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Application of CD73 ADC

A drug conjugate, CD73 technology, applied in the field of medicine

Pending Publication Date: 2020-09-29
FUDAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, the current main strategy for ADC research is to deliver targeted cytotoxics to kill tumors. The content disclosed in the above patents also only studies the ability of CD73 antibody-drug conjugates to directly kill tumor cells with high expression of CD73-

Method used

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  • Application of CD73 ADC

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1 The expression level of CD73 in tumors is higher than that in normal human tissues

[0064] In order to study the expression level of CD73 in tumor and normal tissues, we performed tissue chips (Outdo Biotech, Cat#HLugA180Su07) of clinical lung cancer and paracancerous samples and human lung cancer NCI-H441, NCI-H292 and NCI-H1299 cell lines. CD73 immunohistochemical staining (IHC) was performed on the xenografted tumor sections of nude mice. Staining results for clinical lung and paracancerous tumors were graded by pathologists. IHC combined score (CS) was quantified by staining intensity × percentage of positive tumor cells (cancer specimen) or lung epithelial cells (paracancer specimen). CS values ​​(eligible cancer 86 cases, paracancerous 81 cases) were divided into CD73 negative group (CS=0, n=66) and CD73 positive group (CS>0, n=101). Positive CS specimens were divided into low positive group (< / = median; n=51), and the remaining 50 samples were divide...

Embodiment 2

[0071] Example 2 The killing effect of CD73-ADC on tumor cells with high expression of CD73-

[0072] In order to study the killing effect of CD73-ADC on tumor cells with different CD73 expression levels, we used CD73-low expression cell line MDA-MB-453, CD73-high expression cell lines NCI-H441 and NCI-H292 (purchased from ATCC or Chinese Academy of Sciences cell line Library) was used as an in vitro tumor inhibition experimental model for research.

[0073] The above cells in the logarithmic growth phase were seeded into 96-well cell culture plates at a density of 800-2500 cells per well, 150 μL / well, 37 ° C, 5% CO 2 After culturing for about 5-12 hours, add different concentrations of CD73-ADCHu001-MMAE respectively, set 2-4 duplicate wells for each drug concentration, and corresponding vehicle control and blank control wells, and act for 5-6 days (according to the cell growth rate , to ensure sufficient number of cell divisions), discard the culture medium, add MTS reactio...

Embodiment 3

[0076] Example 3 Inhibitory effect of CD73-ADC on free CD73 and tumor cell membrane CD73 enzyme catalyzed hydrolysis of AMP to generate Ado

[0077] In order to study whether CD73-ADC has the same inhibitory effect as the corresponding monoclonal antibody drug on the activity of CD73 enzyme catalyzing the hydrolysis of adenosine phosphate (AMP) to adenosine (Ado), we conducted parallel studies using CD73-ADC and CD73 antibody.

[0078] Human recombinant free CD73 enzyme (CD73 extracellular region) was diluted to 0.1 μg / mL with antigen diluent, spread evenly in 96-well low adsorption culture plate, 25 μL / well. Add 50 μL of CD73 antibody Hu001 and CD73-ADC Hu001-MMAE into the culture plate according to a 3-fold gradient from 2 nM to 0.0009 nM, mix well (final concentration is 1 nM ~ 0.00045 nM), incubate at 37 °C for 1 hour, add 25 μL The mixture containing 1.2mM AMP and 0.4mM ATP was incubated at 37°C for 1h. Take out 50 μL of the above reaction solution and add it to another ...

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Abstract

The invention belongs to the field of medicine and relates to application of a CD73 ADC and particularly relates to application of the CD73 ADC in preparation of a drug which can kill high-expressiontumor cells in CD73- and activate a tumor immune microenvironment by inhibiting a CD73 adenosinase pathway. Compared with the prior art, the application verifies unique double technical effects of theCD73-ADC, wherein on one side, the CD73 ADC can directly kill the high-expression tumor cells in the CD73- and on the other side, the CD73 ADC activates the immune microenvironment by inhibiting theCD73 adenosinase pathway; and the dual-overlaid pharmacological mechanism is characterized by being efficient and low-toxicity and providing a new strategy for treatment of refractory tumors.

Description

technical field [0001] The invention relates to the field of medicine, in particular to the application of CD73 antibody-drug conjugates. Background technique [0002] In recent years, although the targeted therapy and immunotherapy of malignant tumors have made significant progress, tumor treatment still faces the challenges of low drug response rate and frequent secondary drug resistance. Recent studies have shown that tumor progression and drug resistance mechanisms often involve the interaction between the tumor and the tumor immune microenvironment, and the adenosinase CD73 (NT5E) is a drug target that has attracted much attention in this field. CD73 consists of two identical 70kD subunits anchored on the cell membrane surface by glycosylphosphatidylinositol (GPI). A variety of tumors such as lung cancer, breast cancer, and colorectal cancer have found that high expression of CD73 is closely related to poor prognosis. CD73 generates a large amount of adenosine (Ado) b...

Claims

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Application Information

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IPC IPC(8): A61K47/68A61K39/395A61K45/06A61P35/00
CPCA61K39/3955A61K45/06A61K47/6849A61P35/00
Inventor 余科刘亮
Owner FUDAN UNIV
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