The effects of an anti-CD11a mAb, efalizumab, on allergen-induced airway responses and airway inflammation in subjects with atopic asthma

Gauvreau, Gail M.; Becker, Allan B.; Boulet, Louis‐Philippe; Chakir, Jamila; Fick, Robert B.; Greene, William L.; Killian, Kieran J.; O'Byrne, Paul M.; Reid, John; Cockcroft, Donald W.

doi:10.1067/mai.2003.1689

Cited by 88 publications

(45 citation statements)

References 38 publications

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“…Efalizumab has recently been licensed for use in psoriasis [4,11,12,14,18] and may eventually be used in other indications, such as suppression of transplant rejection [24][25][26][27] , experimental autoimmune encephalomyelitis [28] , asthma [29] and granuloma anulare [30] . Therefore a detailed understanding of its binding properties has potentially enormous practical implications.…”

Section: Discussionmentioning

confidence: 99%

The CD11a Binding Site of Efalizumab in Psoriatic Skin Tissue as Analyzed by Multi-Epitope Ligand Cartography Robot Technology

Bonnekoh

Böckelmann

Pommer

et al. 2006

Skin Pharmacol Physiol

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Efalizumab (Raptiva^TM) is an immunomodulating recombinant humanized IgG1 monoclonal antibody that binds to CD11a, the α-subunit of leukocyte function antigen-1 (LFA-1). By blocking the binding of LFA-1 to ICAM-1, efalizumab inhibits the adhesion of leukocytes to other cell types and interferes with the migration of T lymphocytes to sites of inflammation (including psoriatic skin plaques). Analysis of the response in patients treated with efalizumab to date shows that distinct groups of responders and nonresponders to the drug exist. It would therefore be of great practical value to be able to predict which patients are most likely to respond to treatment, by identifying key parameters in the mechanism of action of efalizumab. Detailed investigation and detection of multiple epitopes in microcompartments of skin tissue has until recently been restricted by the available technology. However, the newly developed technique of Multi-Epitope Ligand Cartography (MELC) robot technology combines proteomics and biomathematical tools to visualize protein networks at the cellular and subcellular levels in situ, and to decipher cell functions. The MELC technique, which is outlined in this paper, was used to help characterize the binding of efalizumab to affected and unaffected psoriatic skin as compared to normal control skin under ex vivomodel conditions. Efalizumab was labeled with fluorescein isothiocyanate and integrated into a MELC library of more than 40 antibodies. These antibodies were selected for their potential to detect epitopes which may be indicative of (a) various cell types, (b) structural components of the extracellular matrix, or (c) the processes of cell proliferation, activation and adhesion. Efalizumab bound to CD11a in affected psoriatic skin by a factor 15× and 32× higher than in unaffected psoriatic skin and normal control skin, respectively. CD11a and the efalizumab binding site were primarily expressed in the extravascular dermis, whereas CD54 (ICAM-1) as its ligand was most prevalent in the dermal vessels. T lymphocytes (for which the markers were CD3, CD8, CD4, and CD45R0) were the major cellular targets of efalizumab. In contrast, NK cells were only a minor target of efalizumab. Our study demonstrated that efalizumab represents a treatment for psoriasis that primarily targets memory CD4+ and CD8+ T cells and has a high specificity for psoriatic disease activity. Moreover, we hereby introduce the novel principle of a biological drug-binding biochip assay being especially useful for the future monitoring of psoriatic skin lesions under efalizumab treatment conditions.

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Section: Discussionmentioning

confidence: 99%

The CD11a Binding Site of Efalizumab in Psoriatic Skin Tissue as Analyzed by Multi-Epitope Ligand Cartography Robot Technology

Bonnekoh

Böckelmann

Pommer

et al. 2006

Skin Pharmacol Physiol

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“…The number of false positive therapies, to-date, are limited and include inhaled PGE 2 [102], furosemide [103] and antihistamines [104]. There have also been potential therapies that have demonstrated inhibition of the LAR but failed to be further developed for treatment of asthma for reasons including unsuitability (adverse events) [105] or lack of business opportunity. To date, there are no cases of therapies giving false-negative results in the allergen challenge model and this statistic is of value to pharmaceutical companies when debating the prospect for further clinical development of a compound.…”

Section: Allergen Inhalation Challenge To Study New Drugs For Asthmamentioning

confidence: 99%

Allergen-induced airway responses

2015

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Environmental allergens are an important cause of asthma and can contribute to loss of asthma control and exacerbations. Allergen inhalation challenge has been a useful clinical model to examine the mechanisms of allergen-induced airway responses and inflammation. Allergen bronchoconstrictor responses are the early response, which reaches a maximum within 30 min and resolves by 1-3 h, and late responses, when bronchoconstriction recurs after 3-4 h and reaches a maximum over 6-12 h. Late responses are followed by an increase in airway hyperresponsiveness. These responses occur when IgE on mast cells is cross-linked by an allergen, causing degranulation and the release of histamine, neutral proteases and chemotactic factors, and the production of newly formed mediators, such as cysteinyl leukotrienes and prostaglandin D 2 . Allergen-induced airway inflammation consists of an increase in airway eosinophils, basophils and, less consistently, neutrophils. These responses are mediated by the trafficking and activation of myeloid dendritic cells into the airways, probably as a result of the release of epithelial cell-derived thymic stromal lymphopoietin, and the release of pro-inflammatory cytokines from type 2 helper T-cells. Allergen inhalation challenge has also been a widely used model to study potential new therapies for asthma and has an excellent negative predictive value for this purpose. @ERSpublications Environmental allergens are an important cause of asthma

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“…Specific bronchial allergen provocation is an established tool in asthma research that can increase our understanding of the pathological mechanisms responsible for allergic asthma and can offer key information concerning the therapeutic potential of new agents [1,2,3,4,5,6,7,8]. …”

Section: Introductionmentioning

confidence: 99%

Bronchial Allergen Challenge Using the Medicaid Dosimeter

Schulze

Rosewich

Dreßler

et al. 2011

Int Arch Allergy Immunol

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Background: Bronchial allergen provocations are well established in asthma research. We evaluated the reproducibility of single-concentration, single-step allergen challenges in volunteers with grass pollen allergy. Methods: Forty-seven subjects underwent bronchial challenges using the aerosol provocation system nebulizer (Medicaid Sidestream) with incremental doses of grass pollen to define the individual allergen dose that causes a 20% drop in FEV₁ (PD₂₀FEV₁). In 39 subjects this procedure was followed by single-step challenges. Early and late asthmatic responses were monitored, and increases in exhaled nitric oxide were measured before and 24 h after single-step challenges. Results: After the first single-step challenge, the maximum drop in FEV₁ was 21.3% ± 8.0. A comparison of the drop in FEV₁ to the initial incremental challenge (29.7% ± 7.5) revealed an intraclass correlation of –0.30 (p < 0.05). In the second single-step challenge, the mean drop in FEV₁ was 20.9% ± 7.2. Compared with the first single-step challenge, the intraclass correlation was 0.37 (p < 0.05) and the 95% limits of agreement according to Bland and Altman were –17.5 to 18.1%. The increases in exhaled nitric oxide revealed substantial agreement in repeated single-step challenges (26.8 ppb ± 27.8 and 21.8 ppb ± 21.9, ICC 0.62, p < 0.001). Conclusions: The use of aerosol provocation system to calculate the PD₂₀FEV₁ allergen is a timesaving procedure and is less prone to errors because only one dilution of the allergen is used. The repeatability in well-defined subjects is excellent to study the mechanisms of allergen-induced airway inflammation and the development of new treatments for allergic diseases.

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The effects of an anti-CD11a mAb, efalizumab, on allergen-induced airway responses and airway inflammation in subjects with atopic asthma

Cited by 88 publications

References 38 publications

The CD11a Binding Site of Efalizumab in Psoriatic Skin Tissue as Analyzed by Multi-Epitope Ligand Cartography Robot Technology

The CD11a Binding Site of Efalizumab in Psoriatic Skin Tissue as Analyzed by Multi-Epitope Ligand Cartography Robot Technology

Allergen-induced airway responses

Bronchial Allergen Challenge Using the Medicaid Dosimeter

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