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Pharmaceutical composition for targeted radiation and immune combined treatment of tumors

A technology of immunotherapeutic drugs and compositions, which is applied in the direction of drug combinations, antineoplastic drugs, radioactive carriers, etc., can solve problems such as insufficient research, unclear immunological effects, and short clinical application time, so as to promote antigen release and increase activation Effect

Active Publication Date: 2021-11-09
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the clinical application time of targeted radiation therapy is short, and the immunological effects it can cause are still unclear, so the research on combined targeted radiation and immune therapy is still insufficient

Method used

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  • Pharmaceutical composition for targeted radiation and immune combined treatment of tumors
  • Pharmaceutical composition for targeted radiation and immune combined treatment of tumors
  • Pharmaceutical composition for targeted radiation and immune combined treatment of tumors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Example 1 Remodeling of tumor immune microenvironment by targeted radiotherapy

[0062] (1) Animal model

[0063] MC-38 (mouse colorectal cancer cell) cells were provided by the Key Research Group of the Institute of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences. Cells were cultured in DMED high-glucose medium containing 10% heat-inactivated fetal bovine serum at 37°C in 5% CO 2 cultured in a humidity incubator. Female C57 / BL6 mice (4-6 weeks old) were purchased from the Experimental Animal Department of Peking University Health Science Center, and the animal experiments were in compliance with the regulations and requirements of the Animal Care and Use Committee of Peking University. In order to prepare the tumor-bearing mouse model, inject 100 μL (amount of 1×10 6 ) of MC-38 single cell suspension, tumors can be formed after about 1 week.

[0064] (2) Targeted radiation therapy

[0065] Twenty-one MC-38 tumor-bearing mice were rando...

Embodiment 2

[0076] Example 2 Image-guided Targeted Radiation Combined with PD-L1 Blocking Therapy

[0077] (1) PD-L1 Nanobody Probe 9m Preparation of Tc-Nanobodies:

[0078] Prepared with PD-L1 as biomarker 9m Tc-Nanobodies. Selected nanobodies against mouse PD-L1 (MY1523) use LPTEG-His at the C-terminus 6 Tags are used for affinity purification on Ni-Sepharose and site-specific ligation of transpeptidase Sortase-A. The KD value of the nanobody and mouse PD-L1 is 49.70±7.90nM, and the IC50 value is 59.23±0.04nM, with high affinity and specificity.

[0079] 9m Tc-Nanobodies were labeled using a two-step process. First, prepare 99m Tc-HYNIC-G 4 K (HYNIC = 6-hydrazinonicotinyl, G4K = Gly-Gly-Gly-Gly-Lys). Add 3 μg HYNIC-G to 200 μL succinic acid buffer (250 mM, pH=4.8) 4 K(NH 2 -G 4 K(HYNIC)-OH), 5mg TPPTS (triphenylphosphine-3,3′, 3″-sodium trisulfonate), 6.5mg tricine (N-tris(hydroxymethyl)methylglycine) and 74~96MBq Na 99m TCO 4 The eluent was mixed and reacted at 99°C for ...

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Abstract

In particular, the present invention relates to a pharmaceutical composition containing a labeled complex Nu-BFC-A-(L) n-RGD polypeptide as defined in the present invention, an immunotherapeutic drug, and an optional nano antibody molecular imaging probe. The labeled complex provided by the invention is an effective targeted radiotherapy drug, can significantly increase infiltration of CD4 + and CD8 + T lymphocytes (rather than T-reg cells), and can significantly up-regulate PD-L1 expression on the surface of host myeloid immune cells (rather than tumor cells) in tumors. Therefore, the optimal synergistic effect can be obtained by carrying out PD-L1 blocking treatment after targeted radioactive drug delivery treatment. Besides, by applying the PD1 or PD-L1 nano antibody molecular imaging probe, the expression of PD-L1 in the tumor after targeted radiation treatment can be observed, and the method has guiding significance for making a treatment strategy of targeted radiation and immune combined treatment and is beneficial to improving the effect of the combined treatment.

Description

technical field [0001] The invention relates to a combination of tumor-targeted RGD polypeptide-modified targeting radiopharmaceuticals combined with immunotherapeutic drugs. Background technique [0002] Conventional treatments for cancer, such as radiation and chemotherapy, typically target the tumor cells themselves and elicit a response in most patients. Although these conventional treatments can produce effective responses in the early stage, drug resistance and recurrence often appear in the advanced stage of cancer, leading to treatment failure. Different from the mode of action of the above-mentioned conventional therapies, immunotherapy promotes the body's own anti-tumor response by activating the immune system, and is less likely to develop drug resistance. Immune checkpoint inhibition therapy (immune checkpoint blockade), as a major breakthrough in tumor treatment, has obvious curative effect on immunotherapy of various malignant solid tumors. Programmed cell de...

Claims

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Application Information

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IPC IPC(8): A61K51/10A61K51/04A61K51/08A61K39/395A61P35/00
CPCA61K51/048A61K51/0482A61K39/395A61K51/1027A61K51/08A61P35/00A61K2039/505Y02A50/30
Inventor 王凡史继云高瀚男贾兵
Owner PEKING UNIV
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