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GPCR Targeted Antibody

G protein-coupled receptors (GPCRs) have been shown to be associated with a variety of diseases and are one of the attractive target molecules for drug development.

Drugs targeting GPCRs have been applied to metabolic diseases, cardiovascular diseases, autoimmunity, respiratory diseases, central nervous system diseases, and others. According to our analysis of GPCR-related drugs based on GlobalData, as of the end of 2020, global sales of all new drugs amounted to 7,953.6 billion (12.7% of the total) and 113 items (19.0% of the total) were sold. It accounts for a high proportion.

However, in recent years, the probability of launching GPCR drug discovery using small compounds has clearly continued to decline. Nevertheless, in addition to its high efficacy and safety, therapeutic monoclonal antibodies are steadily increasing their global sales (17,351.2 billion yen as of the end of 2020) due to the commoditization of commercial mass manufacturing technology.

On the other hand of the steady expansion of sales, the depletion of target molecules for new antibody drugs, which are expected to launch after the latter half of 2020, is becoming apparent. We anticipate future market trends for such biomedicines, and in order to overcome the shortcomings of this conventional GPCR drug discovery, we use antibodies for the Drug discovery with a new concept of “controlling the function of the GPCR using antibodies”.

However, the discovery of therapeutic monoclonal antibody targeting GPCR is difficult because GPCRs have a low expression level in cells and a structure with few exposed parts outside the membrane. Among them, it is particularly difficult to discover a functional monoclonal antibody that can directly control GPCR activation. To overcome this difficulty, we have developed a unique drug discovery exploration platform, MGRAA® Discovery Engine.

To date, there are two GPCR-targeted antibody drugs approved worldwide, one of which is the CGRP receptor inhibitor erenumab (trade name Aimovig) that was launched in 2018. It is projected to become a 100 billion yen product, which is an exceptional sales evaluation for a migraine drug. In addition, the market for GPCR antibody drugs is expected to expand further in the future.

MoGRAA® Discovery Engine

In order to overcome the difficulty of drug discovery targeting GPCRs, we have combined various advanced technology elements for use, and developed the “MoGRAA® Discovery Engine” as a platform optimized for research and development of antibodies targeting GPCRs.

MoGRAA® is an abbreviation for Modification of G-protein coupled Receptor Activation with monoclonal Antibody. It is representative of the concept of a new antibody drug that we propose as “regulating the function of GPCRs with monoclonal antibodies.”

Compared with existing cytokines and single-transmembrane receptors, the difficulties of developing antibody drugs targeting GPCRs are thought to be as follows:

(1) It is difficult to present an antigen that is a binding target to immune cells while maintaining the same three-dimensional structure as the GPCR existing in the living body.

(2) Due to the structure of GPCRs, the exposed sites on the cell surface that antibodies can access and bind to are extremely limited.

(3) The expression level of the target GPCR protein per cell is low, making it difficult to create an antigen or construct an evaluation system.

(4) There are multiple subtypes with high structural homology in GPCR, and it is difficult to obtain binding specificity for a specific subtype among them.

(5) A drug discovery method for efficiently screening functional anti-GPCR antibodies has not been established.

The MoGRAA® discovery engine makes it possible to obtain antibodies that recognize and bind to the extracellular position of GPCRs, as well as to find functional monoclonal antibodies that are suitable for the development of excellent antibody drugs.

Features of the MoGRAA® Discovery Engine

Antigens are vital to the creation of antibodies, particularly when targeting GPCRs.

Rather than using a GPCR protein or a partial peptide of the extracellular domain as an antigen, a method of effectively immunizing animal muscle cells with a plasmid vector expressing the full-length protein of the target GPCR (DNA immunization method) is adopted and optimized for application in the development of various functional anti-GPCR antibodies.

This has made it possible to obtain medical read antibodies with high selectivity for target GPCRs and high affinity.

In addition, the frequency of B cells and plasma cells that produce functional antibodies from immune animals in lymphoid tissues is considered to be extremely low.

It was determined to be extremely difficult and inefficient to obtain a functional anti-GPCR antibody by the so-called “hybridoma method”, the conventional technique of fusing lymphocytes of lymphoid tissue and myeloma cells, and evaluating the antibody in the cell supernatant after culturing.

Therefore, we have developed a technology (RiGRASSTM: Rapid isolation of GPCR-specific Antibody by Single-cell Screening System) for screening B cells and plasma cells from immune animals in a relatively short amount of time without culturing cells for a long period of time (RiGRASSTM: Rapid isolation of GPCR specific antibody by Single-cell Screening System, Patent  WO2020/171020 ).

By combining these technologies, it has become possible to efficiently obtain monoclonal antibodies that specifically bind to target GPCRs and possess functions such as antagonists.

mAb library targeting GPCR under development with NBHL technology platform
Ligand Class Activity Indication
Prostaglandin A Full antagonist Autoimmune disease
Chemokine A Full antagonist Fibrosis
Lipid mediator A Full antagonist Pain, Fibrosis
Fatty acid A Agonist Diabetes
Amine A Modulator Metabolic diseases
Peptide B Modulator Diabetes
Chemokine A Full antagonist Infectious diseases
Wnt FZD Full antagonist Cancer
Orphan C Agonist Respirtory diseases
Peptide A Full antagonist Ophthalmology