Orally available and efficacious α4β1/α4β7 integrin inhibitors

Xu, Yinchuan; Smith, Jenifer; Semko, Christopher M.; Rossiter, Kassandra I.; Fukuda, Juri Y.; Dappen, Michael S.; Quincy, David A.; Konradi, Andrei W.; Mao, Wenxian; Welch, Brent; Dreyer, Mark; Samant, Bhushan; Zhang, Hongbin; Lugar, Judevin; Liao, Ziyuan; Henschel, Carrol; Petersen, Eric; Vandevert, Christopher; Shoemaker, Mark; Wehner, Nancy; Mutter, Linda; Shopp, George M.; Krimm, Michael; Chen, Linda; Wipke, Brian T.; Dofiles, Lilibeth; Gallager, Ian; Sauer, John‐Michael; Messersmith, Elizabeth K.; Pleiss, Michael A.; Bard, Frédérique; Yednock, Ted

doi:10.1016/j.bmcl.2013.05.076

Cited by 9 publications

(11 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To determine the functionality of virion-incorporated α4β7, we tested the ability of α4β7 + HIV-1 virions to bind to the natural integrin ligand, MAdCAM-1, in the presence or absence of various modulators of integrin activation. Magnetic beads were armed with soluble MAdCAM-1, or with mAb ACT-1 as a control, and used to capture HIV-1 virions in the presence or absence of manganese chloride (MnCl 2 ), of the chelating agent EDTA, or of an inhibitory MAdCAM-1 peptide mimetic (ELN) (34). Binding to MAdCAM-1 was detected even in the absence of activating stimuli (Control), indicating that at least a fraction of the incorporated integrin is present in a functionally active state (Fig.…”

Section: Resultsmentioning

confidence: 99%

Virion incorporation of integrin α4β7 facilitates HIV-1 infection and intestinal homing

Guzzo

Ichikawa

Park³

et al. 2017

Sci. Immunol.

View full text Add to dashboard Cite

The intestinal mucosa is a key anatomical site for HIV-1 replication and CD4+ T-cell depletion. Accordingly, in vivo treatment with an antibody to the gut-homing integrin α4β7 was shown to reduce viral transmission, delay disease progression, and induce persistent virus control in macaques challenged with SIV. Here, we show that integrin α4β7 is efficiently incorporated into the envelope of HIV-1 virions. Incorporated α4β7 is functionally active as it binds MAdCAM-1, promoting HIV-1 capture by and infection of MAdCAM-expressing cells, which in turn mediate trans-infection of bystander cells. Functional α4β7 is present in circulating virions from HIV-infected patients and SIV-infected macaques, with peak levels during the early stages of infection. In vivo homing experiments documented selective and specific uptake of α4β7+ HIV-1 virions by high endothelial venules in the intestinal mucosa. These results extend the paradigm of tissue homing to a retrovirus and are relevant for the pathogenesis, treatment and prevention of HIV-1 infection.

show abstract

Section: Resultsmentioning

confidence: 99%

Virion incorporation of integrin α4β7 facilitates HIV-1 infection and intestinal homing

Guzzo

Ichikawa

Park³

et al. 2017

Sci. Immunol.

View full text Add to dashboard Cite

show abstract

“…Vedolizumab (as well as RM-Act-1 and the original mouse version [ 22 ]) binds to a conformational epitope that is unique to the heterodimerized form of the α 4 and β 7 chains [ 23 ]. Together with humanized mAbs, several anti-integrins small molecules are under various stage of development [ 24 – 26 ]. Among them there is a family of α 4 β 1 /α 4 β 7 dual inhibitors, which were synthetized and characterized by scientists at Élan Pharmaceutical [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

“…Together with humanized mAbs, several anti-integrins small molecules are under various stage of development [ 24 – 26 ]. Among them there is a family of α 4 β 1 /α 4 β 7 dual inhibitors, which were synthetized and characterized by scientists at Élan Pharmaceutical [ 24 ]. These molecules have good oral bioavailability and have shown efficacy in rat models of rheumatoid arthritis (RA) and Crohn’s disease (CD).…”

Section: Introductionmentioning

confidence: 99%

“…Unlike mAbs, small-molecule agents can more easily be formulated for topical and oral administration and they can be more easily modified to obtain the desired pharmacokinetics (PK). Since it was shown that the anti-α 4 β 7 mAb RM-Act-1 could reduce susceptibility to infection when given intravenously, we selected one of Élan’s small molecule anti-α 4 β 7 inhibitors (compound 12d in [ 24 ], here called ELN) to test its effect via the oral and the vaginal routes of administration using a repeated low-dose challenges model of SHIV-SF162P3 infection.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A Small Molecule, Which Competes with MAdCAM-1, Activates Integrin α4β7 and Fails to Prevent Mucosal Transmission of SHIV-SF162P3

et al. 2016

View full text Add to dashboard Cite

Mucosal HIV-1 transmission is inefficient. However, certain viral and host characteristics may play a role in facilitating HIV acquisition and systemic expansion. Cells expressing high levels of integrin α4β7 have been implicated in favoring the transmission process and the infusion of an anti-α4β7 mAb (RM-Act-1) prior to, and during a repeated low-dose vaginal challenge (RLDC) regimen with SIVmac251 reduced SIV acquisition and protected the gut-associated lymphoid tissues (GALT) in the macaques that acquired SIV. α4β7 expression is required for lymphocyte trafficking to the gut lamina propria and gut inductive sites. Several therapeutic strategies that target α4β7 have been shown to be effective in treating inflammatory conditions of the intestine, such as inflammatory bowel disease (IBD). To determine if blocking α4β7 with ELN, an orally available anti-α4 small molecule, would inhibit SHIV-SF162P3 acquisition, we tested its ability to block MAdCAM-1 (α4β7 natural ligand) and HIV-gp120 binding in vitro. We studied the pharmacokinetic profile of ELN after oral and vaginal delivery in macaques. Twenty-six macaques were divided into 3 groups: 9 animals were treated with ELN orally, 9 orally and vaginally and 8 were used as controls. All animals were challenged intra-vaginally with SHIV-SF162P3 using the RLDC regimen. We found that ELN did not protect macaques from SHIV acquisition although it reduced the SHIV-induced inflammatory status during the acute phase of infection. Notably, integrins can exist in different activation states and, comparing the effect of ELN and the anti-α4β7 mAb RM-Act-1 that reduced susceptibility to SIV infection, we determined that ELN induces the active conformation of α4β7, while RM-Act-1 inhibits its activation through an allosteric mechanism. These results suggest that inhibition of α4β7 activation may be necessary to reduce susceptibility to SIV/SHIV infection and highlight the complexity of anti-integrins therapeutic approach in HIV as well as in IBD and other autoimmune diseases.

show abstract

“…Vedolizumab is the first humanized monoclonal antibody which can specifically target the α 4 β 7 heterodimer and is approved by the US Food and Drug Administration for therapy of ulcerative colitis (UC) and CD [ 18 ]. Integrin α 4 antibodies have also been used in animal models of autoimmune disease [ 19 , 20 ]. Several lines of evidence have demonstrated that osteoclast function can be regulated through blocking the α v β 3 integrin-dependent signaling pathway in human bone diseases, including rheumatoid arthritis, osteoporosis, and periodontal disease [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Combination Therapy of PEG-HM-3 and Methotrexate Retards Adjuvant-Induced Arthritis

Hao

Setrerrahmane

et al. 2017

IJMS

View full text Add to dashboard Cite

At present, the early phenomenon of inflammatory angiogenesis is rarely studied in Rheumatoid arthritis (RA). Previous research found that PEG-HM-3, an integrin inhibitor, possessed anti-angiogenesis and anti-rheumatic activity. In this study, the advantages of inhibiting angiogenesis and immune cell adhesion and migration, as well as the benefits of anti-arthritis effects, were evaluated using a combination of PEG-HM-3 and methotrexate (MTX). In vitro, spleen cell proliferation and the levels of tumor necrosis factor α (TNF-α) in macrophage supernatant were assessed. Hind paw edema, arthritis index, clinical score, body weight and immunohistochemistry (IHC) of the spleen, thymus, and joint cavity were evaluated in vivo in adjuvant-induced arthritis rats. Joints of the left hind paws were imaged by X-ray. The expression of the toll-like receptor 4 (TLR-4) protein was assessed in lipopolysaccharide (LPS)-induced synoviocytes. PEG-HM-3 combined with MTX significantly reduced primary and secondary swelling of the hind paws, the arthritis index, the clinical score and bone erosion. The results of IHC showed that the levels of interleukin-6 (IL-6) in spleens and the levels of TNF-α, CD31 (cluster of differentiation 31), and CD105 in the joint cavity were decreased. The body weight of rats was maintained during combination therapy. Ankle cavity integrity, and bone erosion and deformity were improved in combination treatment. The expression of TLR-4 was significantly reduced with combination treatment in rat synoviocytes. Co-suppression of both inflammation and angiogenesis in arthritis was achieved in this design with combination therapy. The activity of nuclear transcription factor (NF-κB) and the expression of inflammatory factors were down regulated via integrin αvβ3 and TLR-4 signaling pathways. In the future, the application of this combination can be a candidate in early and mid-term RA therapy.

show abstract

Orally available and efficacious α4β1/α4β7 integrin inhibitors

Cited by 9 publications

References 12 publications

Virion incorporation of integrin α4β7 facilitates HIV-1 infection and intestinal homing

Virion incorporation of integrin α4β7 facilitates HIV-1 infection and intestinal homing

A Small Molecule, Which Competes with MAdCAM-1, Activates Integrin α4β7 and Fails to Prevent Mucosal Transmission of SHIV-SF162P3

Combination Therapy of PEG-HM-3 and Methotrexate Retards Adjuvant-Induced Arthritis

Contact Info

Product

Resources

About