Intestinal barrier tightening by a cell‐penetrating antibody to Bin1, a candidate target for immunotherapy of ulcerative colitis

Thomas, Sunil; Hoxha, Kevt’her; Alexander, Walker; Gilligan, John P.; Dilbarova, Rima; Whittaker, Kelly; Kossenkov, Andrew V.; Prendergast, George C.; Mullin, James M.

doi:10.1002/jcb.27716

Cited by 19 publications

(43 citation statements)

References 50 publications

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“…Based on the observation we asked whether lowering the levels of BIN1 with specific antibodies would provide protection against UC. Our group found that the Bin1 antibody (99D) could exert drug‐like properties in an animal model of UC . Given the clinical genetics associating BIN1 with AD, and their molecular connections to Tau, we formed the hypothesis that anti‐Bin1 might be used as a drug to block Tau accumulation and disease pathology in AD patients.…”

Section: Discussionmentioning

confidence: 99%

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Bin1 antibody lowers the expression of phosphorylated Tau in Alzheimer's disease

Thomas

Hoxha

Tran

et al. 2019

J of Cellular Biochemistry

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Alzheimer's disease (AD) is an irreversible, progressive brain disorder responsible for memory loss leading to the inability to carry out the simplest tasks. AD is one of the leading causes of death in the United States. As yet there are no effective medications to treat this debilitating disease. In recent years, a human gene called bridging integrator 1 (BIN1) has emerged as one of the most important genes in affecting the incidence of sporadic AD. Bin1 can directly bind to Tau and mediates late onset AD risk by modulating Tau pathology. Recently our group found Bin1 antibody could exert drug‐like properties in an animal model of ulcerative colitis. We hypothesized that the Bin1 monoclonal antibody (mAb) could be used in the treatment of AD by lowering the levels of Tau in cell culture and animal models. Cell culture studies confirmed that the Bin1 mAb (99D) could lower the levels of phosphorylated Tau (pTau). Multiple mechanisms aided by endosomal proteins and Fc gamma receptors are involved in the uptake of Bin1 mAb into cells. In Tau expressing cell culture, the Bin1 mAb induces the proteasome machinery leading to ubiquitination of molecules thereby preventing cell stress. In vivo studies demonstrated that treatment of P301S mice expressing Tau with the Bin1 mAb survived longer than the untreated mice. Our data confirm that Bin1 mAb lowers the levels of pTau and could be a drug candidate in the treatment of AD.

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Section: Discussionmentioning

confidence: 99%

“…The fougaro system may be a mechanism to recycle or remove molecules from the nucleus to the external medium. 20 The ubiquitin-proteasome system degrades misfolded proteins including those implicated in AD. 47 A characteristic of AD is a poor proteasome system.…”

Section: Discussionmentioning

confidence: 99%

Bin1 antibody lowers the expression of phosphorylated Tau in Alzheimer's disease

Thomas

Hoxha

Tran

et al. 2019

J of Cellular Biochemistry

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“…Bin1 monoclonal antibodies. We used the therapeutic 99D Bin1 monoclonal antibody for our study (Thomas et al 2016(Thomas et al , 2019a. The antibody 99D recognizes an epitope within the C-terminal Myc binding domain encoded by exon 13 (Wechsler-Reya et al 1997).…”

Section: Methodsmentioning

confidence: 99%

“…Mice induced with UC had severe lesions throughout the mucosa, high-level neutrophil and lymphocyte infiltration into the mucosal and submucosal areas, and loss of crypts. Whereas, animals treated with the cell penetrating Bin1 mAb protects against UC by directly improving colonic epithelial barrier function that limit gene expression and cytokine programs associated with colonic inflammation (Thomas et al 2016;2019a). In this paper, we report progress in how Bin1 mAb treatment protects against UC; specifically, it protects enteric neurons thereby preventing bowel movement dysfunction, and that it promotes formation of a healthy gut microbiome.…”

Section: Introductionmentioning

confidence: 93%

Bin1 Targeted Immunotherapy Alters the Status of the Enteric Neurons and the Microbiome during Ulcerative Colitis Treatment

Thomas¹,

Mercogliano²,

Prendergast³

2020

Preprint

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Ulcerative colitis (UC) is a common chronic disease of the large intestine. Current anti-inflammatory drugs prescribed to treat this disease have limited utility due to significant side-effects. Thus, immunotherapies for UC treatment are still sought. In the DSS mouse model of UC, we recently demonstrated that systemic administration of the Bin1 monoclonal antibody 99D (Bin1 mAb) developed in our laboratory was sufficient to reinforce intestinal barrier function and preserve an intact colonic mucosa, compared to control subjects which displayed severe mucosal lesions, high-level neutrophil and lymphocyte infiltration of mucosal and submucosal areas, and loss of crypts. Here we report effects of Bin1 mAb on colonic neurons and the gut microbiome that correlate with the benefits of treatment. In the DSS model, we found that induction of UC was associated with disintegration of enteric neurons and elevated levels of glial cells, which translocated to the muscularis at distinct sites. Further, we characterized an altered gut microbiome in DSS treated mice associated with pathogenic proinflammatory characters. Both of these features of UC induction were normalized by Bin1 mAb treatment. With regard to microbiome changes, we observed in particular that Firmicutes were eliminated by UC induction and that Bin1 mAb treatment restored this phylum including the genus Lactobacillus and Akkermansia as beneficial microorganisms. Overall, our findings suggest that the intestinal barrier function restored by Bin1 immunotherapy in the DSS model of UC is associated with a preservation of enteric neurons and an improvement in the gut microbiome, contributing overall to a healthy intestinal tract.

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“…Recently, a therapy targeting BIN1 reportedly improved the mucosal barrier function and protected the integrity of the lymphoid follicle, which offers a novel strategy to treat ulcerative colitis and possibly limits the risks for colorectal cancer. 76 Another study indicated that phosphodiesterase 5 inhibition improves contractile function and restores transverse tubule loss and catecholamine responsiveness in HF. A related molecular switch for the loss of T-tubules in HF and their restoration following phosphodiesterase 5 inhibition involves BIN1.…”

Section: Novel Diagnosis and Therapy Targeted For Bin1mentioning

confidence: 99%

Effect of BIN1 on cardiac dysfunction and malignant arrhythmias

et al. 2019

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Heart failure (HF) is the end‐stage syndrome for most cardiac diseases, and the 5‐year morbidity and mortality of HF remain high. Malignant arrhythmia is the main cause of sudden death in the progression of HF. Recently, bridging integrator 1 (BIN1) was discovered as a regulator of transverse tubule function and calcium signalling in cardiomyocytes. BIN1 downregulation is linked to abnormal cardiac contraction, and it increases the possibility of malignant arrhythmias preceding HF. Because of the detectability of cardiac BIN1 in peripheral blood, BIN1 may serve as a predictor of HF and may be useful in therapy development. However, the mechanism of BIN1 downregulation in HF and how BIN1 regulates normal cardiac function under physiological conditions remain unclear. In this review, recent progress in the biological studies of BIN1‐related cardiomyocytes and the effect of cardiac dysfunction and malignant arrhythmia will be discussed.

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Intestinal barrier tightening by a cell‐penetrating antibody to Bin1, a candidate target for immunotherapy of ulcerative colitis

Cited by 19 publications

References 50 publications

Bin1 antibody lowers the expression of phosphorylated Tau in Alzheimer's disease

Bin1 antibody lowers the expression of phosphorylated Tau in Alzheimer's disease

Bin1 Targeted Immunotherapy Alters the Status of the Enteric Neurons and the Microbiome during Ulcerative Colitis Treatment

Effect of BIN1 on cardiac dysfunction and malignant arrhythmias

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