appropriate linkers between antibody and drug provide specific conjugation, which facilitates selective delivery of cytotoxic drugs to tumor cells by antibodies and accurate release of cytotoxic drugs at tumor sites. In addition to conjugation, the linker also maintains the stability of the ADC during the manufacturing and storage phases and during the systemic circulation. ADC linkers currently undergoing clini...

AI Technical Summary

Problems solved by technology

[0003] Maytansinoids and their derivatives are extremely potent inhibitors of microtubule assembly, which can exhibit anti-mitotic effects at subnanomolar levels, and their ED 50 (effective dose) at 10 -5 ~10 -4 Between μg / mL, it is an ideal anticancer drug. Among the ADC drugs that have been marketed, the bioactive drug part of Roche’s Kadcyla (launched in 2013) uses maytansinoids (DM1), The drug uses SMCC as an ADC formed by cross-linking the lysine residues of the trastuzumab antibody with the sulfhydryl group of maytansine DM1, and its linker-toxin (-MCC-DM1) cannot be cleaved. After cells, the whole ADC molecule needs to be hydrolyzed to release the effective small molecule with DM1 (Lys-MCC-DM1). Since this molecule contains amino and carboxyl groups, it cannot be used in vivo due to its charge. Freely pass through the cell membrane, so it cannot kill the cancer cells next to it, does not have the bystander effect, and affects its efficacy to a certain extent

[0004] At present, the cleavable maytansinoid antibody-drug conjugates in clinical use are generally in the form of disulfide bonds. After the drug in this conjugated form reaches the cells, it is released by the high content of glutathione in the tumor to produce Toxins (such as DM1, DM4), but because there is a small amount of glutathione inside and outside normal cells, the disulfide bond will also be reduced, and then the toxin will be released inside and outside normal cells, resulting in non-target degradation, resulting in toxic side effect

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