Anti-Integrins for the Treatment of Inflammatory Bowel Disease: Current Evidence and Perspectives

Gubatan, John; Keyashian, Kian; Rubin, Samuel J.; Wang, Jenny; Buckman, Cyrus A; Sinha, S.

doi:10.2147/ceg.s293272

Cited by 53 publications

(38 citation statements)

References 78 publications

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“… 573 Currently, the antibody in the highest clinical trial stage is Etrolizumab, targeting integrin β7, which recently carried out a head-to-head comparison, phase III study, with infliximab, approved anti-TNF-α antibody, for the treatment of moderately to severely active ulcerative colitis (GAEDENIA). 574 Overall, the GARDENIA study demonstrated that etrolizumab and infliximab achieved the same efficacy and safety endpoints at weeks 10 and 54. 575 This head-to-head comparison also shows that the safety of the two in long-term results at 1 year is comparable.…”

Section: Challenges and Opportunities: Integrin-targeting Drug Discov...mentioning

confidence: 85%

Targeting integrin pathways: mechanisms and advances in therapy

Pang

Qiu

et al. 2023

Sig Transduct Target Ther

323

111

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Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix (ECM)-cytoskeletal linkers and transducers in biochemical and mechanical signals between cells and their environment in a wide range of states in health and diseases. Integrin functions are dependable on a delicate balance between active and inactive status via multiple mechanisms, including protein-protein interactions, conformational changes, and trafficking. Due to their exposure on the cell surface and sensitivity to the molecular blockade, integrins have been investigated as pharmacological targets for nearly 40 years, but given the complexity of integrins and sometimes opposite characteristics, targeting integrin therapeutics has been a challenge. To date, only seven drugs targeting integrins have been successfully marketed, including abciximab, eptifibatide, tirofiban, natalizumab, vedolizumab, lifitegrast, and carotegrast. Currently, there are approximately 90 kinds of integrin-based therapeutic drugs or imaging agents in clinical studies, including small molecules, antibodies, synthetic mimic peptides, antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, imaging agents, etc. A serious lesson from past integrin drug discovery and research efforts is that successes rely on both a deep understanding of integrin-regulatory mechanisms and unmet clinical needs. Herein, we provide a systematic and complete review of all integrin family members and integrin-mediated downstream signal transduction to highlight ongoing efforts to develop new therapies/diagnoses from bench to clinic. In addition, we further discuss the trend of drug development, how to improve the success rate of clinical trials targeting integrin therapies, and the key points for clinical research, basic research, and translational research.

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Section: Challenges and Opportunities: Integrin-targeting Drug Discov...mentioning

confidence: 85%

Targeting integrin pathways: mechanisms and advances in therapy

Pang

Qiu

et al. 2023

Sig Transduct Target Ther

323

111

View full text Add to dashboard Cite

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“…Additionally, PF-00547659, a fully human monoclonal antibody targeting MAdCAM-1, has been proved to be welltolerated and effective in inducing remission in patients with moderate to severe UC (103). PN-943 is another emerging orally administered α4β7 antagonist peptide and it has been confirmed that PN-943 is effective for the induction of remission in UC (104). A phase 2 study is ongoing to evaluate the effects of PN-943 (150 and 450 mg twice daily) on moderate to severe UC patients (NCT04504383).…”

Section: Anti-integrin Therapymentioning

confidence: 99%

Treatment of Inflammatory Bowel Disease: A Comprehensive Review

2021

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Inflammatory bowel disease (IBD), as a global disease, has attracted much research interest. Constant research has led to a better understanding of the disease condition and further promoted its management. We here reviewed the conventional and the novel drugs and therapies, as well as the potential ones, which have shown promise in preclinical studies and are likely to be effective future therapies. The conventional treatments aim at controlling symptoms through pharmacotherapy, including aminosalicylates, corticosteroids, immunomodulators, and biologics, with other general measures and/or surgical resection if necessary. However, a considerable fraction of patients do not respond to available treatments or lose response, which calls for new therapeutic strategies. Diverse therapeutic options are emerging, involving small molecules, apheresis therapy, improved intestinal microecology, cell therapy, and exosome therapy. In addition, patient education partly upgrades the efficacy of IBD treatment. Recent advances in the management of IBD have led to a paradigm shift in the treatment goals, from targeting symptom-free daily life to shooting for mucosal healing. In this review, the latest progress in IBD treatment is summarized to understand the advantages, pitfalls, and research prospects of different drugs and therapies and to provide a basis for the clinical decision and further research of IBD.

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“…Therefore, the treatment duration was limited to <6 months and there was no case of PML reported. Ontamalimab is a monoclonal IgG2 antibody against MAdCAM-1, thus preventing lymphocyte migration into sites of intestinal inflammation and is efficacious for IBD treatment [4]. Other potential targets of adhesion molecules for the treatment of IBD include intercellular adhesion molecules, vascular cellular adhesion molecule-1, P-selectin, and P-selectin glycoprotein ligand-1 [9].…”

Section: New Drugsmentioning

confidence: 99%

New and Emerging Treatments for Inflammatory Bowel Disease

Higashiyama¹,

Hokaria²

2022

Digestion

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Background: The specific etiopathogenesis of inflammatory bowel disease (IBD) is still unknown. Although the conventional anti-inflammatory or immunomodulatory drugs relatively nonspecific to pathogenesis have been quite useful in many cases, elucidating the pathogenesis has gradually facilitated developments of disease-specific therapies for refractory cases in the last 2 decades. Summary: With a greater understanding of the multiple overactive signaling pathways of the gut mucosal immune response and enhanced leukocyte trafficking, several biological agents or small molecule drugs following the first novel biologic, anti-tumor necrosis factor α (anti-TNFα), have been developed against several modes of action including adhesion molecules, sphingosine-1-phospate receptors, cytokines (IL-12/23, TL1A, and IL-36), Janus kinase (JAK), and phosphodiesterase. Although preceding biological agents have dramatically changed the IBD treatment strategy, many patients still require alternative therapies due to failure or side effects. Newer treatments are now expected to be provided for better efficacy with an improved adverse event profile. In addition, translational studies have highlighted the new therapeutic concepts’ potential, including modulation of host-microbiome interactions, stem therapy for perianal fistula, regulation of fibrosis, regulation of the gut-brain axis, and control of previously less targeted immune cells (B cells and innate lymphoid cells). This paper comprehensively reviewed not only the latest already or shortly available therapies but also emerging promising treatments that will be hopefully established in the future for IBD. Key Messages: Many kinds of new treatments are available, and promising treatments with new perspectives are expected to emerge for refractory IBD in the future.

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Anti-Integrins for the Treatment of Inflammatory Bowel Disease: Current Evidence and Perspectives

Cited by 53 publications

References 78 publications

Targeting integrin pathways: mechanisms and advances in therapy

Targeting integrin pathways: mechanisms and advances in therapy

Treatment of Inflammatory Bowel Disease: A Comprehensive Review

New and Emerging Treatments for Inflammatory Bowel Disease

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