Differential effects of treatment with a small-molecule VLA-4 antagonist before and after onset of relapsing EAE

Theien, Bradley E.; Vanderlugt, Carol L.; Nickerson‐Nutter, Cheryl; Cornebise, Mark; Scott, Daniel M.; Perper, S.; Whalley, Eric T.; Miller, Stephen D.

doi:10.1182/blood-2003-03-0974

Cited by 65 publications

(62 citation statements)

References 26 publications

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“…EAE was generated in SJL/J mice through immunization with the PLP 139 -151 peptide as described previously (6,24). Briefly, 9-to 11-wk-old female SJL/J mice were immunized s.c. with the PLP 139 -151 peptide (100 g/ mouse) in CFA.…”

Section: Induction Of Plp 139 -151 -Induced Eae In Sjl/j Micementioning

confidence: 99%

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Reevaluation of P-Selectin and α4 Integrin as Targets for the Treatment of Experimental Autoimmune Encephalomyelitis

Kerfoot

Norman

Lapointe

et al. 2006

The Journal of Immunology

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There has been a great deal of interest in adhesion molecules as targets for the treatment of multiple sclerosis and other inflammatory diseases. In this study, we systematically evaluate α4 integrin and P-selectin as targets for therapy in murine models of multiple sclerosis–for the first time directly measuring the ability of their blockade to inhibit recruitment and relate this to clinical efficacy. Experimental autoimmune encephalomyelitis was induced in C57BL/6 or SJL/J mice and intravital microscopy was used to quantify leukocyte interactions within the CNS microvasculature. In both strains, pretreatment with blocking Abs to either α4 integrin or P-selectin reduced firm adhesion to a similar extent, but did not block it completely. The combination of the Abs was more effective than either Ab alone, although the degree of improvement was more evident in SJL/J mice. Similarly, dual blockade was much more effective at preventing the subsequent accumulation of fluorescently labeled leukocytes in the tissue in both strains. Despite evidence of blockade of leukocyte recruitment mechanisms, no clinical benefit was observed with anti-adhesion molecule treatments or genetic deletion of P-selectin in the C57BL/6 model, or in a pertussis toxin-modified model in SJL/J mice. In contrast, Abs to α4 integrin resulted in a significant delay in the onset of clinical signs of disease in the standard SJL/J model. Despite evidence of a similar ability to block firm adhesion, Abs to P-selectin had no effect. Importantly, combined blockade of both adhesion molecules resulted in significantly better clinical outcome than anti-α4 integrin alone.

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Section: Induction Of Plp 139 -151 -Induced Eae In Sjl/j Micementioning

confidence: 99%

“…In the literature, most studies of adhesion molecule blockade in murine EAE have made use of models in SJL/J mice (6,7,9,14). Therefore, we repeated the above experiments in the PLP 139 -151 -induced model of EAE in this strain.…”

Section: Evaluation Of Adhesion Molecule Blocking Therapy In Plpinducmentioning

confidence: 99%

Reevaluation of P-Selectin and α4 Integrin as Targets for the Treatment of Experimental Autoimmune Encephalomyelitis

Kerfoot

Norman

Lapointe

et al. 2006

The Journal of Immunology

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“…Various aspects of multiple sclerosis have been recapitulated in rodent models of EAE with differing effects and efficacy profiles of ␣4␤1 inhibition observed in rats and mice (Kanwar et al, 2000a,b;Leone et al, 2003;Theien et al, 2003). Rat models of EAE are usually monophasic, and ␣4␤1 inhibition delays the onset of disease.…”

Section: Discussionmentioning

confidence: 99%

Design, Synthesis, and Analysis of a Polyethelene Glycol-Modified (PEGylated) Small Molecule Inhibitor of Integrin α4β1 with Improved Pharmaceutical Properties

Pepinsky¹,

Lee²,

Cornebise³

et al. 2004

J Pharmacol Exp Ther

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Integrin ␣4␤1 plays an important role in inflammatory processes by regulating the migration of leukocytes into inflamed tissues. Previously, we identified BIO5192 [2(S)-{[1-(3,5-dichloro-benzenesulfonyl)-pyrrolidine-2(S)-carbonyl]-amino}-4-[4-methyl-2(S)- (methyl-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-amino)-pentanoylamino]-butyric acid], a highly selective and potent (K D of 9 pM) small molecule inhibitor of ␣4␤1. Although BIO5192 is efficacious in various animal models of inflammatory disease, high doses and daily treatment of the compound are needed to achieve a therapeutic effect because of its relatively short serum half-life. To address this issue, polyethylene glycol modification (PEGylation) was used as an approach to improve systemic exposure. BIO5192 was PEGylated by a targeted approach in which derivatizable amino groups were incorporated into the molecule. Two sites were identified that could be modified, and from these, five PEGylated compounds were synthesized and characterized. One compound, 2a-PEG (K D of 19 pM), was selected for in vivo studies. The pharmacokinetic and pharmacodynamic properties of 2a-PEG were dramatically improved relative to the unmodified compound. The PEGylated compound was efficacious in a rat model of experimental autoimmune encephalomyelitis at a 30-fold lower molar dose than the parent compound and required only a once-aweek dosing regimen compared with a daily treatment for BIO5192. Compound 2a-PEG was highly selective for ␣4␤1. These studies demonstrate the feasibility of PEGylation of ␣4␤1-targeted small molecules with retention of activity in vitro and in vivo. 2a-PEG, and related compounds, will be valuable reagents for assessing ␣4␤1 biology and may provide a new therapeutic approach to treatment of human inflammatory diseases.Integrins are a large family of cell surface receptors that mediate cell-cell and cell-matrix interaction. They exist as noncovalent ␣␤ heterodimers of different combinations of ␣ and ␤ chains and share extensive structural homology. Integrins mediate a wide variety of physiological processes and are relevant to a wide variety of pathological conditions. The integrin ␣4␤1 regulates normal leukocyte trafficking (Lobb and Hemler, 1994) and provides a key costimulatory signal supporting cell activation (Clark and Brugge, 1995). During inflammatory responses, ␣4␤1 regulates leukocyte migration into the damaged tissues and has been recognized as an attractive therapeutic target. In vivo studies using blocking monoclonal antibodies (Lobb and Hemler, 1994;Issekutz et al., 1996;Enders et al., 1998;Hojo et al., 1998;Schneider et al., 1999;Ramos-Barbon et al., 2001), inhibitory peptides (Molossi et al., 1995;Abraham, 1997;van der Laan et al., 2002), and small molecule antagonists (Lin et al., 1999;Kudlacz et al., 2002) have verified the critical role of ␣4␤1 integrins in leukocyte-mediated inflammation and have implicated ␣4␤1 inhibitors as potential treatments for diseases such as asthma and arthritis. Numerous EAE models that recapitulate i...

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“…9 A more optimal dislodgement of leukemic cells from their niches might be attained by combining the CXCR4/CXCL12 blockade with agents that disrupt VLA-4/ VCAM-1 interactions such as natalizumab (anti-VLA-4 monoclonal antibody) or Bio5192, a small peptide that also blocks VLA-4 mediated adhesion (see figure). [10][11][12] Besides abnormal cytogenetics, recently recognized high-risk features in AML include FLT3-ITD/ mutations and prominent CXCR4 surface expression. 13,14 In the other paper addressing leukemic niches in this 15 CXCR4 inhibition partially abrogated the protection conferred by stromal cells, rendering these leukemic cells more susceptible to apoptosis when exposed to cytarabine.…”

Section: Another Nail In the Aml Coffin -----------------------------mentioning

confidence: 99%

Another nail in the AML coffin

Abboud¹

2009

Blood

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Differential effects of treatment with a small-molecule VLA-4 antagonist before and after onset of relapsing EAE

Cited by 65 publications

References 26 publications

Reevaluation of P-Selectin and α4 Integrin as Targets for the Treatment of Experimental Autoimmune Encephalomyelitis

Reevaluation of P-Selectin and α4 Integrin as Targets for the Treatment of Experimental Autoimmune Encephalomyelitis

Design, Synthesis, and Analysis of a Polyethelene Glycol-Modified (PEGylated) Small Molecule Inhibitor of Integrin α4β1 with Improved Pharmaceutical Properties

Another nail in the AML coffin

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