Littérature scientifique sur le sujet « Anti-integrins therapies »

Background: Inflammatory bowel diseases (IBD) are a group of heterogeneous conditions, characterized by immune-mediated inflammation of the gastrointestinal tract. Traditionally, medical management of these disorders has been based on use of systemic immunosuppressives. The development of new drugs that selectively inhibit leukocyte trafficking to the gut has the potential to reduce inflammation and minimize systemic toxicities. Key Messages: In this article, we review the immunology of the gut and the mechanism of action these emerging therapies for IBD. Natalizumab, a monoclonal antibody to the α4 integrin, was approved for the treatment of multiple sclerosis and showed promise in Crohn's disease (CD), however it is encumbered by the risk of progressive multifocal leukoencephalopathy. Vedolizumab inhibits the α4β7 integrin to induce clinical remission in patients with both ulcerative colitis and CD. Long-term safety data on this agent is not yet available. We also review agents in the pipeline. Finally, we discuss the positioning of therapies and potential alterations to therapeutic algorithms as new medications emerge. Conclusions: New therapies are emerging for IBD; however, long-term data are pending. The positioning of these agents in algorithms will evolve.

Neovascular age-related macular degeneration (nAMD) is one of the leading causes of blindness among the aging population. The current treatment options for nAMD include intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF). However, standardized frequent administration of anti-VEGF injections only improves vision in approximately 30–40% of nAMD patients. Current therapies targeting nAMD pose a significant risk of retinal fibrosis and geographic atrophy (GA) development in nAMD patients. A need exists to develop new therapies to treat nAMD with effective and long-term anti-angiogenic effects. Recent research on nAMD has identified novel therapeutic targets and angiogenic signaling mechanisms involved in its pathogenesis. For example, tissue factor, human intravenous immune globulin, interferon-β signaling, cyclooxygenase-2 (COX-2) and cytochrome P450 monooxygenase lipid metabolites have been identified as key players in the development of angiogenesis in AMD disease models. Furthermore, novel therapies such as NACHT, LRR and PYD domains containing protein 3 (NLRP3) inflammasome inhibition, inhibitors of integrins and tissue factor are currently being tested at the level of clinical trials to treat nAMD. The aim of this review is to discuss the scope for alternative therapies proposed as anti-VEGFs for the treatment of nAMD.

Inflammatory Bowel Disease (IBD) comprises a series of chronic and relapsing intestinal diseases, with Crohn’s disease and ulcerative colitis being the most common. The abundant and uncontrolled deposition of extracellular matrix, namely fibrosis, is one of the major hallmarks of IBD and is responsible for the progressive narrowing and closure of the intestine, defined as stenosis. Although fibrosis is usually considered the product of chronic inflammation, the substantial failure of anti-inflammatory therapies to target and reduce fibrosis in IBD suggests that fibrosis might be sustained in an inflammation-independent manner. Pharmacological therapies targeting integrins have recently shown great promise in the treatment of IBD. The efficacy of these therapies mainly relies on their capacity to target the integrin-mediated recruitment and functionality of the immune cells at the damage site. However, by nature, integrins also act as mechanosensitive molecules involved in the intracellular transduction of signals and modifications originating from the extracellular matrix. Therefore, understanding integrin signaling in the context of IBD may offer important insights into mechanisms of matrix remodeling, which are uncoupled from inflammation and could underlie the onset and persistency of intestinal fibrosis. In this review, we present the currently available knowledge on the role of integrins in the etiopathogenesis of IBD, highlighting their role in the context of immune-dependent and independent mechanisms.

The use of biologic agents including anti-tumor necrosis factor monoclonal antibodies followed by anti-integrins and anti-interleukins has drastically changed the treatment paradigm of Crohn’s disease (CD) by improving clinical symptoms and mucosal healing. However, up to 70% of CD patients still eventually undergo surgery mainly due to fibrostenotic strictures. There are no specific anti-fibrotic drugs yet. This review comprehensively addresses the mechanism, prediction, diagnosis and treatment of the fibrostenotic strictures in CD. We also introduce promising anti-fibrotic agents which may be available in the near future and summarize challenges in developing novel therapies to treat fibrostenotic strictures in CD.

:Despite the great progress in the development of targeted therapies for different types of cancer utilizing monoclonal antibodies (e.g., cetuximab for colorectal cancer and head and neck cancer therapy), kinase inhibitors (e.g., sorafenib for kidney cancer and gastrointestinal stromal tumours therapy), and immunomodulatory treatments (e.g., nivolumab and pembrolizumab for melanoma therapy and lung cancer therapy), there is still a need to search for new, more effective treatments.:Integrins are responsible for intercellular adhesion and interaction with the cellular matrix. The function of integrins is related to the transduction of intracellular signals associated with adhesion, migration, cell proliferation, differentiation, and apoptosis. Molecules targeting integrins that lead to cancer cell death have been developed. The most advanced molecules studied in clinical trials are abituzumab, intetumumab and cilengitide. There are different groups of anti-integrin drugs: monoclonal antibodies (e.g., abituzumab) and other such as cilengitide, E7820 and MK-0429. These drugs have been evaluated in various cancer types. However, they have shown modest efficacy, and none of them have yet been approved for cancer treatment. Studies have shown that patient selection using biomarkers might improve the efficacy of anti-integrin cancer treatment. Many preclinical models have demonstrated promising results using integrin visualization for cancer detection and treatment efficacy monitoring; however, these strategies require further evaluation in humans.

Ovarian cancer is a deadly disease, with a cure rate of only 30%. Despite aggressive treatments, relapse remains almost inevitable in patients with advanced-stage disease. In recent years, great progress has been made towards targeting integrins in cancer treatment, and clinical studies with various integrin inhibitors have demonstrated their effectiveness in blocking cancer progression. Given that the initial critical step of ovarian cancer metastasis is the attachment of cancer cells onto the peritoneum or omentum, in addition to the proven positive clinical results of anti-angiogenic therapy, targeting integrins is likely to be one of the most feasible approaches. This paper summarizes the current understanding of the integrin biology in ovarian cancer metastasis and the various therapeutic approaches attempted with integrin inhibitors. Although no integrin inhibitors have shown favorable results so far, integrin-targeted therapies continue to be a promising approach to be explored for further clinical investigation.

Adenocarcinoma lung cancer is a type of non-small cell lung carcinoma (NSCLC), which accounts for 85% of lung cancer incidence globally. The therapies that are being applied, both conventional therapies and antibody-based treatments, are still found to have side effects. Several previous studies have demonstrated the ability of the ethanolic extract of Ocimum sanctum Linn. (EEOS) as an ethnomedicine with anti-tumor properties. The aim of this study was to determine the effect of Ocimum sanctum Linn. ethanolic extract in inhibiting the proliferation, angiogenesis, and migration of A549 cells (NSCLC). The adhesion as well as the migration assay was performed. Furthermore, enzyme-linked immunosorbent assay (ELISA) was used to measure the expression of αvβ3 integrins, α5β1 integrins, and VEGF. The cells were divided into the following treatment groups: control (non-treated/NT), positive control (AP3/inhibitor β3 80 µg/mL), cisplatin (9 µg/mL), and EEOS at concentrations of 50, 70, 100, and 200 µg/mL. The results showed that EEOS inhibits the adhesion ability and migration of A549 cells, with an optimal concentration of 200 µg/mL. ELISA testing showed that the group of A549 cells given EEOS 200 µg/mL presented a decrease in the optimal expression of integrin α5β1, integrin αvβ3, and VEGF.

The so-called “biologicals” (monoclonal antibodies to various inflammatory targets like tumor necrosis factor or integrins) have revolutionized the treatment of inflammatory bowel diseases. In ulcerative colitis, they have an established role in inducing remission in steroid-refractory disease and, thereafter, maintaining remission with or without azathioprine. Nevertheless, their limitations are also obvious: lack of primary response or loss of response during maintenance as well as various, in part severe, side effects. The latter are less frequent in anti-integrin treatment, but efficacy, especially during induction, is delayed. New antibodies as well as small molecules have also demonstrated clinical efficacy and are soon to be licensed for ulcerative colitis. None of these novel drugs seems to be much more effective overall than the competition, but they provide new options in otherwise refractory patients. This increasing complexity requires new algorithms, but it is still premature to outline each drug’s role in future treatment paradigms.

Alzheimer’s disease (AD) is characterized by severe, progressive decline of cognition due to neuronal loss in brain regions involved in learning and memory. Two main pathophysiological hallmarks of AD are well characterized: amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein. Significant evidence obtained over the last decade has shown that neuroinflammation is also associated with AD pathology. Furthermore, vascular leakage and endothelial activation were reported in AD brains, suggesting a role for vascular inflammation and leukocyte trafficking in the pathogenesis of AD. However, the inflammation mechanisms involved in AD pathogenesis remain largely unknown and a better understanding of the role of inflammation in AD may help to develop new therapeutic approaches to slow the progression of this disorder. Bloodderived leukocyte subpopulations, including lymphocytes, monocytes, and neutrophils, have been identified in the brains of patients with AD and in corresponding animal models, but their role in disease pathogenesis is unclear. We have recently reported an active inflammatory process taking place during AD, which includes up-regulation of adhesion molecules on cerebrovascular endothelium and leukocyte trans-endothelial migration into the brain of AD-like disease mice. Notably, neutrophil depletion during the early phase of disease led to an amelioration of cognitive deficits and neuropathological condition in mouse models of AD, suggesting their contribution to the pathology. Indeed, the inhibition of neutrophil function strongly reduced microglial activation and Aβ deposition, suggesting that neutrophils play a key role in disease progression. The GOAL of the present study was to investigate the role of LFA-1 and VLA-4 integrins in the pathogenesis of AD-like disease. LFA-1, the predominant β2-integrin expressed on leukocytes, is known to play a key role in leukocyte adhesion on inflamed endothelium. Instead VLA-4, the predominant α4-integrin expressed on the surface of lymphocytes, is expressed only by approximately 3% of circulating neutrophils, but several studies demonstrated it represents an alternative pathway for neutrophil migration to inflammatory sites. Interestingly, in addition to neutrophil infiltration we found T cells infiltrating the brain in mouse models of AD at different time points of disease. Therefore, different leukocyte subpopulations migrate into the brain of 3xTg-AD mice, suggesting that neutrophils and T cells may play a role in disease evolution. We performed our experiments in 3xTg-AD mice, which reproduces AD-like cerebral amyloidosis and tangle pathology, and closely resemble the cognitive and behavioral alterations reported in human disease. We first evaluated by two-photon microscopy the effect of monoclonal antibodies known to block the integrin LFA-1 on neutrophil thus affecting adhesion and extravasation in the central nervous system (CNS). Our results showed that LFA-1 integrin blockade prevents neutrophil adhesion, extravasation, and inhibits intraparenchymal motility in the brain of 3xTg-AD mice. In addition, we demonstrate that both oligomeric and fibrillary Aβ are able - 4 - to trigger rapid LFA-1- dependent neutrophil adhesion to its counterligand ICAM-1, with oligomeric Aβ preparation being more effective. Subsequently, we assessed the blockade of neutrophil trafficking by an anti-LFA–1 integrin antibody treatment in 3xTg-AD mice at early stages of the disease confirming that the integrin LFA-1 is fundamental for brain infiltration of neutrophils in AD-like mice. We next studied the effects of LFA-1 ablation on 3xTg-ADxItgal-/- mice lacking LFA-1 integrin. We found that they show improved memory in cognitive tests compared to wild-type animals. Our results demonstrated a reduced of cognitive dysfunctions in 3xTg-ADxItgal-/- compared to age-matched 3xTg-AD mice. These findings were supported by neuropathological data showing a lower density and activation state of microglia in the CA1 and DG and a reduction of Ab deposition and tau hyperphosphorylation in 3xTg-ADxItgal-/- compared to 3xTg-AD aged-matched controls. Taken together, these results suggest that the inhibition of neutrophil trafficking through the blockade of LFA-1 integrin may represent a new therapeutic strategy for AD. In addition, our results showed that treated 3xTg-AD mice with an anti-a4 integrin antibody improved memory function compared to control treated mice in behavioral tests. Notably, restoration of cognitve function in mice that received anti-a4 treatment during early stages of disease was also maintained at late time points in aged animals, suggesting that therapeutic blockade of leukocyte adhesion during the early stages of disease has a longterm beneficial effect on cognition in older mice. In support of the results obtained in cognitive tests, neuropathological studies showed a reduction of amyloid beta deposition, tau hyperphosphorylated and microglial activation. Therefore, VLA-4 integrin may also play a key role in the induction of cognitive deficit and progression of AD-like disease. In summary, the results obtained in the present study show that LFA-1 and VLA-4 integrins contribute to disease pathogenesis and may represent novel therapeutic targets in AD.