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Preparation and application of PD-L1-targeted polypeptide derivative and 99mTc complex thereof

A technology of PD-L1 and peptide derivatives, which is applied in the field of preparation and application of PD-L1-targeting peptide derivatives and their 99mTc complexes, can solve the problems of not reflecting the immune status of tumors, and achieve a simple and stable labeling method Good performance and high marking rate

Inactive Publication Date: 2018-12-21
FUDAN UNIV SHANGHAI CANCER CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to its invasiveness, this method can only obtain part of the tumor tissue. Based on the heterogeneity of the tumor, the PD-L1 level determined by immunohistochemistry cannot reflect the overall immune status of the tumor.

Method used

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  • Preparation and application of PD-L1-targeted polypeptide derivative and 99mTc complex thereof
  • Preparation and application of PD-L1-targeted polypeptide derivative and 99mTc complex thereof
  • Preparation and application of PD-L1-targeted polypeptide derivative and 99mTc complex thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] The synthesis of embodiment 1 polypeptide compound HYNIC-Acp-NYSKPTDRQYHF

[0030] It was synthesized by solid phase synthesis. Take Wang-Phe-NH 2 Resin is the starting material, add 3 times molar equivalents of Fmoc-His-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Arg-OH, Fmoc-Asp(tBu) in sequence -OH, Fmoc-Thr(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Asn(Trt )-OH, Fmoc-Acp-OH and Boc-Hynic. Each amidation reaction uses 6-fold molar equivalents of HBTU and 6-fold molar equivalents of N,N-diisopropylethylamine as catalysts. After each amidation reaction, the Fmoc protecting group was removed with 20% piperidine, and finally trifluoroacetic acid was used to remove the remaining protecting group and Wang-Phe-NH 2 resin. The polypeptide was isolated and purified by semi-preparative HPLC. The product was characterized by mass spectrometry and HPLC. Its spectrogram is attached figure 1 and 2 .

Embodiment 2L-99

[0031] Example 2L- 99mSynthesis of Tc-HYNIC-Acp-NYSKPTDRQYHF Complex

[0032] Take 10 μg of the above product HYNIC-Acp-NYSKPTDRQYHF and add it to the mixture of 0.5mL EDDA solution (20mg / mL dissolved in 0.1M NaOH solution) and 0.5mL Tricine solution (40mg / mL dissolved in 0.05M pH 6.0 phosphate buffer) Dissolve, then add 25 μL SnCl 2 solution (0.1-10mg / mL dissolved in 0.01-1M HCl), 30mCi Na 99m TCO 4 Solution, react at 100°C for 10min. After the reaction, the reaction solution was sterilized by a 0.22 μm Millipore needle filter. The product does not need to be purified, and the labeling rate is >99%.

[0033]

[0034] The above-mentioned labeled products were identified by reversed-phase high-performance liquid chromatography.

[0035] Reversed-phase high-performance liquid chromatography method: the chromatographic column is Agilent ZOBRAX C-18 column (5 μm, 4.6×250 mm). The mobile phase was acetonitrile / 0.1% trifluoroacetic acid / water. The washing conditions are 0...

Embodiment 3

[0037] Embodiment 3 polypeptide compound HYNIC-NH 2 -(CH 2 ) m Synthesis of -C(O)-NYSKPTDRQYHF

[0038] It was synthesized by solid phase synthesis. Take Wang-Phe-NH 2 The resin is the starting material, and Fmoc-His-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Arg-OH, Fmoc-Asp( tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Asn (Trt)-OH, Fmoc-NH 2 -(CH 2 ) m -COOH (m=1-20) and Boc-Hynic. Each amidation reaction uses 1-6 molar equivalents of HBTU and 1-10 molar equivalents of N,N-diisopropylethylamine as catalysts. After each step of the amidation reaction, the Fmoc protecting group was removed with 5%-50% piperidine, and finally trifluoroacetic acid was used to remove the remaining protecting group and Wang-Phe-NH 2 resin. The polypeptide was isolated and purified by semi-preparative HPLC.

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Abstract

The invention discloses a PD-L1-targeted polypeptide derivative and a 99mTc complex of the PD-L1-targeted polypeptide derivative. The PD-L1-targeted polypeptide derivative and the 99mTc complex respectively have structures shown in structural formulas I and II. The PD-L1-targeted polypeptide derivative is labeled with 99mTc to form the complex, and the complex is used as a PD-L1 specific SPECT / CTdeveloping agent. The developing agent has the advantages that the PD-L1 positive tumor specificity is high, any toxic or side effect is small, and the absorbing dose is low; the developing agent is avery excellent SPECT / CT developing agent. The structure formulas I and II are shown in the attached figures.

Description

technical field [0001] The invention relates to a polypeptide derivative targeting PD-L1 and its 99m The preparation method and application of Tc complex, especially relate to a kind of 99m A Tc-labeled PD-L1-specific polypeptide derivative, a preparation method thereof, and an application thereof as a PD-L1-specific SPECT / CT imaging agent. Background technique [0002] In recent years, immunotherapy has become a research hotspot in tumor treatment. Immunotherapy restores the body's normal anti-tumor immune response by activating the body's own immune cells suppressed by tumor cells, thereby controlling and eliminating tumors. There are many mechanisms of immunotherapy, among which the research on PD-1 / PD-L1 is the most popular. The surface of tumor cells generally expresses excessive PD-L1 receptors, which will inhibit the proliferation of T lymphocytes and release cytotoxins after binding to the PD-1 receptors on the surface of immune T cells, thereby causing the vitali...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/08C07K1/00A61K51/08
CPCA61K51/08C07K7/08Y02P20/55
Inventor 许晓平章英剑
Owner FUDAN UNIV SHANGHAI CANCER CENT
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