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Application of novel function of CD146 targeted as co-receptor of vascular endothelial growth factor receptor-2 (VEGFR-2) in anti-tumor angiogenesis treatment

A tumor blood vessel and tumor technology, applied in the field of tumor treatment, can solve the problems of inability to completely kill tumor cells, inability to achieve therapeutic effects, and recurrence of remaining cells.

Inactive Publication Date: 2014-01-15
INSITUTE OF BIOPHYSICS CHINESE ACADEMY OF SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At the same time, there are still some problems and bottlenecks in antibody immunotherapy targeting tumor blood vessels. For example, antibody therapy often cannot completely kill all tumor cells, and the remaining cells are prone to relapse after drug withdrawal
Moreover, single-target antibody therapy has limitations and cannot achieve effective therapeutic effects

Method used

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  • Application of novel function of CD146 targeted as co-receptor of vascular endothelial growth factor receptor-2 (VEGFR-2) in anti-tumor angiogenesis treatment
  • Application of novel function of CD146 targeted as co-receptor of vascular endothelial growth factor receptor-2 (VEGFR-2) in anti-tumor angiogenesis treatment
  • Application of novel function of CD146 targeted as co-receptor of vascular endothelial growth factor receptor-2 (VEGFR-2) in anti-tumor angiogenesis treatment

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1: Interaction between CD146 and VEGFR-2 at the cellular level;

[0024] Both CD146 and VEGFR-2 are markers of endothelial cells and are key molecules in the process of angiogenesis, but their connection is not clear. In order to study the relationship between the two, we confirmed the interaction between CD146 and VEGFR-2 at the cellular level by co-immunoprecipitation and other methods. Anti-CD146 monoclonal antibody AA98 can block the interaction between CD146 and VEGFR-2.

[0025] Main materials: human umbilical vein endothelial cell line (HUVECs) (ATCC, CRL-1730), HEK293T cell line stably transfected with CD146cDNA (ATCC, CRL-11268) (HEK293T / CD146), etc.

[0026]Main reagents: cell lysate, PBS, mouse-derived anti-CD146 monoclonal antibody AA1 (produced by our laboratory independently. Preservation institution: China General Microbiology Collection Center; preservation number: CGMCC No.2310; preservation date: 2007.12.28), rabbit Anti-VEGFR-2 antibody (pur...

Embodiment 2

[0043] Example 2: The anti-CD146 antibody blocks the activation of the VEGFR-2 signaling pathway caused by VEGF stimulation by blocking the interaction between CD146 and VEGFR-2;

[0044] The adhesion molecule CD146 has a key role in angiogenesis. As a co-receptor of VEGFR-2, CD146 regulates the VEGFR-2 signaling pathway. Anti-CD146 monoclonal antibody AA98 can block the interaction between CD146 and VEGFR-2, thereby blocking the activation of VEGFR-2 signaling pathway induced by VEGF stimulation.

[0045] Incubate HUVECs with anti-CD146 monoclonal antibody AA98 or AA1 (100μg / ml), and after 1 hour at 37°C, wash with cell culture medium three times, then stimulate with VEGF (50ng / ml) and lyse the cells for biochemical analysis path. Such as figure 2 (A) As shown in HUVECs, AA98 can block the interaction between endogenous CD146 and VEGFR-2. As shown in (B-F), VEGF stimulation (5 minutes) can cause the phosphorylation of VEGFR-2, as well as the activation of downstream sign...

Embodiment 3

[0046] Example 3: Anti-CD146 antibody inhibits endothelial cell migration and angiogenesis induced by VEGF stimulation;

[0047] Angiogenesis mainly provides nutrients for tumors and provides pathways for tumor cell metastasis, so it plays a vital role in tumor growth. Inhibition of angiogenesis can inhibit tumor growth to a great extent. VEGF is the main cytokine secreted by tumor cells, and the signaling pathway mediated by it ultimately determines tumor angiogenesis. CD146 participates in and regulates VEGF-VEGFR-2 signaling pathway, and anti-CD146 antibody inhibits the migration and angiogenesis of endothelial cells stimulated by VEGF.

[0048] Main materials: human umbilical vein endothelial cell line, 96-well Transwell plate (Corning HTS Transwell-96 Cell Migration Products), etc.

[0049] Main reagents: VEGF (purchased from Upstate Biotechnology, Cat. No. B500014), anti-CD146 antibodies AA98 and AA1, mouse IgG (mIgG, purchased from Sigma-Aldrich, Cat. No. I5381), Matr...

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Abstract

The present invention provides a composite for suppressing tumor angiogenesis so as to suppress tumor growth, comprising: an anti-CD146 antibody or a function fragment thereof; and an anti-VEGF antibody or a function fragment thereof. The present invention further provides use of the composite in preparing medicine for suppressing tumor growth.

Description

technical field [0001] The present invention relates to compositions useful in the treatment of tumors. Specifically, the present invention relates to a combination of anti-CD146 antibody and anti-VEGF antibody, which can be used for treating tumors. More specifically, the composition of the anti-CD146 monoclonal antibody AA98 or its functional fragments and the anti-VEGF monoclonal antibody bevacizumab or its functional fragments involved in the present invention can jointly inhibit the activation and activation of the VEGF-VEGFR-2 signaling pathway. The endothelial cell migration, angiogenesis and other functions caused by it can more effectively inhibit tumor growth, and more specifically inhibit pancreatic tumors. Background technique [0002] Cancer is currently the number one killer that endangers human life and health. The annual incidence of malignant tumors in my country is about 2.6 million. People who died of cancer accounted for more than 20% of the total numb...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61P35/00
CPCA61K2039/507A61P35/00C07K16/22C07K16/3092C07K2317/73
Inventor 阎锡蕴姜天霞罗永挺段红霞卢迪杨东玲冯静
Owner INSITUTE OF BIOPHYSICS CHINESE ACADEMY OF SCIENCES
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