Compositions containing antibodies that block vegf signaling pathway in low doses and uses thereof

A signaling pathway and composition technology, applied in the field of medicine, can solve problems such as damaging the survival of CAR-T cells, hindering CAR-T cells, and unsatisfactory effects

Active Publication Date: 2021-09-10
PERSONGEN BIOTHERAPEUTICS (SUZHOU) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the existence of abnormal tumor blood vessels and immunosuppressive tumor microenvironment, it seriously hinders the homing of intravenously infused CAR-T cells to the tumor lesion and impairs the survival of CAR-T cells inside the tumor, making The effect of this revolutionary technology in the treatment of solid tumors is still very unsatisfactory, and the application of CAR-T cells in the treatment of solid tumors still faces serious challenges internationally

Method used

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  • Compositions containing antibodies that block vegf signaling pathway in low doses and uses thereof
  • Compositions containing antibodies that block vegf signaling pathway in low doses and uses thereof
  • Compositions containing antibodies that block vegf signaling pathway in low doses and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0102] Effects of low-dose anti-angiogenic drugs on tumor blood vessels

[0103] The orthotopic MCaP0008 breast cancer model was constructed, and when the tumor diameter of MCaP0008 breast cancer mice reached 4-5mm, the mice were given the first low dose (1 / 4 of the general dose of mice) to block the VEGF signaling pathway drug (DC101 ) and rabbit anti-mouse IgG monoclonal antibody (control) treatment (set as 0 days), the frequency of drug injection was once every three days, and the dose was 10mg / kg (only 1 / 4 of the general dose for mice). Medicine 4 times. On the 11th day, the mice were perfused with 4% paraformaldehyde, and frozen sections (20 μm) of tumor tissues were prepared, and the tissue sections were stained for endothelial cell marker CD31 molecules and pericyte marker NG2 molecules. Tumor areas were randomly selected using a confocal laser scanning microscope for immunohistochemical image acquisition (4-6 areas per tumor tissue, 6-8 tumors per group), with a magni...

Embodiment 2

[0106] Effects of low-dose anti-angiogenic drugs combined with vaccine therapy on tumors in mice

[0107] In order to study the effect of tumor vascular normalization on tumor immunotherapy, a low-dose anti-angiogenic drug combined with vaccine treatment experiment was conducted. When the tumor diameter of the breast cancer mouse tumor model MCaP0008 reached 3 mm, they were randomly divided into groups and intraperitoneally injected 5×10 6 Mitomycin-pretreated MCaP0008 tumor cell vaccine or an equal volume of PBS (control) were injected on days 7, 9, 12, and 14, respectively. The anti-angiogenic drug DC101 (10 mg / kg) or rabbit anti-mouse IgG (10 mg / kg) were injected on the 13th, 16th, 19th, and 20th days respectively. Tumor size was measured starting on day 13 and every three days. Draw tumor growth curves. 10 mice per group.

[0108] The result is as figure 2 As shown, vaccine treatment alone had no significant inhibitory effect on tumor growth in mice, while normalizat...

Embodiment 3

[0110] Effects of low-dose anti-angiogenic drug therapy on tumor infiltration of T cells

[0111] To investigate the mechanism by which normalization of tumor vasculature enhances immunotherapy, infiltrating CD8+ and CD4+ T lymphocytes in tumor tissues were analyzed. When the tumor diameter of MCaP0008 breast cancer mice reaches 4-5mm, the mice are treated with low doses of DC101 and tumor cell vaccines. The frequency of DC101 and control rabbit anti-mouse IgG drug injections is once every three days, and the dose is 10mg / kg, administered 4 times in total. Then the tumor tissue was collected, a single cell suspension was prepared, and then the tumor infiltrating CD4+T cells and CD8+T cells were analyzed by flow cytometry.

[0112] The result is as image 3 As shown, the single low-dose blocking VEGF signaling pathway drug (group: PBS / D10) can significantly improve the infiltration ability of CD8+ and CD4+ lymphocytes, while the low-dose VEGF signaling pathway blocking drug ...

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Abstract

The invention provides a composition containing a low-dose VEGF signaling pathway blocker and its application. Specifically, the present invention provides the use of a low-dose VEGF signaling pathway blocker in the preparation of a tumor immunotherapy promoter, and a composition containing a low-dose VEGF signaling pathway blocker. Experiments of the present invention show that the low dose of VEGF signaling pathway blocker can induce the normalization of tumor blood vessels, significantly improve the effect of tumor immunotherapy, and can promote the infiltration of T lymphocytes into tumor tissues.

Description

technical field [0001] The present invention relates to the field of medicine, and more specifically relates to a composition containing a low-dose VEGF signaling pathway blocker, such as an antibody for blocking VEGF signaling pathway, and its application. Background technique [0002] First reported by Folkman in 1971, the volume of solid tumors exceeds 2-3mm 3 At this time, simple oxygen diffusion cannot support the growth of the tumor, and the formation of new blood vessels is necessary to support its continued growth. Compared with normal blood vessels, these new tumor blood vessels have the phenomenon of vascular expansion, tortuosity, cystic structure formation, irregularly connected branches, and uneven distribution of blood vessel density; the loss of the diameter adjustment mechanism leads to abnormal shunting, vascular permeability and Vascular spaces were significantly increased. Abnormal tumor neovascularization will eventually lead to uneven distribution of b...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K45/06A61K39/395A61K39/00A61P35/00
CPCA61K39/0011A61K39/3955A61K45/06A61K2300/00A61K2039/5156A61K2039/5158C07K14/7051C07K2319/03
Inventor 杨林黄玉辉游凤涛
Owner PERSONGEN BIOTHERAPEUTICS (SUZHOU) CO LTD
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