Tumor targeting polypeptide and application thereof in preparation of polypeptide drug conjugate

A drug conjugate, tumor targeting technology, applied in the field of anti-tumor, can solve the problem of difficulty in 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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  • Tumor targeting polypeptide and application thereof in preparation of polypeptide drug conjugate
  • Tumor targeting polypeptide and application thereof in preparation of polypeptide drug conjugate
  • Tumor targeting polypeptide and application thereof in preparation of polypeptide drug conjugate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] The synthesis of embodiment 1, LLC2B

[0077] 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:

[0078](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

[0084] Example 2: Affinity detection results of LLC2B and RTK family members

[0085] (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 protein were purchased from Beijing Sino Biological Technology Co., Ltd.;

[0086] (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);

[0087] (3) After the sample is prepared, it is filtered, and it is placed at room temperature for 30 minutes to be operated on the machine (the instrument used is an isothermal titration calorimeter ITC200)

[0088] (4) Manually clean the sample pool and reference pool for 7 to 8 times, and then machine clean the sample pool and titr...

Embodiment 3

[0094] Example 3: Synthesis of LLC2B-SS-DM1

[0095] The structure of LLC2B-SS-DM1 is as figure 1 As shown, the coupling process is as figure 2 Shown:

[0096] (1) Weigh 1.0 g of amide resin, then put the amide resin into the reaction tube, add 2 times the volume of DMF (N,N-dimethylformamide) and soak for 2 to 3 hours; discard the solution by suction, add 20% (w / w) DMF solution (8 milliliters) of 4-methylpiperidine, reacted for 5 minutes, removed the solution and added DMF solution (8 milliliters) containing 20% ​​(w / w) 4-methylpiperidine ), and reacted for 15 minutes; the solvent was drained through a suction filtration device, followed by washing with DMF three times, methanol three times and DMF three times, and then adding analytical grade DMF to balance for 2 to 5 minutes.

[0097] (2) Drain the solvent through a suction filtration device, add 2 times the volume of the compound Fmoc-Lys(Dde)-OH and 5 times the molar concentration of HCTU containing 5 times the molar ...

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Abstract

The invention discloses a tumor targeting polypeptide and application thereof in preparation of a polypeptide drug conjugate. The amino acid sequence of the tumor targeting polypeptide is (Hyp)-(D-Asn)-(D-Leu)-(D-Lys)-(Cit)-(Acpc)-(D-Asp)-(Aad)-(Nva). According to the present invention, the small molecule polypeptide is adopted as the target head, and effect molecules and linker molecules commonlyused in the ADC drug research and development at present are selected for combination and coupling to form the new polypeptide drug conjugate, and the conjugate has characteristics of relatively small molecular weight, good penetrability, and multi-targeting. The polypeptide can play a role on tumors with high expression of a plurality of tyrosine kinase receptors including Her2 and FGFR2, and can be used as a novel tumor treatment pathway.

Description

technical field [0001] The invention belongs to the field of anti-tumor technology, in particular to a tumor-targeting polypeptide and its application in preparing polypeptide drug conjugates. 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 Bortezomib can inhibit proteasome and NF-κB pathways, etc., but these drugs have a short half-life and are likely to cause tumor drug resistance; antibody drugs that have been marketed in recent years mainly target the membrane on the surface of tumor cells Receptors such as EGFR, HER2 / neu, VEGFR, etc., ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06A61K47/64A61K31/537A61P35/00
CPCA61K31/537A61K47/64A61P35/00C07K7/06
Inventor 陈小佳洪岸
Owner JINAN UNIVERSITY
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