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Multi-target-point anti-tumor polypeptide medicine conjugate and preparation method and application thereof

A technology of drug conjugates and anti-tumor drugs, which is applied in the field of anti-tumor, and can solve problems such as the difficulty of coupling antibodies and effector molecules

Active Publication Date: 2020-06-05
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, there are also difficulties in the development of ADC drugs: (1) The coupling of antibodies and effector molecules is difficult

Method used

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  • Multi-target-point anti-tumor polypeptide medicine conjugate and preparation method and application thereof
  • Multi-target-point anti-tumor polypeptide medicine conjugate and preparation method and application thereof
  • Multi-target-point anti-tumor polypeptide medicine conjugate and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] The synthesis of embodiment 1, LLC2B

[0078]The sequence (Hyp)-(D-Asn)-(D-Leu)-D-Lys)-(Cit)-(Acpc)-(D-Asp)-(Aad)-(Nva) is the synthesis and conventional polypeptide of LLC2B The synthesis method is similar, as follows:

[0079] (1) Weigh the unnatural amino acid containing the Fmoc protection group according to the following formula: grams of amide resin × degree of substitution of amide resin × 4 times molar concentration × molecular weight of a certain Fmoc-amino acid. 6-Cl HOBt and DIC are also weighed according to the following formula: grams of amide resin × degree of substitution of amide resin × 4 times molar concentration × molecular weight. After weighing 6-Cl HOBt and DIC, add analytical grade DMF solution, that is, the mass of HOBt in 1ml solution = 0.05 × 0.31 × 4 × 169.7 = 10.52 mg; the volume of DIC = 0.05 × 0.31 × 4 × 126.2 / 0.815 = 96 μl, and then add the weighed non-natural amino acid containing Fmoc protection group (in operation, it can be prepared ...

Embodiment 2

[0085] Example 2: Affinity detection results of LLC2B and RTK family members

[0086] (1) Prepare sterilized and filtered ultrapure water as the sample solvent, dissolve the small molecule polypeptide (LLC2B) and protein (FGFR2 protein and HER2 protein) and then store in a -80°C refrigerator; among them, the FGFR2 protein and HER2 proteins were purchased from Beijing Yiqiao Shenzhou Biotechnology Co., Ltd.

[0087] (2) Configure the pre-set small molecule concentration and protein concentration, and the ratio of small molecule polypeptide to protein concentration is 80 to 150 times (this concentration ratio is the concentration ratio of μM level);

[0088] (3) After the sample is prepared, it is filtered, and placed at room temperature for 30 minutes to carry out the operation on the machine (the instrument used is an isothermal titration calorimeter ITC200);

[0089] (4) Manually clean the sample pool and reference pool for 7 to 8 times, and then machine clean the sample poo...

Embodiment 3

[0095] Example 3: Synthesis of LLC2B-Mal-DM1

[0096] The structure of LLC2B-Mal-DM1 is as figure 1 As shown, the coupling process is as figure 2 Shown:

[0097] (1) Weigh 1.0g amide resin, then put the amide resin into the reaction tube, add 2 times the volume of DMF (N,N-dimethylformamide) to soak for 2 to 3 hours; discard the solution by suction, add DMF solution (8 milliliters) containing 20% ​​(w / w) 4-methylpiperidine, reacted for 5 minutes, and contained 20% (w / w) DMF solution (8 milliliters) of 4-methylpiperidine after removing the solution , and reacted for 15 minutes; the solvent was drained through a suction filtration device, and then washed with DMF three times, methanol three times and DMF three times, and then added analytical grade DMF to balance for 2 to 5 minutes.

[0098] (2) Drain the solvent through a suction filtration device, add 2 times the volume of the compound Fmoc-Lys(Dde)-OH containing 5 times the molar concentration of the Fmoc (ie fluorenylmet...

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Abstract

The invention discloses a multi-target-point anti-tumor polypeptide medicine conjugate and a preparation method and application thereof. The method comprises the following steps of: with a micromolecule polypeptide which can target a plurality of tyrosinase receptor family members including FGFR2 and Her2, as a target head, selecting effector molecules and connector molecules, which are frequentlyused in current ADC medicine research and development, and performing combination and coupling, so as to form a novel polypeptide medicine conjugate, wherein the amino acid sequence of the micromolecule polypeptide is (Hyp)-(D-Asn)-(D-Leu)-(D-Lys)-(Cit)-(Acpc)-(D-Asp)-(Aad)-(Nva). The prepared polypeptide medicine conjugate disclosed by the invention is relatively small in molecular weight and good in penetrability, has multiple targeting properties, can exert effects on tumors high in expression of a plurality of tyrosine kinase receptors including Her2 and FGFR2, and is relatively stable inactivity, so that the polypeptide medicine conjugate can be used for the field of tumor treatment.

Description

technical field [0001] The invention belongs to the field of anti-tumor technology, in particular to a multi-target anti-tumor polypeptide drug conjugate and its preparation method and application. Background technique [0002] In addition to surgical resection and radiotherapy, drug intervention is an important means for the treatment of cancer patients. Currently commonly used drug treatment methods are chemotherapy and targeted therapy. The toxic and side effects of chemotherapy are well known; small molecule compounds currently used in targeted therapy such as Imatinib target to inhibit Bcr–Abl tyrosine kinase in chronic myelogenic leukemia, Erlotinib inhibits EGFR tyrosine Acid kinase activity, bortezomib (Bortezomib) inhibits proteasome and NF-κB pathways, etc., but these drugs have a short half-life and are prone to lead to tumor drug resistance. Antibody drugs that have been marketed in recent years mainly target membrane receptors on the surface of tumor cells, su...

Claims

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Application Information

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IPC IPC(8): A61K47/64A61K31/537A61P35/00C07K7/06C07K1/02
CPCA61K47/64A61K31/537A61P35/00C07K7/06C07K19/00Y02P20/55
Inventor 陈小佳洪岸
Owner JINAN UNIVERSITY
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