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Respiratory diseases & chronic inflammation

Selective anti-GPCR antibodies for fibrosis (P007 and P013)

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with median survival of 2 to 4 years after diagnosis1. The incidence of IPF in the USA is estimated to be between 6.8 and 16.3 per 100,000 persons2. Pharmacological treatments are limited, however. NBHL is currently developing two therapeutic mAbs for IPF.

Project P007 is a first-in-class therapeutic mAb targeting a chemokine receptor involved in the tissue fibrosis pathway. The dissociation constant (Kd) of the lead mAb at the target GPCR is approximately 10-10 M. The mAb exerts a therapeutic effect by shutting down chemokine-induced GPCR signaling, including Ca2+ elevation and beta-arrestin activation. Using the surrogate mAb for the rat homologue of the target GPCR, we proved the therapeutic concept of the antibody treatment in a lung fibrosis model, with superiority over the existing small molecule drug for IPF. The mAb for the chemokine receptor also has a potential application for kidney fibrosis. NBHL is now progressing the optimization of humanized antibody ready for preclinical development for pulmonary fibrosis.

Patents have been granted in Japan (2013) and the USA (2014). Patent applications have been filed in other major countries and we are planning to enter the clinical stage of development in 2018.

Project P013 is an antibody targeting a GPCR for a bioactive lipid mediator, which is considered to be involved in fibrosis and pain. NBHL is now progressing optimization of the lead mAb for further development.

References
  1. Kim DS, et al. Proc Am Thorac Soc. 2006; 3:285-92.
  2. Raghu G, et al. Am J Respir Crit Care Med. 2006; 174:810-6.

Anti EP4 receptor antibody (P001)

Prostaglandin E2 receptor subtype, EP4, is thought to be involved in chronic inflammation, cancer immunosuppression and cardiovascular disease. No small molecule drug targeting EP4 is available due to problems with selectivity for other prostanoid receptors and off-target effects.

NBHL’s anti-human EP4 antibody is a first-in-class EP4 receptor selective antibody. It fully antagonizes EP4-dependent cAMP elevation and beta-arrestin activity without antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). The antibody has been shown to inhibit EP4-dependent cAMP elevation and modulate IL-17 production in human primary CD4+ T cells. NBHL is now optimizing the antibody for preclinical testing.

The EP4 antibody treatment has advantages compared with small molecule drugs in terms of its receptor subtype selectivity, limited distribution and long duration. There are several potential applications for the mAb in diseases that are characterized by chronic inflammation, such as colitis, severe asthma and chronic obstructive pulmonary disease (COPD), which involve the Th17 cell pathway.

In addition, the mAb has potential applications in congenital cardiovascular diseases, such as patent ductus arteriosus (PDA), in which EP4-dependent cAMP elevation plays a critical role. Patents for the anti-EP4 mAb have been granted in Japan (2013) and Europe (2014). Patents have been filed in other major countries and we are planning to enter the clinical stage of development in 2018.