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Novel cd73 antibody, preparation and uses thereof

A -CD73, antibody technology, applied in the field of improved anti-CD73 antibody, can solve the problem that CD73 protein does not inhibit CD73 protease activity

Pending Publication Date: 2020-02-04
HELMHOLTZ ZENT MUNCHEN DEUTES FORSCHUNGSZENT FUR GESUNDHEIT & UMWELT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Several anti-CD73 mAbs are known in the prior art (WO2016081748), however, none of them are able to specifically inhibit the membrane-bound form of the CD73 protein while substantially not inhibiting the enzymatic activity of the soluble form of the CD73 protein

Method used

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  • Novel cd73 antibody, preparation and uses thereof
  • Novel cd73 antibody, preparation and uses thereof
  • Novel cd73 antibody, preparation and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0563] Example 1: Preparation of functional mAbs targeting membrane proteins on the surface of cancer cells

[0564] In this example, mAb 22E6 ( figure 2 ). Extracellular vesicles (EVs) were obtained from the GBM20 cell line by centrifugation, isolated from the supernatant, and injected into rats using standard immunization techniques known in the art. Hybridoma cell lines derived from rat splenocytes were generated and screened for antibodies that bind to and specifically inhibit the enzymatic activity of the membrane-bound form of CD73 protein. Identification of the mAb of interest, and thus mAb 22E6, was performed by immunoprecipitation coupled to mass spectrometry (IP-MS).

Embodiment 2

[0565] Example 2: Characterization of the binding affinity and specificity of mAb 22E6

[0566] In this example, mAb 22E6 binding affinity was characterized (Table 3). It has been shown that mAb 22E6 recognizes the CD73 protein on cancer cells. Using specific flow cytometry techniques, fluorescence-activated cell sorting (FACS) with 22E6 and a secondary mAb labeled with an anti-rat-IgG-specific fluorophore, it has been shown that the protein recognized by the 22E6 mAb of the present invention exists On the surface of human cancer cells of a total of about 30 cell lines tested. Four representative cell lines of the 30 tested cell lines are shown here in image 3 In A. U138 MG and GBM20 are glioblastoma cell lines, and MDA-MB231 and T47D are human breast cancer cell lines. To compare the specificity of mAb 22E6 with that of a commercially available CD73 mAb, immunoblotting was performed with the same cell lines (U138 MG, GBM20, MDA-MB231, and T47D) using a commercially avail...

Embodiment 3

[0567] Example 3: Characterization of the inhibitory properties of mAb 22E6

[0568] In this example, the inhibitory properties of mAb 22E6 were characterized and it has been shown that 22E6 blocks the production of adenosine ( Figure 4 ). Therefore, in this Figure 4 As indicated, CD73-positive human A375 melanoma cells were incubated with AMP (adenosine monophosphate) for 60 min, and the concentrations of AMP (left) and ADO (adenosine, right) in the supernatant were measured. Furthermore, it has been shown that 22E6 mAb inhibits ADO production by human CLL cells ( Figure 5 ). Adenosine 5'-(α,β-methylene)diphosphate (APCP) is a small molecule specific CD73 inhibitor.

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Abstract

The present invention relates to improved anti-CD73 antibodies which, in comparison to prior art anti-CD73 antibodies bind to a membrane-bound form of CD73 protein having cancer-promoting role and inhibit its enzymatic activity, while essentially not inhibiting a soluble form of CD73 protein involved in cardioprotection. The present invention further relates to methods of generation of such specific anti-CD73 antibodies and uses thereof including uses as medicaments and in methods for treatment, amelioration, prophylaxis and diagnostics of cancer.

Description

[0001] This application contains a Sequence Listing in computer readable form, which is hereby incorporated by reference. [0002] field of invention [0003] The present invention relates to an improved anti-CD73 antibody which binds a membrane-bound form of the CD73 protein with a tumor-promoting effect and specifically inhibits its enzymatic activity as compared to prior art anti-CD73 antibodies, while substantially Up does not inhibit the soluble form of the CD73 protein involved in cardioprotection. The invention also relates to methods of producing such specific anti-CD73 antibodies, and uses thereof, including as medicines and in methods for treating, alleviating, preventing and diagnosing cancer. Accordingly, the anti-CD73 monoclonal antibodies of the invention have novel drug potential as immune checkpoint inhibitors for the treatment of cancer (eg, AML, ALL) and other immune-mediated diseases, either as a sole therapy or in combination with doxorubicin. Background t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28
CPCC07K16/2896A61P35/00C07K2317/565C07K2317/76C07K2317/92
Inventor R·蔡德勒B·冯诺贝克R·菲德勒S·浩克
Owner HELMHOLTZ ZENT MUNCHEN DEUTES FORSCHUNGSZENT FUR GESUNDHEIT & UMWELT
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