Potent in vivo suppression of inflammation by selectively targeting the high affinity conformation of integrin α4β1

Vanderslice, Peter; Woodside, Darren G.; Caivano, Amy R.; Decker, E. Radford; Munsch, Christy L.; Sherwood, Sidney J.; LeJeune, Wanda; Miyamoto, Yuko; McIntyre, Bradley W.; Tilton, Ronald G.; Dixon, Richard A. F.

doi:10.1016/j.bbrc.2010.08.114

Cited by 14 publications

(21 citation statements)

References 25 publications

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“…Binding of ligand induces a conformational rearrangement in the ␤1 subunit that results in the exposure of these epitopes and increased antibody binding. In a similar fashion, the antagonist TBC3486, a ligand mimetic, has been shown to also increase binding of LIBS antibodies (31). Flow cytometry experiments (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…For each assay, the cells expressed the appropriate integrin receptor either endogenously (Jurkat/␣4␤1, Jurkat/␣2␤1, EPC/ ␣4␤1, TF-1/␣4␤1, K562/␣5␤1, K562/␣1␤1, human umbilical vein endothelial cells/␣v␤3, Jurkat (␣4Ϫ)/␣L␤2, and HSB/ ␣L␤2) or in recombinant form (K562/␣4␤1, K562/␣4␤7, and K562/␣1␤1). Generation of the recombinant K562 cell lines has been described previously (31). The binding buffer was TBS with 1 mM MgCl 2 and 1 mM CaCl 2 for low affinity ␣4␤1 assays or TBS with 1 mM MnCl 2 for high affinity ␣4␤1 assays.…”

Section: Methodsmentioning

confidence: 99%

“…THI0019 Cross-reacts with Other Integrins-THI0019 was derived from the antagonist TBC3486, which is highly selective for ␣4␤1 (31). Because the agonist was active in the micromolar range, cross-reactivity with other integrins was possible.…”

Section: Thi0019 Is Synergistic With Mn 2ϩ and Activating Mab Ts2/16-mnmentioning

confidence: 99%

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Small Molecule Agonist of Very Late Antigen-4 (VLA-4) Integrin Induces Progenitor Cell Adhesion

Vanderslice

Biediger

Woodside

et al. 2013

Journal of Biological Chemistry

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Background: Activation of integrins may improve cell retention rates in stem cell transplantation. Results:The first small molecule agonist of integrin ␣4␤1 is generated and enhances cell adhesion mechanisms in vitro. Conclusion:The agonist binds at the subunit interface, inducing ligand binding with consequent displacement of compound. Significance: The agonist may improve progenitor cell retention as an adjunct to cell-based therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Small Molecule Agonist of Very Late Antigen-4 (VLA-4) Integrin Induces Progenitor Cell Adhesion

Vanderslice

Biediger

Woodside

et al. 2013

Journal of Biological Chemistry

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“…The urea-based antagonists are Bio-1211 (101), Bio5192 (92, 102), IVL745 (103), and TBC3486 (104), which is the parent molecule to THI0019 (105). These small molecule antagonists can further be categorized by the presence of a leucine–aspartic acid–valine (LDV) motif.…”

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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“…The clinical trial studies are need to learn more about the BIO-1211 role in MS treatment. The future of leukocyte integrin antagonist therapy is exciting, promising a new class of therapeutics with the potential to impact not only autoimmune disease but also a broad spectrum of human diseases (Kenyon et al, 2009;Paskowitz et al, 2012;Vanderslice et al, 2010;Yonekawa & Harlan, 2005;). Some functional limitations of therapeutic antibodies have come to light, such as inadequate pharmacokinetics and tissue accessibility as well as impaired interactions with the immune system, and these deficiencies point to areas where additional research is needed (Chames et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Prophylactic Effect of BIO-1211 Small-Molecule Antagonist of VLA-4 in the EAE Mouse Model of Multiple Sclerosis

Ramroodi

Khani

Ganjali

et al. 2015

Immunological Investigations

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Potent in vivo suppression of inflammation by selectively targeting the high affinity conformation of integrin α4β1

Cited by 14 publications

References 25 publications

Small Molecule Agonist of Very Late Antigen-4 (VLA-4) Integrin Induces Progenitor Cell Adhesion

Small Molecule Agonist of Very Late Antigen-4 (VLA-4) Integrin Induces Progenitor Cell Adhesion

Role of Integrin Alpha4 in Drug Resistance of Leukemia

Prophylactic Effect of BIO-1211 Small-Molecule Antagonist of VLA-4 in the EAE Mouse Model of Multiple Sclerosis

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