Preclinical pharmacokinetics, interspecies scaling, and tissue distribution of humanized monoclonal anti-IL-13 antibodies with different IL-13 neutralization mechanisms

Vugmeyster, Yulia; Szklut, Pamela; Tchistiakova, Lioudmila; Abraham, William M.; Kasaian, Marion T.; Xu, Xin

doi:10.1016/j.intimp.2007.12.004

Cited by 39 publications

(38 citation statements)

References 15 publications

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“…Treatment with monoclonal antibody against IL-5 showed reduction in the numbers of blood and sputum eosinophils, airway hyperresponsiveness and late asthmatic response in asthmatic patients [44]. In various animal and in-vitro studies, administration of anti-IL-13 antibody prevents or reverses the symptoms of bronchial asthma [45]. Table 1).…”

Section: Cytokines As Therapeutic Targetsmentioning

confidence: 97%

“…Disease Targets IFN-α Hepatitis B and C [5] IFN-β Multiple sclerosis [5] IFN-γ Chronic granulomatous disease [38], Crohn's disease [65], Multidrug resistant tuberculosis [42] TNF-α Rheumatoid arthritis [30,31], Sepsis [32], Refractory asthma [33], Psoriasis [2] G-CSF Idiopathic neutropenia, Congenital neutropenia, Febrile neutropenia, Leukemic neutropenia, Aplastic neutropenia [37], Bone marrow suppression [5] GM-CSF Bone marrow suppression, Crohn's disease [5] IL-2 Metastatic melanoma, Renal cell carcinoma [46] IL-4 Asthma [43] IL-5 Asthma [44] IL-6 Rheumatic diseases [34] IL-10 Crohn's disease, Ulcerative colitis [2], Psoriasis, Rheumatoid arthritis [5] IL-11 Crohn's disease, Ulcerative colitis, Psoriasis, Rheumatoid arthritis [2] IL-13 Asthma [2,45] Erythropoietin Anaemia, Bone marrow failure [5] HER2-Specific Monoclonal Antibody Adenocarcinoma of stomach, Breast cancer [35,36] …”

Section: Cytokinesmentioning

confidence: 99%

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Cytokines and their Role in Health and Disease: A Brief Overview

Gulati¹,

Guhathakurta²,

Joshi³

et al. 2016

MOJI

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Cytokines are small, non-structural proteins with low molecular weights which have a complex regulatory influence on inflammation and immunity. It has long been considered that development of immune and inflammatory response involves hematopoietic cells, lymphoid cell, and various pro-inflammatory and anti-inflammatory cells, and cytokines mediate the complex interactions of these cells. Cytokines are the intercellular messengers in the immune system where they integrate function of several cell types in various body compartments into a coherent immune response. They have evolved over the years and now include the interferons, the interleukins, the chemokine family, mesenchymal growth factors, the tumor necrosis factor family and adipokines. Earlier known as `soluble factors`, cytokines are produced by and elicit a response from every cell, with the lone exception of the red blood cell. In response to various stimulus cytokines are secreted from various cells including white blood cells. Pleiotropism is the hallmark of a cytokine and there are failures and successes of cytokines and related agents as therapeutic agents. In the membrane of target cells they have specific receptors for their signal transduction and regulatory functions. Beyond the innate and adaptive immunity, cytokines has a major role in many diverse functions including immune cell differentiation, inflammation, angiogenesis, tumorigenesis, neurobiology, viral pathogenesis etc. In addition to inflammation, immunity and infections, cytokines have now expanded their domain to atherosclerosis and cancer. Thus, cytokines may be useful biomarkers for health and disease and act as diagnostic, prognostic and therapeutic agents. This review will highlight the impact of cytokines in various physiological actions, pathophysiological states, therapeutics and the complex interactions between brain and immune cells. knowledge has highlighted the complexity and biphasic nature of cytokines -and the same molecule may have beneficial as well as detrimental effects. For example, interferon-γ (IFNγ), which is essential for defense against several intracellular microorganism such as Mycobacterium tuberculosis, is also a major cytokine in the pathogenesis of several autoimmune diseases. IL-2 is needed for the generation of cytotoxic T-cells (CTL) and forms the basis for several vaccines but the same cytokine drives graft versus host disease and limits the success of bone marrow transplantation [5]. Keywords: Cytokine ReceptorsThe cytokines exert various biological effects through receptors present on the membranes of responsive target cells. These receptors have an extracellular domain, a cytoplasmic domain and a single membrane spanning domain. There is the presence of conserved amino acid sequence motifs on the extracellular domain and these motifs include four conserved cysteine residues. There is also the presence of two polypeptide chains. One is the cytokine specific α subunit and other is a signal transducing β subunit.The nature of the target cell ...

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Section: Cytokines As Therapeutic Targetsmentioning

confidence: 97%

Section: Cytokinesmentioning

confidence: 99%

Cytokines and their Role in Health and Disease: A Brief Overview

Gulati¹,

Guhathakurta²,

Joshi³

et al. 2016

MOJI

View full text Add to dashboard Cite

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“…All study agents, including Ab01 and Ab02, were well tolerated. Each antibody had a circulating half-life of approximately 14 days in NHP (Vugmeyster et al, 2008).…”

Section: Downloaded Frommentioning

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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“…These Abs have very similar affinities and neutralization activity for IL-13 (2) and achieved comparable serum concentrations in these studies (3), in accordance with their similar pharmacokinetic characteristics (37). Both Abs were safe and well tolerated (3).…”

Section: Discussionmentioning

confidence: 57%

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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Preclinical pharmacokinetics, interspecies scaling, and tissue distribution of humanized monoclonal anti-IL-13 antibodies with different IL-13 neutralization mechanisms

Cited by 39 publications

References 15 publications

Cytokines and their Role in Health and Disease: A Brief Overview

Cytokines and their Role in Health and Disease: A Brief Overview

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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