Clinical efficacy of recombinant human latrophilin 3 antibody in the treatment of pediatric asthma

Abstract

Abstract. Pediatric asthma is a chronic pulmonary inflammatory disease featuring hypersecretion of mucus and inflammation in the airway, resulting in dysfunction of the airway smooth muscle. Previous evidence demonstrated that latrophilins, a novel family of receptors, present a beneficial effect on airway smooth muscle cells. In the present study, the therapeutic effects of recombinant human latrophilin 3 (rhLPHN3) antibody (Ab) in patients with pediatric asthma were investigated, and the molecular mechanism underlying the function of LPHN3 in the treatment of asthma in clinical practice was examined. A total of 342 pediatric asthma cases were recruited and randomly divided into three groups, receiving treatment with rhLPHN3 Ab (n=134), salbutamol (n=108) or montelukast (n=100) by nasal aerosolization. Each group received the respective clinically tested dose for 16 weeks. Inflammatory factors interleukin (IL)-10, IL-17, IL-4, matrix metallopeptidase-9 (MMP-9), interferon-γ (IFN-γ) and transforming growth factor-β (TGF-β) levels in peripheral blood mononuclear cells were analyzed prior to and post treatment. The clinical outcomes revealed that pathological alterations were significantly improved following treatment with rhLPHN3 Ab for patients with pediatric asthma when compared with those receiving salbutamol and montelukast. It was also observed that rhLPHN3 Ab downregulated the plasma concentration levels of IL-10, IL-17, IL-4 and MMP-9, and upregulated IFN-γ and TGF-β levels in the three groups. In addition, clinical data demonstrated that rhLPHN3 Ab significantly promoted E-selectin and mucin 5AC expression, as well as improved the activation of nuclear factor (NF)-κB p65 DNA binding activity and the phosphorylation levels of protein kinase A. Furthermore, rhLPHN3 Ab markedly improved adhesion and proliferation of airway smooth muscle cells, which led to promotion of the contraction of these cells.In conclusion, these clinical data suggest that rhLPHN3 Ab serves an important role in the inhibition of inflammatory mediators through downregulation of NF-κB signaling pathway, which contributes to airway remodeling and bronchodilation in patients with pediatric asthma.

A guide to adhesion GPCR research

“…These antibodies were shown to inhibit their respective receptor function in vitro , affecting the adhesion and migration of neutrophils [136], granulocyte migration [189], as well as the migration of neural progenitor cells [188], but their efficacy in disease‐relevant in vivo models still needs to be elucidated. An anti‐EMR1/ADGRE1 antibody, however, induced natural NK cell‐mediated removal of eosinophils in vivo in monkeys [190], while in a clinical phase‐I study recombinant antibodies against LPHN3/ADGRL3 [191] resulted in beneficial effects on the secretion of inflammatory mediators through downregulating of NF k B signaling pathways [191]. Thus, aGPCR‐targeted antibodies also offer an exciting approach to therapeutically target aGPCRs.…”