Medicine composition for treating non-hodgkin lymphoma

A non-Hodgkin, lymphoma technology, used in drug combinations, anti-tumor drugs, pharmaceutical formulations, etc., can solve the problem of no clinical trial reports

Active Publication Date: 2019-11-26
FUDAN UNIV SHANGHAI CANCER CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, only CpG oligodeoxynucleotides were further evaluated in clinical trials (Phase I) for their safety in patients with B-cell NHL, and no further clinical trials were reported

Method used

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  • Medicine composition for treating non-hodgkin lymphoma
  • Medicine composition for treating non-hodgkin lymphoma
  • Medicine composition for treating non-hodgkin lymphoma

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1 Construction of Rituximab-mediated CDC-tolerant Raji cells and Ramos cells

[0056] Rituximab-mediated ADCC is carried out by immune cells of individual patients, and their resistance to ADCC is caused by intrinsic characteristics of immune cells, such as FcγRIIIa gene polymorphisms. However, apoptosis plays only a negligible role in the antitumor activity of rituximab. Therefore, we constructed two BL cell lines, Ramos640 and Raji32, that were resistant to rituximab-mediated complement-dependent cytotoxicity at rituximab concentrations of 640 and 32 μg / mL, respectively. Its construction method is as follows:

[0057]Two BL cell lines, Raji and Ramos, were purchased from American typeculture collection (ATCC) (Manassas, VA), and the cells were cultured in 10% (volume content) fetal bovine serum (GIBCO BRL Company, Grand Island, NY) and 1% (volume content) penicillin / streptomycin (Ambion, Austin, TX) in RPMI 1640 medium.

[0058] As a complement resource, no...

Embodiment 2

[0060] Example 2 Western blot analysis and CDC effect determination

[0061] The present invention performed immunoblot analysis according to standard methods.

[0062] The CDC effect was determined by fluorescence-activated cell sorting (FACS) analysis to detect propidium iodide (PI)-stained positive cells. Specifically, after washing with PBS, cells were incubated with fluorescein-conjugated antibodies for 30 minutes, then rinsed and resuspended in PBS. Flow cytometric analysis was performed on a Cytomics FC500MPL flow cytometer (Beckman Coulter, Brea, CA) and analyzed with FlowJo software (Ashland, OR). We sorted cells based on the relative fluorescence with the MoFlo XDP instrument (Beckman Coulter, Brea, CA) using the PE Annexin V Apoptosis Detection Kit (BD Pharmingen, San Diego, CA) according to its manufacturer's instructions Apoptosis analysis.

Embodiment 3

[0063] Example 3 Down-regulation of CD20 and up-regulation of CD59 lead to tolerance of BL cells to rituximab-mediated CDC

[0064] Using Western blot analysis ( figure 1 and image 3 ) and FACS ( figure 2 and Figure 4 ), we found that the expression of CD20 was decreased and the expression of CD59 was increased in both drug-resistant cells compared with their original cells ( Figure 1-Figure 4 ). However, the expression of two other membrane complement regulatory proteins (mCRP), CD55 and CD46, was not consistent in the two resistant cells. The expression of CD55 decreased in Ramos640, but increased in Raji32; while the expression of CD46 did not change in Ramos640, but decreased in Raji32 ( Figure 1-Figure 4 ). These results are consistent with previous reports that decreased CD20 expression and elevated CD59 expression lead to resistance of BL cells to rituximab-mediated CDC. However, since the previous studies did not obtain good results in the studies on increa...

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Abstract

The invention discloses a medicine composition for treating non-hodgkin lymphoma. The medicine composition is prepared from a protein kinase C inhibitor and rituximab, and thus the medicine composition for treating non-hodgkin lymphoma is further disclosed, the protein kinase C inhibitor and a pharmacologically-acceptable carrier are included to form a first preparation, and the rituximab and a pharmacologically-acceptable carrier form a second preparation. According to the medicine composition for treating non-hodgkin lymphoma, according to the discovery of hyperphosphorylation of PKC in rituximab resistant non-hodgkin lymphoma cells, apoptosis-promoting effect principle of a PKC inhibitor is combined, and researches indicate that the protein kinase C inhibitor used solely or combined with the rituximab can be used for treating rituximab resistant relapsed / refractory non-hodgkin lymphoma, and the overall survival can be significantly improved.

Description

technical field [0001] The invention relates to a pharmaceutical composition for treating non-Hodgkin's lymphoma, in particular to a pharmaceutical composition for treating B-cell non-Hodgkin's lymphoma. Background technique [0002] Burkitt's lymphoma (BL) is a highly aggressive B-cell non-Hodgkin's lymphoma (non-Hodgkin's lymphoma, NHL) that accounts for 3-5% of lymphomas in all age groups, including children 40-50% of lymphomas are characterized by high expression of c-MYC targets and germinal center-associated B-cell genes, and low expression of MHC-I molecules and NF-κB target genes. Adult BL patients respond poorly to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)-based regimens, with 2- and 5-year overall survival (OS) rates of approximately 50-65% , If it spreads to the bone marrow or the central nervous system, it will be further reduced to below 30%. In contrast, an intensive short-term chemotherapy regimen significantly increased survival to...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61K39/395A61K31/553A61P35/00
CPCA61K31/553A61K39/3955A61K45/06A61P35/00A61K2300/00A61K39/395
Inventor 胡维国
Owner FUDAN UNIV SHANGHAI CANCER CENT
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