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Respiratory diseases & Chronic inflammation

Selective anti-GPCR antibodies for Fibrosis and Cancer (P-007 and P-013)

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with a median survival rate 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, however, limited. NBHL is currently developing two therapeutic mAbs for IPF. In addition to pulmonary, fibrosis occurs in other major organs, to include fibrosis in heart disease, liver fibrosis, renal fibrosis and skin fibrosis. The control of fibrosis is positioned as an important strategy that is directly linked to prevention of the development of lifestyle-related diseases (Journal of Clinical and Experimental Medicine, Volume75, Number 10, December 5th, 2020).

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 with the optimization of humanized antibodies ready for preclinical development for pulmonary fibrosis.

Patents have been granted in Japan (2013), the USA (2014) , Europe (2019) and the other major countries. Patent applications have been filed in other major countries and we are planning to enter the clinical stage of development in 2024.

In addition, this CCR7 is said to be involved in blood cancer and cancer metastasis, leading to our belief that it is positioned for further study and use in the diagnosis and treatment of cancer.

Project P013 is an antibody targeting a GPCR for a bioactive lipid mediator 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 (P-001)

Autoimmune diseases occur when the body’s own immune cells misdentifies then attacks its own organisms.

Various GPCRs (chemokine receptors, lipid-related receptors) work in concert with cytokines and adhesion molecules to promote activation of Th17 cells and dendritic cells, which are the causative cells of autoimmune diseases and chronic inflammation, and consequently thought to be involved in chronic inflammation.

As a therapeutic drug for autoimmune diseases, the development of antibody drugs targeting cytokines is the mainstream application while antibody drugs targeting GPCRs have not yet been put on the market.

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 owing to the problems with selectivity for other prostanoid receptors and off-target effects.

NBHL’s anti-human EP4 antibody(Project P001) 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 currently optimizing the antibody for preclinical testing.

The EP4 antibody treatment has its 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 recent years, it has been reported that there is a correlation between the severity of ankylosing spondylitis and EP4 expression. It is expected to be a diagnostic and therapeutic agent for Ankylosing Spondylitis as well in addition to therapeutic agents for autoimmune diseases such as colitis, psoriatic arthritis.

Patents for the anti-EP4 mAb have been granted in Japan (2013) and Europe (2014). Patents have also been filed in other major countries and we are planning to enter the clinical stage of development in 2024.