Early and non invasive method for assessing a subject's risk of having pancreatic ductal adenocarcinoma and methods of treatment of such disease

Patent metadata

Field	Value
Publication number	US-11740243-B2
Application number	US-201716081462-A
Country	US
Kind code	B2
Filing date	Mar 15, 2017
Priority date	Mar 15, 2016
Publication date	Aug 29, 2023
Grant date	Aug 29, 2023

Abstract

A non invasive diagnostic method of pancreatic ductal adenocarcinoma (PDAC) in a subject is provided. The method comprises the step of measuring the level of βig-h3 protein in a blood sample wherein the serum level of βig-h3 is positively correlated with the risk of having a PDAC. By following studies on 2 distinct cohorts of 20 and 104 of PDAC patients, and on PDAC mouse model, the inventors show that βig-h3 can be directly detected in the blood sample and βig-h3 is expressed very early in tumorigenesis in pancreatic neoplastic lesions. Also provided is a βig-h3 protein, for use in the treatment of PDAC. The inventors found that βig-h3 bind directly on CD8 + T cells by reducing their activation and cytotoxic properties. Furthermore, the use of neutralizing βig-h3 antibodies in PDAC mouse model reduced tumor growth by enhancing CD8 + T cell anti-tumoral response. Thus, neutralizing βig-h3 which acts as a novel immunological check-point target in PDAC therefore allows to restore beneficial anti-tumor immunity in PDAC.

First claim

The invention claimed is:

1. A method of treating a patient afflicted with pancreatic ductal adenocarcinoma having a stroma comprising cancer associated fibroblasts producing transforming growth factor β-induced protein (βig-h3), comprising
selecting an anti-βig-h3 neutralizing antibody capable of binding to stroma-produced βig-h3 protein and inhibiting interaction between stroma-produced βig-h3 protein and αVβ3 integrin,
administering to the patient a therapeutically effective amount of the anti-βig-h3 neutralizing antibody binding to stroma-produced βig-h3 protein and inhibiting interaction between stroma-produced βig-h3 protein and αVβ3 integrin,
obtaining specific binding of said anti-βig-h3 neutralizing antibody to stroma-produced βig-h3,
inhibiting interaction between stroma-produced βig-h3 protein and αVβ3 integrin, and
inhibiting the inhibition of cluster of differentiation 8 (CD8)+T cell activation.

2. A method to activate the anti-tumoral cluster of differentiation 8 (CD8)+T cell response of a patient affected with a cancer having a stroma comprising cancer associated fibroblasts expressing or secreting a transforming growth factor β-induced protein (βig-h3), comprising
selecting an anti-βig-h3 neutralizing antibody capable of inhibiting interaction between stroma-produced βig-h3 protein and αVβ3 integrin, and
administering to the patient a therapeutically effective amount of the anti-βig-h3 neutralizing antibody inhibiting interaction between βig-h3 protein and αVβ3 integrin.

3. The method according to claim 2 , wherein the cancer is a solid tumor selected from the group consisting of pancreatic cancer, esophageal cancer, squamous cell carcinoma, gastric carcinoma, hepatic carcinoma, colon cancer, and melanoma.

4. The method according to claim 3 , wherein the solid tumor is pancreatic cancer.

5. The method according to claim 3 wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.

6. A method of reducing of tumor growth in vivo or inducing neutralization of tumor growth in vivo in a patient afflicted with pancreatic ductal adenocarcinoma having a stroma comprising cancer associated fibroblasts producing βig-h3 protein, comprising
selecting an anti-βig-h3 neutralizing antibody capable of binding to stroma-produced βig-h3 protein and inhibiting interaction between stroma-produced βig-h3 protein and αVβ3 integrin,
administering to the patient a therapeutically effective amount of the anti-βig-h3 neutralizing antibody inhibiting interaction between βig-h3 protein and αVβ3 integrin,
obtaining specific binding of said anti-βig-h3 neutralizing antibody to stroma-expressed βig-h3,
inhibiting interaction between stroma-produced βig-h3 protein and αVβ3 integrin, and
inhibiting the inhibition of cluster of differentiation 8 (CD8)+T cell activation.

7. A method to activate the anti-tumoral cluster of differentiation 8 (CD8)+T cell response of a patient affected with a cancer having a stroma comprising cancer associated fibroblasts expressing or secreting a transforming growth factor β-induced protein (βig-h3) and obtaining anti-transforming growth factor β-induced protein (βig-h3) neutralizing effect on tumor growth in vivo, comprising
selecting an anti-βig-h3 neutralizing antibody capable of inhibiting interaction between stroma-produced βig-h3 protein and αVβ3 integrin,
administering to the patient a therapeutically effective amount of the anti-βig-h3 neutralizing antibody inhibiting interaction between βig-h3 protein and αVβ3 integrin,
inhibiting interaction between stroma-produced βig-h3 protein and αVβ3 integrin,
wherein tumor growth in vivo is reduced.

8. The method of claim 7 , further comprising the step of inhibiting tumor cell growth.

9. The method according to claim 7 , wherein the cancer is a solid tumor selected from the group consisting of pancreatic cancer, esophageal cancer, squamous cell carcinoma, gastric carcinoma, hepatic carcinoma, colon cancer, and melanoma.

10. The method according to claim 9 , wherein the solid tumor is pancreatic cancer.

11. The method according to claim 9 , wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.

12. A method of treating a patient afflicted with pancreatic ductal adenocarcinoma having a stroma comprising cancer associated fibroblasts producing βig-h3 protein, comprising
selecting an anti-βig-h3 neutralizing antibody capable of binding to stroma-produced βig-h3 protein and inhibiting interaction between stroma-produced βig-h3 protein and αVβ3 integrin,
administering to the patient a therapeutically effective amount of the anti-βig-h3 neutralizing antibody
specifically binding to βig-h3, and
neutralizing an interaction between βig-h3 protein and αVβ3 integrin.

Assignees

• Inst Nat Sante Rech Med
• Centre Nat Rech Scient
• Univ Claude Bernard—Lyon 1
• Centre Leon Berard
• Kist Korea Institute Of Science And Tech
• Univ Claude Bernard—Lyon

Inventors

• In-San Kim
• Bertolino Philippe
• Hennino Ana

Classifications

• G01N33/57525 Primary

  of the liver or pancreas · CPC title

• G01N33/57585

  involving compounds identifiable in body fluids · CPC title

• G01N33/57438 Primary

  Physics · mapped topic

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title