IL-13 blockade reduces lung inflammation after Ascaris suum challenge in cynomolgus monkeys

Bree, Andrea; Schlerman, Franklin J.; Wadanoli, Michael; Tchistiakova, Lioudmila; Marquette, Kimberly; Tan, Xiang-Yang; Jacobson, Bruce A.; Widom, Angela; Cook, Timothy A.; Wood, Nancy; Vunnum, Suresh; Krykbaev, Rustem; Xu, Xin; Donaldson, Debra D.; Goldman, Samuel J.; Sypek, Joseph P.; Kasaian, Marion T.

doi:10.1016/j.jaci.2007.02.009

Cited by 72 publications

(64 citation statements)

References 39 publications

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“…Sens/chall, sensitization and challenge. **P < 0.01; ***P < 0.001. modality known reduce Th2-dependent allergic asthma responses and currently being evaluated in human clinical trials (34,35). Notably, anti-human TIM-1 mAb A6G2 treatment resulted in even stronger therapeutic benefit than anti-IL-13 mAb treatment in this model.…”

Section: Tim1 Has Been Identified As a Gene Associated With Asthma Andmentioning

confidence: 91%

“…Expression of human TIM-1 has not been as conclusively demonstrated, with only a few studies showing expression on activated T cells (34) and kidney epithelium (37). As TIM1 mRNA was seen to be selectively expressed in CD4 + T cells of asthmatic patients, the increase in human TIM1 mRNA in lungs of SCID mice is suggested to result from the subsequent expansion of D. pteronyssinus-specific T cells by antigen challenge.…”

Section: Tim1 Has Been Identified As a Gene Associated With Asthma Andmentioning

confidence: 99%

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Antagonism of TIM-1 blocks the development of disease in a humanized mouse model of allergic asthma

Sonar¹,

Hsu²,

Conrad³

et al. 2010

J. Clin. Invest.

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Studies in mice and humans have revealed that the T cell, immunoglobulin, mucin (TIM) genes are associated with several atopic diseases. TIM-1 is a type I membrane protein that is expressed on T cells upon stimulation and has been shown to modulate their activation. In addition to a recently described interaction with dendritic cells, TIM-1 has also been identified as a phosphatidylserine recognition molecule, and several protein ligands have been proposed. Our understanding of its activity is complicated by the possibility that TIM-1 possesses multiple and diverse binding partners. In order to delineate the function of TIM-1, we generated monoclonal antibodies directed to a cleft formed within the IgV domain of TIM-1. We have shown here that antibodies that bind to this defined cleft antagonize TIM-1 binding to specific ligands and cells. Notably, these antibodies exhibited therapeutic activity in a humanized SCID model of experimental asthma, ameliorating inflammation, and airway hyperresponsiveness. Further experiments demonstrated that the effects of the TIM-1-specific antibodies were mediated via suppression of Th2 cell proliferation and cytokine production. These results demonstrate that modulation of the TIM-1 pathway can critically influence activated T cells in a humanized disease model, suggesting that TIM-1 antagonists may provide potent therapeutic benefit in asthma and other immune-mediated disorders.

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Section: Tim1 Has Been Identified As a Gene Associated With Asthma Andmentioning

confidence: 91%

Section: Tim1 Has Been Identified As a Gene Associated With Asthma Andmentioning

confidence: 99%

Antagonism of TIM-1 blocks the development of disease in a humanized mouse model of allergic asthma

Sonar¹,

Hsu²,

Conrad³

et al. 2010

J. Clin. Invest.

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“…Antibody to human IL-13 was generated in BALB/c mice and humanized at Wyeth Research (Cambridge, MA) to generate Ab01 (IgG1, ). A second antibody was raised in BALB/c mice against a series of overlapping peptides corresponding to the amino acid sequence of cynomolgus monkey IL-13 (Bree et al, 2007) conjugated to KLH and humanized at Wyeth Research to generate Ab02 (IgG1, ). Both antibodies were formulated in 10 mM L-histidine, pH 6, containing 5% (w/v) sucrose.…”

Section: Methodsmentioning

confidence: 99%

“…Neutralization of IL-13 bioactivity with a soluble Fc fusion of IL-13 receptor ␣2 (IL-13R␣2-Fc) or with anti-IL-13 antibody prevents asthmatic changes in rodents (Grü nig et al, 1998;Yang et al, 2004) and in sheep (Kasaian et al, 2007). We have recently demonstrated a role for IL-13 in supporting allergen-induced lung inflammation in a cynomolgus monkey [nonhuman primate (NHP)] model of allergic respiratory disease triggered by segmental lung challenge with the antigen, Ascaris suum (Bree et al, 2007).…”

mentioning

confidence: 99%

Interleukin-13 Neutralization by Two Distinct Receptor Blocking Mechanisms Reduces Immunoglobulin E Responses and Lung Inflammation in Cynomolgus Monkeys

Kasaian

Tan²,

Jin³

et al. 2008

J Pharmacol Exp Ther

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Interleukin (IL)-13 is a key cytokine driving allergic and asthmatic responses and contributes to airway inflammation in cynomolgus monkeys after segmental challenge with Ascaris suum antigen. IL-13 bioactivity is mediated by a heterodimeric receptor (IL-13R␣1/IL-4R␣) and can be inhibited in vitro by targeting IL-13 interaction with either chain. However, in cytokine systems, in vitro neutralization activity may not always predict inhibitory function in vivo. To address the efficacy of two different IL-13 neutralization mechanisms in a primate model of atopic disease, two humanized monoclonal antibodies to IL-13 were generated, with highly homologous properties, differing in epitope recognition. Ab01 blocks IL-13 interaction with IL-4R␣, and Ab02 blocks IL-13 interaction with IL-13R␣1. In a cynomolgus monkey model of IgE responses to A. suum antigen, both Ab01 and Ab02 effectively reduced serum titers of Ascaris-specific IgE and diminished ex vivo Ascaris-triggered basophil histamine release, assayed 8 weeks after a single administration of antibody. The two antibodies also produced comparable reductions in pulmonary inflammation after lung segmental challenge with Ascaris antigen. Increased serum levels of IL-13, lacking demonstrable biological activity, were seen postchallenge in animals given either anti-IL-13 antibody but not in control animals given human IgG of irrelevant specificity. These findings demonstrate a potent effect of IL-13 neutralization on IgE-mediated atopic responses in a primate system and show that IL-13 can be efficiently neutralized by targeting either the IL-4R␣-binding epitope or the IL-13R␣1-binding epitope.

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“…A second Ab was raised in BALB/c mice against peptides corresponding to the amino acid sequence of cynomolgus monkey IL-13 (30), conjugated to keyhole limpet hemocyanin, and humanized at Pfizer Research to generate IMA-026 (IgG1, k). Carimune NH immune globulin i.v.…”

Section: Test and Control Articlesmentioning

confidence: 99%

IL-13 Antibodies Influence IL-13 Clearance in Humans by Modulating Scavenger Activity of IL-13Rα2

Kasaian

Raible²,

Marquette

et al. 2011

The Journal of Immunology

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Human studies using Abs to two different, nonoverlapping epitopes of IL-13 suggested that epitope specificity can have a clinically significant impact on clearance of IL-13. We propose that Ab modulation of IL-13 interaction with IL-13Rα2 underlies this effect. Two Abs were administered to healthy subjects and mild asthmatics in separate dose-ranging studies and allergen-challenge studies. IMA-638 allows IL-13 interaction with IL-13Rα1 or IL-13Rα2 but blocks recruitment of IL-4Rα to the IL-13/IL-13Rα1 complex, whereas IMA-026 competes with IL-13 interaction with IL-13Rα1 and IL-13Rα2. We found ∼10-fold higher circulating titer of captured IL-13 in subjects treated with IMA-026 compared with those administered IMA-638. To understand how this difference could be related to epitope, we asked whether either Ab affects IL-13 internalization through cell surface IL-13Rα2. Humans inducibly express cell surface IL-13Rα2 but lack the soluble form that regulates IL-13 responses in mice. Cells with high IL-13Rα2 expression rapidly and efficiently depleted extracellular IL-13, and this activity persisted in the presence of IMA-638 but not IMA-026. The potency and efficiency of this clearance pathway suggest that cell surface IL-13Rα2 acts as a scavenger for IL-13. These findings could have important implications for the design and characterization of IL-13 antagonists.

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IL-13 blockade reduces lung inflammation after Ascaris suum challenge in cynomolgus monkeys

Cited by 72 publications

References 39 publications

Antagonism of TIM-1 blocks the development of disease in a humanized mouse model of allergic asthma

Antagonism of TIM-1 blocks the development of disease in a humanized mouse model of allergic asthma

Interleukin-13 Neutralization by Two Distinct Receptor Blocking Mechanisms Reduces Immunoglobulin E Responses and Lung Inflammation in Cynomolgus Monkeys

IL-13 Antibodies Influence IL-13 Clearance in Humans by Modulating Scavenger Activity of IL-13Rα2

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