Dual specificity dimer, dual specificity dimer-drug conjugate and application of dual specificity dimer and dual specificity dimer-drug conjugate

A drug conjugate and bispecific technology, which is applied in the field of bispecific dimer-drug conjugates and bispecific dimers, can solve the problems such as the stability of receptor ligand binding needs to be improved, To achieve high-efficiency and low-toxicity treatment, reduce adverse reactions, and reduce dosage

Pending Publication Date: 2020-09-11
REMEGEN CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the heterogeneity of tumor surface antigens, the binding, targeting and stability of receptor ligands in tumor tissues need to be improved.

Method used

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  • Dual specificity dimer, dual specificity dimer-drug conjugate and application of dual specificity dimer and dual specificity dimer-drug conjugate
  • Dual specificity dimer, dual specificity dimer-drug conjugate and application of dual specificity dimer and dual specificity dimer-drug conjugate
  • Dual specificity dimer, dual specificity dimer-drug conjugate and application of dual specificity dimer and dual specificity dimer-drug conjugate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Embodiment 1 compound I-1', I-2', I-3', I-4', I-5', I-6', I-7', I-8' (ie L 1 -L 2 -A 2 ) preparation

[0053] (1) Preparation of I-1'

[0054]

[0055]

[0056] N 2 Under protection, weigh MTX (227mg, 0.5mmol, purchased from Bailingwei Technology) into a 50mL one-mouth eggplant-shaped bottle, add TEA (101.2mg, 1mmol) and 3mL DMF, and stir at -5°C for 10min. Weigh TSTU (113.5mg, 0.55mmol), dissolve in 1mL DMF, add dropwise to the above reaction solution, and stir for 3h. Compound 1 (212mg, 0.5mmol) was weighed, dissolved in 2mL DMF, added dropwise to the above reaction solution, and stirred for 5h. After the reaction, the reaction solution was diluted with 3 mL of water, separated by preparative HPLC, and the prepared solution was freeze-dried to obtain 288.1 mg of yellow oily compound 2 with a yield of 67%. LC-MS (ESI + )861[M+H] + .

[0057]

[0058]

[0059] N 2 Under protection, compound 2 (288.1 mg, 0.34 mmol) was weighed into a 10 mL single-ne...

Embodiment 2

[0113] Example 2 General preparation method of bispecific dimer

[0114] Antibody (10mg / mL), DTPA (10mM) and 2.5eq. of TCEP (5mM) were added to the PCR tube, and the reaction was stirred at room temperature for 2h. Then add 25% DMSO and 5eq. of methotrexate-L in ice bath 1 (5mM) (such as I-1', I-2', I-3', I-4', I-5', I-6', I-7', I-8' and other compounds), stirring at room temperature Reaction 10h. After the reaction, centrifuge and ultrafilter three times with PBS buffer to purify and remove residual unreacted drugs and free small molecules such as DMSO.

[0115] We used the method described above to prepare the following bispecific dimers:

[0116]

[0117]

[0118]

Embodiment 3

[0119] Example 3 General Preparation Method of Bispecific Dimer-Drug Conjugate

[0120] Antibody (10mg / mL), DTPA (10mM) and 2.5eq. of TCEP (5mM) were added to the PCR tube, and the reaction was stirred at room temperature for 2h. Then add 25% DMSO and 5eq. of the corresponding linker-toxin in ice bath, and react for 2h. 2.5eq. of TCEP (5mM) was added, stirred at room temperature for 2h, and then linker-MTX (5mM) was added, stirred at room temperature for 10h. After the reaction, centrifuge and ultrafilter three times with PBS buffer to purify and remove residual unreacted drugs and free small molecules such as DMSO.

[0121] We used the above method to prepare the following bispecific dimer-drug conjugates:

[0122]

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Abstract

The invention provides a dual specificity dimer capable of targeting folate receptors, a dual specificity dimer-drug conjugate and an application of the dual specificity dimer and the dual specificitydimer-drug conjugate to preparation of drugs for treating tumors and autoimmune diseases. Compared with a traditional antibody mediated or receptor mediated targeted drug delivery system in single use, the dual specificity conjugate provided by the invention can target antigens and receptors on surfaces of tumor cells at the same time, so that the objective of combining two antigens or two epitopes of one antigen can be achieved, and the combining capacity of the conjugate and the tumor cells can be greatly improved. Treatment drugs can be transported to diseased regions to the maximum extent, and are enriched in disease focus regions, and the drug concentration at the disease focus regions is several times and even hundreds of times than that of a conventional preparation, so that the treatment effects are notably increased; besides, the consumption of drugs can be reduced, so that adverse reactions of drugs can be reduced; and in addition, drug delivery speed and drug delivery manner are convenient to control, so that treatment effects high in efficiency and low in toxicity are achieved.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a bispecific dimer, a bispecific dimer-drug conjugate and applications thereof. Background technique [0002] Malignant tumors are a class of diseases that seriously endanger human physical and mental health and affect the social labor force, and have brought heavy economic burdens to many families and society. According to statistics, the incidence of cancer worldwide will increase by 50% in 2020, and the number of new cancer patients worldwide will reach 15 million each year. In the past 20 years, the incidence of cancer in my country has increased by 69%, and the death rate has increased by 29%. There are 2.2 million new cancer cases and 1.6 million cancer deaths every year. One out of every four or five deaths is due to cancer, and cancer has become the main killer threatening human life and health. [0003] At present, the traditional methods for treating malignant tumors includ...

Claims

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Application Information

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IPC IPC(8): A61K47/68A61K47/58A61K47/59A61K47/60A61K31/519A61K45/06A61P35/00A61P37/02
CPCA61K47/6851A61K47/58A61K47/59A61K47/60A61K31/519A61K45/06A61P35/00A61P37/02A61K2300/00Y02A50/30
Inventor 罗文婷张信玲陈虎黄长江侯巧华张钦斌姚雪静朱梅英
Owner REMEGEN CO LTD
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