GPCR (G Protein-Coupled Receptor), the largest membrane protein family in the mammalian genome, is widely distributed in the central nervous system, the immune system, the cardiovascular, retina and other organs and tissues, and is involved in the development of the body and the functioning of normal functions. If the regulation of the intracellular pathway is abnormal, or the exogenous pathogen is used as a receptor to attack the cell, it will lead to a series of diseases. Therefore, GPCR is regarded as an important target for drug development, and the development of GPCR antibody is of great value.
A brief introduction to the GPCR family
The body of GPCR is composed of 7 segments of alpha helical structure across the plasma membrane. The N terminal and three loop are located outside the cell, participating in the interaction between the receptor and its ligands, and the C terminal and the 3 loop are located in the cell.
The binding of a specific ligand to GPCR causes the activation of the G protein, producing second messenger Ca2+ or cAMP, which transfers the extracellular signal received by GPCR to the downstream; but GPCR can also mediate the signal transduction that does not depend on the G protein, such as regulating the downstream pathways through interaction with the molecules of beta -arrestin.
For members of GPCR superfamily, there are a variety of different classification methods. There are two popular types: one is A-F classification system; the other is based on sequence similarity and functional similarity, the GPCR is divided into 5 categories, such as Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, Secretin and so on, and the vast majority of the human GPCR are available.  is classified in it.
The relationship between GPCR protein and disease
The GPCR family is widely distributed in the human body and has complex functions. Therefore, it plays an important role in the occurrence and progression of many diseases. According to a clearer study up to now, GPCR’s diseases are divided into 3 main categories: cancer, inflammation and cardiovascular / metabolic diseases.
GPCR and cancer
Studies have shown that many members of the GPCR family are involved in the occurrence and progression of various types of cancer. Hormone receptor GPCR is involved in some hormone dependent cancers. Some protease activated receptors, such as PAR1, activate and activate downstream signaling pathways under the catalysis of MMP-1, thus promoting the invasion and deterioration of cancer cells. Some chemokine receptors, such as CXCR2 and CXCR4, are highly expressed in myeloma and lymphoma cells, and may also be highly expressed on solid tumor cells such as pancreatic cancer and participate in the migration of cells and angiogenesis.
GPCR and inflammation
The chemokine receptor family is mainly expressed on all kinds of cells of the immune system, and is involved in the physiological and pathological processes, such as the development, migration, survival and immune function of immune cells, . Among them, the inflammatory reaction is a kind of pathological phenomenon that the chemokine receptor on the immune cells is activated by chemokines, which mediates the immune function of the immune cells. If CXCR1 and CXCR2 are mainly expressed on neutrophils, when an infection or injury occurs somewhere in the body, the central granulocyte will migrate to the focus of the chemokines (CXCL1, CXCL2, CXCL8) and release the inflammatory factors after reaching the focus, thus producing local inflammatory response .
GPCR and cardiovascular / metabolic diseases
GPCR members associated with cardiovascular disease are mainly distributed in the alpha subclasses of the Class A family, such as one of the most important neurohumoral regulating systems in the human body, AT1R, AT2R, and Mas-R in the angiotensin system (RAAS). The activation of AT1R receptor causes vasoconstriction, proliferation and migration of cells, inflammatory fibrosis, myocardial Replasticity and hypertrophy, sodium water retention and ROS formation, while Mas receptor activates the vasodilatation, inhibition of cell proliferation and migration, anti inflammatory fibrosis, anticoagulation, EDRF, NO production, inhibition of myocardial hypertrophy and growth, and so on. The mutual antagonistic action can maintain the homeostasis of human body.
Development of antibody drugs targeting GPCR
The feasibility of GPCR as a target of antibody drug
At present, there are about 370 GPCR targets. For GPCR targets, the role of antibody drugs is mainly to block the activation of extracellular signal to target and regulate intracellular signal transduction mediated by target.
The characteristics and advantages of antibody drugs for GPCR targets
Compared with small molecules, the antibody has a lower clearance rate in the body, longer time, and lower frequency of delivery; and at a given dose, the individual difference in the plasma concentration of the antibody is smaller.
Research and development of antibody against GPCR
At present, only Mogamulizumab of the Japanese Concord fermented Kirin company (trade name Potelieo) is listed in Japan. The drug is targeted at CCR4, and is suitable for recurrent or refractory CCR4 positive adult T cell leukemia / lymphoma.
In the pipeline, the types and types of indications are varied.
Erenumab, Galcanezumab, Fremanezumab and Eptinezumab are all antibodies to migraine, Erenumab targets CGRPR, and the latter three targets CGRP. At present, the first three have applied for listing, and Eptinezumab has been in the three phase. It can be predicted that the field of migraine will soon enter the state of giant competition without effective treatment.
PRO-40 targets CCR5 on the surface of T cells for the treatment of AIDS. If it is successful, it will be the Ibalizumab-uiyk antibody after the Zhongyu new drug (Trogarzo).
Beijing Kexin REMD-477 is an inhibitory antibody against glucagon receptor GCGR. Inhibition of GCGR reduces glucagon signaling in hepatocytes, thereby inhibiting glycogen degradation and endogenous de novo glucose synthesis. At present, the project is in the two phase of clinical research for the indication of diabetes.
Bird Rock Bio (prior to rename) has reached a cooperation agreement with Johnson on the phase I clinical antibody RIY-018. The target of the drug is CB1 receptor, and its indication is nonalcoholic fatty liver disease (NASH).