Therapeutic Targeting Of CCL17 Via The Systemic Administration Of A Monoclonal Antibody Ameliorates Experimental Fungal Asthma

Ismailoglu, Ugur B.; Moreira, Ana Paula; Ryan, Mary H.; Das, Anuk; Santulli-Marotto, Sandy; Coelho, Ana Lúcia; Hogaboam, Cory M.

doi:10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a4504

Cited by 2 publications

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“…(25) More recently, using the A. fumigatus model of allergic airway inflammation, a commercially available monoclonal antibody specific for murine CCL22 failed to inhibit airway hyper-responsiveness (AHR). (26) This is in contrast to what was observed following neutralization of CCL17 in the same model system. (26,27) Following four rounds of phage library panning, a panel of eight CCL22 specific antibodies was identified from which three unique clones were chosen for in vitro characterization.…”

Section: Introductionmentioning

confidence: 70%

“…(26) This is in contrast to what was observed following neutralization of CCL17 in the same model system. (26,27) Following four rounds of phage library panning, a panel of eight CCL22 specific antibodies was identified from which three unique clones were chosen for in vitro characterization. Based on the ability to block CCL22-mediated calcium flux and b-arrestin recruitment comparably to a commercially available antibody, MAB4391, we characterized the CCL22 binding characteristics of two of these antibodies and established that MC2B7 recognizes a distinct epitope from MAB4391.…”

Section: Introductionmentioning

confidence: 70%

“…Functional activity of CCL22 can be inhibited using MAbs that recognize either one of two non-overlapping sites; also blocking either site impairs function. The previously reported lack of in vivo impact with anti-CCL22 treatment using MAB4391 (26) raised questions as to whether MAB4391 has potent inhibitory activity. Two parallel strategies were pursued to address this question: generation of additional anti-CCL22 antibodies and confirmation of the inhibitory activity of MAB4391 in vitro.…”

Section: Discussionmentioning

confidence: 99%

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CCL22-specific Antibodies Reveal That Engagement of Two Distinct Binding Domains on CCL22 Is Required for CCR4-mediated Function

Santulli-Marotto

Wheeler

Lacy

et al. 2015

Monoclonal Antibodies in Immunodiagnosis and Immunotherapy

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CCL22 inactivation in vivo occurs by cleavage at the N-terminus; however, it is unclear whether this encompasses the entire site of CCR4 interaction. CCL17 also binds CCR4 and its function requires binding via two discrete binding sites. Using monoclonal antibodies (MAbs), we report that there are two separate sites on CCL22 that are required for CCR4-mediated function. The CCL22-specific antibodies bind with affinities of 632 ± 297 pM (MC2B7) and 308 ± 43 pM (MAB4391) and neither exhibited detectable binding to CCL17. Both antibodies are comparable in their ability to inhibit CCL22-mediated calcium mobilization; however, competition binding studies demonstrate that MC2B7 and MAB4391 bind to distinct epitopes on CCL22. Both antibodies inhibit function through CCR4, which is demonstrated by loss of β-arrestin recruitment in a reporter cell line. In both assays, blocking either site independently abolished CCL22 function, suggesting that concurrent engagement of both sites with CCR4 is necessary for function. This is the first demonstration that CCL22 has two distinct binding sites that are required for CCR4 function. These antibodies are valuable tools for better understanding the interaction and function of CCL22 and CCR4 and will potentially help further understanding of the differential outcomes of CCL17 and CCL22 interaction with CCR4.

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Section: Introductionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

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CCL22-specific Antibodies Reveal That Engagement of Two Distinct Binding Domains on CCL22 Is Required for CCR4-mediated Function

Santulli-Marotto

Wheeler

Lacy

et al. 2015

Monoclonal Antibodies in Immunodiagnosis and Immunotherapy

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Engagement of Two Distinct Binding Domains on CCL17 Is Required for Signaling through CCR4 and Establishment of Localized Inflammatory Conditions in the Lung

Santulli-Marotto

Boakye²,

Lacy³

et al. 2013

PLoS ONE

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CCL17 (TARC) function can be completely abolished by mAbs that block either one of two distinct sites required for CCR4 signaling. This chemokine is elevated in sera of asthma patients and is responsible for establishing inflammatory sites through CCR4-mediated recruitment of immune cells. CCL17 shares the GPCR CCR4, with CCL22 (MDC) but these two chemokines differentially affect the immune response. To better understand chemokine mediated effects through CCR4, we have generated chimeric anti-mouse CCL17 surrogate antibodies that inhibit function of this ligand in vitro and in vivo. The affinities of the surrogate antibodies for CCL17 range from 685 pM for B225 to 4.9 nM for B202. One antibody, B202, also exhibits weak binding to CCL22 (KD∼2 µM) and no binding to CCL22 is detectable with the second antibody, B225. In vitro, both antibodies inhibit CCL17-mediated calcium mobilization, β-arrestin recruitment and chemotaxis; B202 can also partially inhibit CCL22-mediated β-arrestin recruitment. Both B202 and B225 antibodies neutralize CCL17 in vivo as demonstrated by reduction of methacholine-induced airway hyperreactivity in the A. fumigatus model of asthma. That both antibodies block CCL17 function but only B202 shows any inhibition of CCL22 function suggests that they bind CCL17 at different sites. Competition binding studies confirm that these two antibodies recognize unique epitopes that are non-overlapping despite the small size of CCL17. Taking into consideration the data from both the functional and binding studies, we propose that effective engagement of CCR4 by CCL17 involves two distinct binding domains and interaction with both is required for signaling.

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Therapeutic Targeting Of CCL17 Via The Systemic Administration Of A Monoclonal Antibody Ameliorates Experimental Fungal Asthma

Cited by 2 publications

References 0 publications

CCL22-specific Antibodies Reveal That Engagement of Two Distinct Binding Domains on CCL22 Is Required for CCR4-mediated Function

CCL22-specific Antibodies Reveal That Engagement of Two Distinct Binding Domains on CCL22 Is Required for CCR4-mediated Function

Engagement of Two Distinct Binding Domains on CCL17 Is Required for Signaling through CCR4 and Establishment of Localized Inflammatory Conditions in the Lung

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