Oral treatment with a novel small molecule alpha 4 integrin antagonist, AJM300, prevents the development of experimental colitis in mice

Sugiura, Toshihiko; Kageyama, Shunsuke; Andou, Ayatoshi; Miyazawa, Tomoko; Ejima, Chieko; Nakayama, Akira; Dohi, Taeko; Eda, Hiroyuki

doi:10.1016/j.crohns.2013.03.014

Cited by 58 publications

(35 citation statements)

References 48 publications

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“…CD4 + T cells were isolated from the spleens and MLNs of diseased IL-10 KO mice (21–35 weeks of age, male) and adoptively transferred to female C.B-17/lcr-scid/scid Jcl (SCID) mice (8 weeks of age, female) [15–17]. …”

Section: Methodsmentioning

confidence: 99%

Food antigen-induced immune responses in Crohn’s disease patients and experimental colitis mice

et al. 2014

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BackgroundIn Crohn’s disease (CD), the involvement of food antigens in immune responses remains unclear. The objective of this study was to detect immune responses against food antigens in CD patients and examine the mechanism in a mouse model of colitis.MethodsWe enrolled 98 CD patients, 50 ulcerative colitis patients, and 52 healthy controls (HCs) to compare the levels of serum immunoglobulin (Ig)Gs against 88 foods. The presence of serum IgGs against foods was also examined in interleukin (IL)-10 knockout (KO) mice in which CD4+ T cell activation by antigenic food protein was assessed. Mice transferred with IL-10 KO cells received diets with or without food antigens, and the development of colitis was evaluated.ResultsThe prevalence of IgGs against various foods, especially vegetables, grains, and nuts, was significantly higher in CD patients than in HCs. Similarly, the prevalence of IgGs against food proteins was higher in IL-10 KO mice than in BALB/c mice. Beta-conglycinin, identified as an antigenic food proteins in IL-10 KO mice, induced CD4+ T cell production of interferon-γ and IL-17 through dendritic cell antigen presentation. Elimination of the food antigens ameliorated the development of colitis in mice without altering the composition of their intestinal microbiota.ConclusionsIn CD colitis mice, intestinal inflammation via CD4+ T cell hyperactivation was induced by food antigens associated with high serum IgG levels and was ameliorated by the elimination of food antigens. This disrupted immunological tolerance to food antigen, which might act as an exacerbating factor, remains to be elucidated in CD patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s00535-014-0981-8) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Food antigen-induced immune responses in Crohn’s disease patients and experimental colitis mice

et al. 2014

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“…There are two main classes of alpha4 integrin antagonists: urea-based and phenylalanine-based antagonists. The N -acetyl phenylalanine group consists of the small molecules AJM300 (94), SB683699 (Firategrast) (95), R-411 (Valategrast) (96, 97), and CDP323 (98, 99). These phenylalanine derivatives are novel compounds with improved potency against alpha4 integrins, through the formation of a cyclic peptide (100).…”

Section: Targeting Of Alpha4 Integrinmentioning

confidence: 99%

Role of Integrin Alpha4 in Drug Resistance of Leukemia

2014

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Chemotherapeutic drug resistance in acute lymphoblastic leukemia (ALL) is a significant problem, resulting in poor responsiveness to first-line treatment or relapse after transient remission. Classical anti-leukemic drugs are non-specific cell cycle poisons; some more modern drugs target oncogenic pathways in leukemia cells, although in ALL these do not play a very significant role. By contrast, the molecular interactions between microenvironment and leukemia cells are often neglected in the design of novel therapies against drug resistant leukemia. It was shown however, that chemotherapy resistance is promoted in part through cell–cell contact of leukemia cells with bone marrow (BM) stromal cells, also called cell adhesion-mediated drug resistance (CAM-DR). Incomplete response to chemotherapy results in persistence of resistant clones with or without detectable minimal residual disease (MRD). Approaches for how to address CAM-DR and MRD remain elusive. Specifically, studies using anti-functional antibodies and genetic models have identified integrin alpha4 as a critical molecule regulating BM homing and active retention of normal and leukemic cells. Pre-clinical evidence has been provided that interference with alpha4-mediated adhesion of ALL cells can sensitize them to chemotherapy and thus facilitate eradication of ALL cells in an MRD setting. To this end, Andreeff and colleagues recently provided evidence of stroma-induced and alpha4-mediated nuclear factor-κB signaling in leukemia cells, disruption of which depletes leukemia cells of strong survival signals. We here review the available evidence supporting the targeting of alpha4 as a novel strategy for treatment of drug resistant leukemia.

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“…It is effective in attenuating murine models of colitis. [54] A randomized, double-blind, placebo-controlled multicenter trial was performed to evaluate the safety, efficacy, and dose response of AJM300 in patients with CD. Seventy-one patients with active CD were randomized to receive AJM300 40 mg, AJM300 120 mg, AJM300 240 mg, or placebo three times daily for 8 weeks (Table 3).…”

Section: In Developmentmentioning

confidence: 99%

Integrin antagonists as potential therapeutic options for the treatment of Crohn’s disease

McLean

Cross

2016

Expert Opinion on Investigational Drugs

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Introduction Anti-integrin therapy for the treatment of patients with Crohn’s disease is rapidly evolving. Two agents, natalizumab and vedolizumab, are approved by the United States Food and Drug Administration for the treatment of Crohn’s disease, with vedolizumab the primary anti-integrin used due to a more favorable safety profile. Several other anti-integrins are in various stages of development. Areas Covered This review discusses the current state of anti-integrin therapy as well as suggestions for positioning of these agents in clinical practice. Emerging anti-integrin therapies, their underlying mechanisms of action, and available safety and clinical data are also reviewed. Expert Opinion Anti-integrins are effective for the treatment of Crohn’s disease, even in patients refractory to other therapies. Their use should be considered in patients with Crohn’s disease who do not respond to, develop non-response to, or have contraindications to anti-TNF therapy. Anti-integrin therapies can be offered as a first biologic therapy, in particular for older patients, patients with concurrent multiple sclerosis (natalizumab only), and in patients with contraindications to anti-TNF therapy. In patients with more severe symptoms, providers should consider co-induction with corticosteroids if possible to hasten remission.

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Oral treatment with a novel small molecule alpha 4 integrin antagonist, AJM300, prevents the development of experimental colitis in mice

Abstract: Oral treatment with the selective small molecule α4 integrin antagonist (AJM300) prevented the development of colitis and its efficacy was comparable to that of the anti-α4 integrin antibody.

Cited by 58 publications

References 48 publications

Food antigen-induced immune responses in Crohn’s disease patients and experimental colitis mice

Food antigen-induced immune responses in Crohn’s disease patients and experimental colitis mice

Role of Integrin Alpha4 in Drug Resistance of Leukemia

Integrin antagonists as potential therapeutic options for the treatment of Crohn’s disease

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