Novel Colitis Immunotherapy Targets Bin1 and Improves Colon Cell Barrier Function.

Abstract

BACKGROUND:

Ulcerative colitis (UC) is associated with defects in colonic epithelial barriers as well as inflammation of the colon mucosa resulting from the recruitment of lymphocytes and neutrophils in the lamina propria. Patients afflicted with UC are at increased risk of colorectal cancer. Currently, UC management employs general anti-inflammatory strategies associated with a variety of side effects, including heightened risks of infection, in patients where the therapy is variably effective. Thus, second generation drugs that can more effectively and selectively limit UC are desired.

AIM:

Building on genetic evidence that attenuation of the Bin1 (Bridging integrator 1) gene can limit UC pathogenicity in the mouse, we pursued Bin1 targeting as a therapeutic option.

METHODS:

Mice were injected with a single dose of Bin1 mAb followed by oral administration of 3 % DSS in water for 7 days.

RESULTS:

In this study, we offer preclinical proof of concept for a monoclonal antibody (mAb) targeting the Bin1 protein that blunts UC pathogenicity in a mouse model of experimental colitis. Administration of Bin1 mAb reduced colitis morbidity in mice; whereas unprotected mice is characterized by severe lesions throughout the mucosa, rupture of the lymphoid follicle, high-level neutrophil and lymphocyte infiltration into the mucosal and submucosal areas, and loss of surface crypts. In vitro studies in human Caco-2 cells showed that Bin1 antibody altered the expression of tight junction proteins and improved barrier function.

CONCLUSIONS:

Our results suggest that a therapy based on Bin1 monoclonal antibody supporting mucosal barrier function and protecting integrity of the lymphoid follicle could offer a novel strategy to treat UC and possibly limit risks of colorectal cancer.

• Authors: Sunil Thomas, Joanna M Mercado, James DuHadaway, Kate DiGuilio, James M Mullin, George C Prendergast
• Journal: Digestive diseases and sciences (Dig Dis Sci) Vol. 61 Issue 2 Pg. 423-32 (Feb 2016) ISSN: 1573-2568 [Electronic] United States
• PMID: 26195312 (Publication Type: Journal Article)

Chemical References

• Adaptor Proteins, Signal Transducing
• Antibodies, Monoclonal
• BIN1 protein, human
• Bin1 protein, mouse
• Immunoglobulin G
• Indoleamine-Pyrrole 2,3,-Dioxygenase
• Nerve Tissue Proteins
• Nuclear Proteins
• Tumor Suppressor Proteins

Topics

• Adaptor Proteins, Signal Transducing (antagonists & inhibitors, genetics, immunology, metabolism)
• Animals
• Antibodies, Monoclonal (administration & dosage, therapeutic use)
• Cell Line
• Colitis (therapy)
• Dose-Response Relationship, Drug
• Humans
• Immunoglobulin G
• Indoleamine-Pyrrole 2,3,-Dioxygenase (genetics, metabolism)
• Mice
• Nerve Tissue Proteins (antagonists & inhibitors, immunology)
• Nuclear Proteins (genetics, metabolism)
• Tumor Suppressor Proteins (antagonists & inhibitors, genetics, immunology, metabolism)