Reversal of airway inflammation and remodeling in asthma by a bispecific antibody fragment linking CCR3 to CD300a.
BACKGROUND
Mast cells (MCs) and eosinophils are critically involved in asthma-associated airway damage and remodeling. However, molecular pathways that inhibit their functions in this process have been scarcely characterized. Recently we established that cross-linking of CD300a inhibits MC and eosinophil activation.


OBJECTIVE
To inhibit effector cell functions in a chronic model of experimental asthma by coaggregation of CD300a with CC chemokine receptor 3 (CCR3) using a bispecific antibody fragment (LC1).


METHODS
Mast cells and eosinophils were treated with LC1 before their activation. Mediator release, survival, and intracellular signaling were assessed. Furthermore, chronic experimental asthma was induced, and starting on day 30, the mice were challenged (3 challenges/wk) for an additional 38 days. With each challenge, the mice received LC1 intranasally.


RESULTS
LC1 inhibited MCs and eosinophil activation in vitro and in vivo. Mice that displayed airway inflammation on day 28 and were treated with LC1 completely recovered from the disease process. In the bronchoalveolar lavage fluid of these mice, cellular inflammation cytokine expression was comparable to that of saline-treated mice. Bronchoalveolar lavage fluid levels of TGF-beta1 correlated significantly with reduced eosinophilia. Histologic analysis revealed significant reduction in lung inflammation, mucus production, collagen deposition, and peribronchial smooth-muscle thickening.


CONCLUSIONS
CD300a is a critical modulator of MCs and eosinophil functions in allergic settings.


CONCLUSIONS
Specific targeting of CD300a in CCR3(+) cells may be a potent tool for treating airway inflammation and tissue remodeling in asthma.
Munitz
Ariel
A
Department of Pharmacology, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Israel.
Bachelet
Ido
I
Levi-Schaffer
Francesca
F
D000281:Administration, Intranasal; D000818:Animals; D018033:Antibodies, Bispecific / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D001249:Asthma / Q000276:immunology / Q000473:pathology* / Q000628:therapy*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D007128:Immunoglobulin Fragments / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000276:immunology* / Q000378:metabolism; D011971:Receptors, Immunologic / Q000276:immunology* / Q000378:metabolism; D054340:Receptors, KIR
D018033:Antibodies, Bispecific; C515351:Ccr3 protein, mouse; D007128:Immunoglobulin Fragments; D018836:Inflammation Mediators; C476771:LMIR1 protein, mouse; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D011971:Receptors, Immunologic; D054340:Receptors, KIR