SCTR

On May 22, local time, Biogen Inc. and Human Immunology Biosciences (HI-Bio) jointly announced that they had reached an acquisition agreement, in which Biogen agreed to acquire HI-Bio for an upfront payment of $1.15 billion and potential milestone payments of up to $650 million. HI-Bio is a clinical-stage biotechnology company focused on providing targeted therapies for patients with serious immune-mediated diseases (IMDs). Inspired by the rise of targeted therapies in clinical oncology, the company pursues a treatment strategy that targets and depletes specific types of immune cells driving IMDs. The company's most advanced candidate, felzartamab, is a CD38-targeting antibody that has shown the ability to deplete CD38+ cells, including plasma cells and natural killer (NK) cells, in clinical studies. These cells are implicated in a range of conditions, including antibody-mediated rejection (AMR), IgA nephropathy (IgAN), lupus nephritis (LN), and primary membranous nephropathy (PMN). Felzartamab has received Breakthrough Therapy Designation (BTD) and Orphan Drug Designation (ODD) from the U.S. Food and Drug Administration (FDA) for the treatment of primary membranous nephropathy (PMN). It has also received ODD for the treatment of antibody-mediated rejection (AMR) in kidney transplant recipients. According to a recent HI-Bio study published in The New England Journal of Medicine, titled "A Randomized Phase 2 Trial of Felzartamab in Antibody-Mediated Rejection," the results of a Phase 2 clinical trial related to felzartamab for antibody-mediated rejection were disclosed. In this phase II, double-blind, randomized, placebo-controlled clinical trial, researchers included patients who experienced antibody-mediated rejection (AMR) at least 180 days post-transplantation. The participants were randomly assigned into two groups: one receiving felzartamab (at a dose of 16 mg/kg body weight) and the other receiving a placebo. The treatment period lasted for 6 months, followed by a 6-month observation period. The primary endpoint was the safety and side effect profile of felzartamab. Key secondary endpoints included renal biopsy results at 24 and 52 weeks, levels of donor-specific antibodies (DSA), counts of peripheral blood NK cells, and levels of donor-derived cell-free DNA. The results showed that, in the felzartamab group (total of 11 patients), 8 patients experienced mild to moderate infusion reactions. Serious adverse events occurred in 1 patient in the felzartamab group and in 4 patients in the placebo group, with 1 patient in the placebo group experiencing graft loss. After 24 weeks of treatment, the rate of morphological resolution of AMR in the felzartamab group (82%; 9 out of 11 patients) was significantly higher than in the placebo group (20%; 2 out of 10 patients), with a difference of 62 percentage points. The felzartamab group demonstrated lower scores in microvascular inflammation, molecular scores indicative of the probability of AMR, and levels of donor-derived cell-free DNA compared to the placebo group. By week 52, 3 of the 9 patients who initially responded to felzartamab reported a recurrence of AMR, accompanied by a return of molecular activity and biomarker levels to near-baseline levels. Regarding C5aR1 and the complement systemNotably, in addition to its primary project, felzartamab, HI-Bio's pipeline also includes izastobart/HIB210, a monoclonal antibody product targeting C5aR1 currently undergoing Phase I trials. This product shows potential for further development in a range of complement-mediated diseases, including autoimmune disorders and refractory malignant solid tumors. The C5aR1 receptor is one of the key receptors in the human complement system. The complement system is a crucial component of the human immune response, primarily responsible for identifying and eliminating pathogens, as well as participating in the clearance of apoptotic cells and the regulation of immune responses. Complement system activation can occur via three pathways: the classical pathway, the alternative pathway, and the lectin pathway. This activation ultimately leads to a cascade of proteolytic reactions, resulting in the formation of the membrane attack complex, which lyses target cells and generates various bioactive fragments. These fragments can bind to specific cell surface receptors, inducing a series of biological effects. Complement receptors are named according to the complement components they recognize. For example, the receptor that binds to the C3a cleavage product is called the C3a receptor, whereas those binding to the C5a cleavage product are called the C5a receptor 1 (C5aR1) and C5a receptor 2 (C5aR2). The C5a1 receptor (C5aR1) belongs to the GPCR (G-protein coupled receptor) family and is widely expressed on immune cells such as neutrophils, monocytes, macrophages, dendritic cells, mast cells, and certain T cells, as well as on non-immune cells. Upon binding to C5a, a potent inflammatory fragment generated by the cleavage of C5, the C5a1 receptor robustly activates immune cells, triggering a strong inflammatory response that includes cell activation, migration, depolarization, and oxidative burst. It is a key regulator of complement-mediated inflammatory responses. The figure below illustrates the wide tissue distribution of the C5a1 receptor in the human body. The types of diseases associated with C5a1 receptor dysfunction include cancer, immune system disorders, cardiovascular and metabolic diseases, as well as reproductive and urinary system disorders. Currently, the major agonist molecules targeting the C5a1 receptor are primarily peptides, with activity ranges distributed between nM and µM. In contrast, a significant number of small-molecule compounds exist among the antagonists and inverse agonists targeting the C5a1 receptor. Additionally, there are also some peptide-based antagonist molecules. Among them, Avacopan, the molecule with the highest antagonistic activity, was approved for market release in Japan and the United States in September and October 2021, respectively, for the treatment of severe anti-neutrophil cytoplasmic (auto) antibody-associated vasculitis. In January 2022, the European Commission approved Avacopan for use in combination with rituximab or cyclophosphamide for the treatment of adult patients with severe, active granulomatosis with polyangiitis or microscopic polyangiitis. Data from a pivotal Phase 3 clinical study supporting Avacopan's approval were published in The New England Journal of Medicine. Another small-molecule antagonist, ACT-1014-6470, developed by Idorsia Pharmaceuticals, has a lower activity compared to Avacopan (pIC50 8.0 vs. 9.7). Two Phase 1 safety studies were published in 2022 and 2023, respectively. Among the 16 study completers, 4 cases of transient and mild adverse events were reported in subjects with severe renal impairment, but 3 of these AEs were deemed unrelated to ACT-1014-6470. The clinical Phase 2 efficacy of ACT-1014-6470 for patients with severe renal impairment remains promising. Compared to traditional small molecule antagonists, monoclonal antibody drugs targeting C5aR1 are also considered to have significant advantages in inhibiting receptor activity. A representative antagonistic antibody molecule is Avdoralimab (IPH-5401). Avdoralimab is a humanized monoclonal antibody targeting the C5a receptor 1 (C5aR1) with potential immunomodulatory activity. Upon administration, avdoralimab specifically targets, binds to, and blocks C5aR1 expressed on myeloid-derived suppressor cells and neutrophil subsets. This action prevents its ligand C5a from binding to C5aR1, thereby inhibiting the C5aR1-mediated activation of these cells within the tumor microenvironment. This blockade also curtails these cells' capacity to secrete inflammatory and angiogenic factors. Consequently, this promotes the activation of T cells and natural killer (NK) cells, induces an anti-tumor immune response, and inhibits the proliferation of tumor cells. Avdoralimab was initially developed by Novo Nordisk. In 2017, the French biotechnology company Innate Pharma acquired the Avdoralimab project from Novo Nordisk for €40 million. Since then, this antibody has been utilized in clinical development for the treatment of solid tumors, COVID-19 infections, and chronic urticaria. In addition to Avdoralimab, there are several monoclonal antibody products targeting C5aR1 in the market, including Izastobart, originally developed by MorphoSys AG and transferred to HI-Bio, as well as VIS-954, an antagonist monoclonal antibody developed by Visterra. Izastobart (MOR210) is a humanized antibody that was developed by MorphoSys in the preclinical stage. It targets the C5a receptor and is derived from MorphoSys's HuCAL Platinum® technology. Research indicates that tumors produce significant amounts of C5a, which, by recruiting and activating myeloid-derived suppressor cells (MDSCs), is believed to contribute to the formation of an immunosuppressive pro-tumor microenvironment. MOR210 aims to block the interaction between C5a and its receptor, thereby potentially neutralizing the immunosuppressive function of MDSCs and enabling immune cells to attack the tumor. In 2018, MorphoSys entered into an exclusive strategic collaboration and regional licensing agreement with I-Mab for MOR210. Under this agreement, I-Mab obtained exclusive rights to develop and commercialize MOR210 in China, Hong Kong, Macau, Taiwan, and South Korea, while MorphoSys retained rights for the rest of the world. MorphoSys received an upfront payment of $3.5 million from I-Mab and is eligible for up to $101.5 million in development and commercialization milestone payments, as well as mid-single-digit tiered royalties on net sales of MOR210 within I-Mab's territories. In 2022, MorphoSys transferred the global rights to develop Felzartamab (excluding Greater China) and MOR210 (excluding China and South Korea) to HI-Bio. As part of this agreement, MorphoSys received a 15% equity stake in HI-Bio, along with specific equity earn-out clauses and customary investment rights. MorphoSys also secured a position on the HI-Bio Board of Directors. Upon achieving research, regulatory, and commercialization milestones, MorphoSys is entitled to receive up to $1 billion from HI-Bio for the two projects combined. Additionally, MorphoSys is eligible for low-to-mid double-digit tiered royalties based on net sales of felzartamab and MOR210, along with compensation for ongoing project expenses. HI-Bio will bear all future developmental and commercialization costs. Upon signing, MorphoSys received a $15 million upfront payment for MOR210. Additionally, MorphoSys has several pipeline products co-developed with Lilly, Anthos, Novartis, and others. On February 5, 2024, MorphoSys and Novartis entered into a merger agreement. Novartis offered MorphoSys shareholders a cash price of €68.00 per share, bringing the total equity value to €2.7 billion. This offer represents a premium of 94% and 142% over the unaffected volume-weighted average prices one month and three months prior to the closing price on January 25, 2024, respectively. In addition, there is an ADC product targeting the C5a receptor, SAND-5 RGD, currently in the drug discovery phase, developed by Adienne SA. How to obtain the latest research advancements in the field of biopharmaceuticals? In the Synapse database, you can keep abreast of the latest research and development advances in drugs, targets, indications, organizations, etc., anywhere and anytime, on a daily or weekly basis. Click on the image below to embark on a brand new journey of drug discovery!

On March 20th, the Swiss pharmaceutical company Idorsia announced that the U.S. FDA has approved TRYVIO™ (aprocitentan) for use in combination with other antihypertensive medications to treat adult hypertension, in order to lower blood pressure levels in the adult patient population whose blood pressure has not been effectively controlled. Hypertension is a common chronic condition characterized by persistently high blood pressure readings (140/90 mmHg or higher). Lowering high blood pressure can reduce the risk of fatal and non-fatal cardiovascular events, with stroke and myocardial infarction being the primary concerns. ·TRYVIO acts by targeting endothelin-1 (ET-1), which is a potent vasoconstrictor closely associated with the mechanisms leading to hypertension. It mitigates the detrimental effects of ET-1 by preventing its binding to ETA and ETB receptors, thereby reducing the vasoconstrictive, fibrotic, cellular proliferative, and inflammatory responses induced by ET-1. ·TRYVIO tablets are required to be taken only once daily and can be ingested with or without food. ·TRYVIO comes with a black box warning, indicating its teratogenic toxicity. It is contraindicated for use in pregnant women. Effective contraceptive measures must be taken before starting treatment, throughout the course of treatment, and for one month after discontinuation. ·Warnings and precautions associated with TRYVIO include risks of hepatotoxicity, fluid retention, decrease in hemoglobin, and reduced sperm count. Common adverse reactions comprise edema/fluid retention and anemia. The following is a retrospective review of TRYVIO's R&D milestones over the past 10 years at various time points: 2023: Submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA). 2022: Filed a New Drug Application (NDA) with the U.S. FDA, and in the same year, presented the work as a late-stage breakthrough study at an American Heart Association (AHA) meeting, with relevant Phase III clinical trial data published in the prestigious medical journal The Lancet. 2022: Successfully completed Phase III clinical studies, demonstrating the drug's safety and efficacy in the targeted patient population. 2018: Initiated Phase III clinical trial, a crucial step in validating the drug's therapeutic effectiveness and safety in a large population. 2017: The dose-response study yielded positive results, confirming the pharmacodynamic response of Aprocitentan at different dosages, laying the foundation for subsequent research. 2015: Began Phase II dose-response relationship studies aimed at further exploring the optimal dosage range of the drug and its response in humans. 2014: Launched Phase I clinical trial program, marking the first step for Aprocitentan to move from laboratory to human clinical testing, primarily to assess the drug's safety, tolerability, and preliminary pharmacokinetic characteristics in humans. Hypertension Medication Returned by Johnson & JohnsonOn January 26, 2017, Johnson & Johnson announced a proposal to acquire the Swiss pharmaceutical company Actelion in an all-cash tender offer, at a price of $280 per share (totaling $30 billion in cash) for all of Actelion's outstanding shares. As part of the transaction, Actelion will spin off its drug research and early-stage clinical development assets into a newly formed Swiss biopharmaceutical company called Idorsia. Idorsia will be listed on the Swiss Stock Exchange, and Johnson & Johnson will initially hold a 16% stake in the newly established R&D company. In November 2017, the newly formed Idorsia announced a collaboration with Janssen Biotech, a subsidiary of Johnson & Johnson, focusing on Aprocitentan. As part of the agreement, Idorsia will receive about $230 million in milestone payments; Idorsia and Janssen Biotech will share the development costs of aprocitentan during the Phase III clinical trials; and Idorsia will be entitled to royalty fees on potential future net sales. On September 6th, 2023, Idorsia announced that the company had reached an agreement with Janssen Biotech, a subsidiary of Janssen Pharmaceuticals, to reacquire the rights to Aprocitentan. It was reported that, although Phase 3 clinical trial results of the drug showed a significant reduction in blood pressure compared to placebo, they also revealed an issue where 18% of patients on high doses experienced mild to moderate fluid retention. Johnson & Johnson deemed that the drug might not meet their commercial development objectives and therefore decided to return the rights. In return, Idorsia will pay Janssen Biotech approximately 306 million Swiss francs, contingent upon the approval of Aprocitentan's marketing application by the US FDA and the European EMA. Additionally, Idorsia is currently exploring the best approach to maximize the value of aprocitentan." Aprocitentan is a novel oral dual endothelin receptor antagonist currently being developed by Idorsia Pharmaceuticals. It effectively inhibits the binding of ET-1 to both ETA and ETB receptors. It is reported that the potential for drug-drug interactions with Aprocitentan is low, and its mechanism of action is highly suitable for the pathophysiology of resistant hypertension. The Latest Clinical Data on AprocitentanIn November 2022, the team from Idorsia and Johnson & Johnson published an article in The Lancet journal, presenting Phase 3 clinical study data of aprocitentan for the treatment of resistant hypertension. The results indicated that aprocitentan was well-tolerated in patients with resistant hypertension, showing a superior blood pressure-lowering effect compared to placebo at week 4 and sustained efficacy at week 40. The data demonstrated that among the 730 patients enrolled in the study, the least squares mean changes in systolic blood pressure after the first 4 weeks of treatment were -15.3 mm Hg for aprocitentan 12.5 mg, -15.2 mm Hg for aprocitentan 25 mg, and -11.5 mm Hg for placebo. The differences compared to placebo were -3.8 mm Hg and -3.7 mm Hg, respectively. Four weeks after discontinuation of the medication, systolic blood pressure significantly increased by 5.8 mm Hg compared to placebo. The most common adverse events were mild to moderate edema or fluid retention, leading to discontinuation of aprocitentan treatment in 7 patients. There were 11 cases of sudden death during the trial, which the researchers considered unrelated to the treatment. Based on this positive Phase 3 clinical data, Idorsia and Johnson & Johnson submitted marketing authorization applications for Aprocitentan to the United States in December 2022 and to the European Union in January 2023. About Endothelin (ET)Endothelin (ET) is a potent peptide vasoconstrictor, discovered in 1988 by Japanese scientist Yanagisawa and colleagues. It regulates blood pressure through its actions on blood vessels, the heart, and kidneys. The ET peptide family consists of three members: ET-1, ET-2, and ET-3. These ET peptides are each 21 amino acids in length and their overall structure is constrained by two disulfide bonds. The carboxyl-terminal sequence is essential for their activity. Taking ET-1 as an example, the translated ET-1 exists in the form of a precursor. Under the action of endothelin-converting enzyme (ECE), it undergoes proteolytic processing from an inactive precursor to a mature peptide, providing a potential pathway for inhibiting the production and action of ET-1. From, DOI: 10.1038/s41569-019-0176-3Humans have two types of ET receptors, the ETA receptor (ETA) has a higher binding affinity with ET-1 and ET-2 than with ET-3; the ETB receptor (ETB) has comparable binding affinity with all three isoforms. The figure below shows the relative mRNA expression levels of the ETA receptor and ETB receptor in 41 types of adult mouse tissues. The ETA receptor is highly expressed in the cardiovascular and pulmonary tissues, whereas the ETB receptor is highly expressed in the brain tissue. From,DOI: 10.1038/s41569-019-0176-3About Endothelin Receptor AntagonistsEndothelin receptors are widely known for their involvement in the physiological regulation of vascular tone due to their potent vasoconstrictive action. Excessive secretion of endothelin in the lungs can lead to pulmonary arterial hypertension. Endothelin autoregulates itself through physical and chemical factors such as blood flow, mechanical stretch, or pH changes and triggers the production of growth factors. Moreover, chronic endothelin stimulation has been shown to be associated with a variety of human cardiovascular, inflammatory, fibrotic, and neoplastic diseases. Additionally, endothelin may also play a role in conditions such as heart failure, renal insufficiency, septic shock, atherosclerosis, and hemorrhage-associated cerebrovascular diseases. Therefore, drugs that act on endothelin receptors may be beneficial in the treatment of a multitude of diseases. Source: DOI: 10.3390/jcm9030824Currently, several companies are screening antagonists targeting the ETA and ETB receptors, including selective antagonists for the ETA receptor, selective antagonists for the ETB receptor, or dual antagonists. Multiple endothelin receptor antagonists have been approved for the treatment of this disease. Current Status of Drug Development According to statistics from the Synapse database, there are a total of 5 endothein receptor antagonists (ETA or ETB antagonists) approved by the FDA, including Bosentan (2001, dual antagonist), Sitaxentan (2006, withdrawn), Ambrisentan (2007, ETA receptor selective), Macitentan (2013, dual antagonist), and Sparsentan (2023, ETA+AT1R dual antagonist). In February 2023, a dual antagonist targeting the inner ETA receptor and angiotensin II (Ang II) type 1 receptor (AT1R) named Filspari (Sparsentan) was approved by the FDA for marketing. The pharmaceutical is indicated for adults with primary immunoglobulin A nephropathy who are at risk of rapid disease progression and aims to reduce proteinuria. In May 2023, an ETA receptor selective agonist developed by the biopharmaceutical company Pharmazz, Sovateltide injectable solution, was approved for marketing in India for the treatment of patients with acute ischemic stroke. On September 14, Pharmazz entered into a licensing agreement with the Indian pharmaceutical company Sun Pharma. Under this agreement, Sun Pharma will have the rights to sell Sovateltide in India under the brand name Tyvalzi™. Pharmazz will be entitled to upfront and milestone payments, including royalties. Regarding Endothelin and Antitumor Drugs Aside from the symptoms of hypertension, endothelin receptors have multiple functions related to fundamental cellular processes such as cell proliferation and apoptosis. Aberrant expression of ET1 or overexpression of endothelin receptors or their associated signaling pathways can promote the occurrence and development of tumors through autocrine and paracrine mechanisms. These altered mechanisms can originate from genetic and epigenetic changes. In addition, a complex crosstalk network between ET1 signaling and other growth factor pathways propels tumor progression. This includes the interactions between endothelin receptors and receptors for epidermal growth factor and vascular endothelial growth factor. The ET1 signal can promote cell proliferation, survival, epithelial-mesenchymal transition (EMT), angiogenesis, immune cell responses, and drug resistance, with its mechanisms of action depending on specific contexts. Consequently, endothelin receptors have become key targets in cancer therapy. The figure below shows the expression of endothelin receptors in some human malignancies. According to statistics from the Synapse database, there are currently several clinical candidate drugs globally targeting ETA or ETB receptors for research into various types of solid tumors. This includes the ETB receptor antagonist VRP-1620, developed by the University of Illinois for breast cancer research, and ENB Medical's selective ETB receptor small molecule antagonist ENB-003, both of which are in clinical research stages. Chinese innovative pharmaceutical company Gmax Biopharm LLC is conducting research on GMA202, a bispecific M-Body molecule consisting of an antibody targeting the ETA receptor and an antibody fragment targeting CD3. Reportedly, GMA202 achieves a unique and precise tumor immunotherapy effect by pairing activated T cells with ovarian cancer cells that highly express the ETA receptor. RG-7636 (DEDN6526A) is an ADC product developed by Genentech, which uses the ETB receptor as the mAb target linked to MMAE. Preclinical studies have shown that RG-7636 exhibits dose-dependent antitumor activity against xenografts expressing the ETB receptor. Phase 1 clinical trials have demonstrated that RG-7636 has antitumor activity in patients with melanoma.

Gastric Cancer (GC), also known simply as GC, is one of the most lethal malignancies worldwide, with over one hundred million new cases reported in 2022, leading to the death of 783,000 individuals. Globally, the incidence and mortality rates of gastric cancer have been on the decline in most regions over the past few decades. This considerable change is largely attributed to economic development and improved practices in food preservation associated with refrigeration technology during food transport and storage. In 2020, it was estimated that there were 1.1 million cases of stomach cancer diagnosed globally, with 720,000 in males and 370,000 in females. Stomach cancer ranks among the top three most common cancers in 19 countries worldwide and is the most common cancer in four countries: Bhutan, Kyrgyzstan, Cape Verde, and Tajikistan. Sixty percent of all stomach cancer cases occur in East Asia, with China alone accounting for 43.9% of cases. The incidence of stomach cancer is higher in males, with 66% of all cases occurring in men. There are significant differences in the incidence rates across different regions; in several African countries, the incidence rate is less than 5 cases per 100,000 person-years in males, whereas in East Asian countries, it exceeds 30 cases per 100,000 person-years. This indicates that factors such as gender, region, and level of economic development have a significant impact on the incidence of stomach cancer. Moreover, in high-incidence areas such as East Asia, especially China, the prevention and control of stomach cancer represent a considerable challenge. In 2020, it was estimated that there were 1.1 million cases of stomach cancer diagnosed globally, with 720,000 in males and 370,000 in females. Stomach cancer ranks among the top three most common cancers in 19 countries worldwide and is the most common cancer in four countries: Bhutan, Kyrgyzstan, Cape Verde, and Tajikistan. Sixty percent of all stomach cancer cases occur in East Asia, with China alone accounting for 43.9% of cases. The incidence of stomach cancer is higher in males, with 66% of all cases occurring in men. There are significant differences in the incidence rates across different regions; in several African countries, the incidence rate is less than 5 cases per 100,000 person-years in males, whereas in East Asian countries, it exceeds 30 cases per 100,000 person-years. This indicates that factors such as gender, region, and level of economic development have a significant impact on the incidence of stomach cancer. Moreover, in high-incidence areas such as East Asia, especially China, the prevention and control of stomach cancer represent a considerable challenge. From: DOI: 10.1016/j.eclinm.2022.101404However, unlike the previously reported continuous decline in the overall incidence rate across all age groups, recent reports indicate an increase in the incidence of gastric cancer among young adults (under the age of 50), particularly a noticeable growth in the incidence of non-cardia tumors among the more affluent population. Gastric cancer can be roughly divided into two major anatomical sub-sites: although the majority of gastric cancers occur in the distal part of the stomach (non-cardia), globally, about 18% of gastric cancers originate in the cardia, which is the region adjacent to the gastroesophageal junction. Both anatomical locations of gastric cancer have overlapping risk factors, such as smoking, heavy alcohol consumption, and consumption of pickled foods; however, they also have their distinct etiologies. Cardia gastric cancer is often associated with gastroesophageal reflux disease and obesity, while approximately 90% of non-cardia gastric cancers can be attributed to Helicobacter pylori (H. pylori) infection. This implies that prevention and treatment strategies for different types of gastric cancer may need to be distinct, especially considering the rising incidence rates in young populations and the etiological differences between cardia and non-cardia gastric cancers. From: DOI: 10.1016/ S0140-6736(16)30354-3Timeline of Significant Discoveries and Key Advances in the Treatment of Gastric Cancer: In recent years, targeted therapies against specific molecular targets have been introduced into clinical practice, such as the anti-HER2 antibody trastuzumab and the anti-VEGFR-2 antibody ramucirumab. Claudin 18.2 is also a significant target for gastric cancer treatment, as the gene is associated with specific molecular subtypes involved in the development and progression of gastric cancer. This gene and its interaction pathways serve as potential targets for the development of new personalized treatment strategies. The G protein-coupled receptor (GPCR) signaling pathway is one of those pathways. Abnormal activation of GPCRs and G proteins can promote the progression of gastric cancer. Activated GPCRs/G proteins may serve as effective biomarkers for early diagnosis, prognostic prediction, and clinical therapeutic targets. This indicates that through the detection and intervention of these receptors and their aberrant activation states, it is possible to achieve early detection, accurate prognostic assessment, and targeted treatment of gastric cancer, thereby improving patient survival rates and quality of life. GPCR and Gastric CancerAs early as 1986, a study by Young et al. was the first to link G protein-coupled receptors (GPCRs) with tumorigenic activity. They demonstrated through experiments that the Mas proto-oncogene could confer tumorigenicity to NIH 3T3 cells in vivo in nude mice. Mas encodes a typical GPCR and, unlike most oncogenes, does not carry activating oncogenic mutations. Instead, tumorigenicity is caused by its overexpression and the abundance of ligands in the circulation system or locally produced ligands. There is now a substantial body of evidence suggesting that various wild-type GPCRs, acting under the influence of excessive circulating agonists or agonists produced within the tumor microenvironment, can induce oncogenic transformation and drive tumor progression. Specific neuropeptides, particularly neurotransmitters and intestinal hormones, play an autocrine and paracrine role in various cancers. These neuropeptides include Gastrin-Releasing Peptide (GRP), Endothelin, Bradykinin, Neuromedin B, Neuropeptide Y, Gastrin, Cholecystokinin, Arginine Vasopressin, and Angiotensin II, among others. Each, upon binding to their respective GPCRs, triggers sustained activation, thereby stimulating proliferation in a variety of cell types and playing a crucial role in many malignant human cancers, such as small cell lung carcinoma, pancreatic cancer, head and neck squamous cell carcinoma, prostate cancer, and gastric cancer. From: DOI: 10.3390/cancers15030736Progress in the development of new drugs for gastric cancer targeting GPCR-class receptorsAccording to statistics from the Synapse database, there are currently nearly 1000 research and development pipelines for gastric cancer globally, of which 38 are GPCR (G protein-coupled receptor) type target pipelines. Popular pipeline targets include SSTR, EP2R, EP4R, CCR8, CCKR, SMO, NTSR1, A2bR, CCR7, among others. The leading indications related to gastric cancer include gastric cancer, gastro-enteropancreatic neuroendocrine tumors, gastroesophageal junction tumors, and Her2-negative gastric cancer, among others. The principal types of therapeutic agents include radiopharmaceuticals, peptide conjugates, radionuclide-conjugated drugs, synthetic peptides, monoclonal antibodies, and fusion proteins. In the field of clinical research, the major regions for clinical studies on gastric medications are the United States, China, Japan, Europe, Australia, and others. Several drugs are currently in the late stages of clinical trials (Phase 2, Phase 2/3, Phase 3, etc.). Representative investigational drugs include: Representative Pipeline: (177Lu) Lutetium-DOTATATE and SSTRs ReceptorLutetium-177 Dotatate (LU-177 Lutetium Dotatate, also known as Lutathera) is a radiopharmaceutical developed by Advanced Accelerator Applications. It is primarily used for the treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This medicinal product is formed by the conjugation of the somatostatin analogue Dotatate with the radioactive isotope Lutetium-177. Dotatate is a compound that can specifically bind to somatostatin receptors (SSTRs) that are overexpressed on neuroendocrine tumor cells. Lutetium-177 is a beta-emitting radioisotope. When combined with Dotatate, the resultant Lutetium-177 Dotatate can accurately target and accumulate within tumor cells that express high levels of somatostatin receptors. The radioactive decay of Lutetium-177 releases beta radiation, which destroys the cancer cells, thereby achieving a localized radiation therapy effect. Somatostatin is a peptide hormone composed of 14 amino acid residues and features a single disulfide bond. This hormone is capable of inhibiting the secretion of growth hormone, insulin, glucagon, gastrin, cholecystokinin, and thyrotropin, but due to its extremely short half-life in the body (less than 3 minutes), its value in therapy is limited. Research has identified the β-turn pharmacophore of somatostatin, which has become the lead sequence for the development of analogs with greater biological stability and potency. Based on this, octreotide was developed and approved for the treatment of acromegaly, adenomas, and pancreatic, breast, and prostate tumors. Subsequent research has spurred the development of selective receptor antagonists, such as lanreotide, vapreotide, and pasireotide, and has introduced the fields of peptide imaging and peptide receptor radionuclide therapy. In these radionuclide therapies, radioactive elements such as ^111In, ^90Y, ^68Ga, or ^99mTc are linked to selective somatostatin analogs through chelating groups, leading to approved radiopharmaceutical formulations. These drugs can be used for tumor detection. In 2001, a preclinical animal model study on Lutetium Dotatate LU-177 was published in the International Journal of Cancer. It reported on the investigation of the biologic distribution of the drug in a rat model of pancreatic tumors, and these data were used to estimate the absorbed doses in normal human tissue. A 2004 study on the treatment effectiveness in patients with metastatic gastroenteropancreatic tumors positive for the somatostatin receptor revealed that, out of 50 patients treated with Lutetium Dotatate LU-177, disease stabilization was achieved in 24 patients, 19 patients experienced stable disease, the condition of 6 patients progressed, and 1 patient's disease status could not be assessed. The therapy significantly improved their overall health condition, quality of life, and scores for various functions and symptoms. In 2005, a clinical study on the use of Lutetium Dotatate LU-177 in 131 patients with metastatic or inoperable somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors was announced. After treatment with a maximum cumulative dose of 600 to 800 mCi of Lutetium Dotatate LU-177, 3 patients (2%) achieved complete remission, 32 patients (26%) had partial remission, 24 patients (19%) showed a minor response (tumor size reduction of 25% to 50%), 44 patients (35%) had stable disease, whereas 22 patients (18%) experienced disease progression. A high remission rate correlated positively with high uptake shown on pre-treatment somatostatin receptor imaging and fewer liver metastases. In contrast, patients with lower performance scores and extensive disease distribution had a significantly higher frequency of disease progression. Severe side effects were very rare, and the median time to disease progression was comparable to that with chemotherapy, with better effectiveness in patients with a limited tumor burden. An expanded clinical study published in 2008 further validated the safety and efficacy of Lutetium Dotatate LU-177. In a study involving 310 patients with gastroenteropancreatic neuroendocrine tumors, complete and partial tumor response rates were observed at 2% and 28%, respectively, with minor response rates (tumor size reduction of over 25% but less than 50%) at 16%. Compared with historical controls, this treatment method provided a survival benefit of 40 to 72 months from the point of diagnosis. From: DOI: 10.1200/JCO.2007.15.2553In 2017, results from a Phase 3 clinical study published in The New England Journal of Medicine indicated that, in a randomized, controlled trial involving 210 patients with gastroenteropancreatic neuroendocrine tumors, the experimental group (116 patients) receiving intravenous injections of 7.4 GBq dose of Lutetium Lu 177 Dotatate every 8 weeks for a total of four times, along with a concurrent intramuscular injection of 30 mg of long-acting octreotide every 4 weeks, had a significantly higher estimated progression-free survival rate at 20 months (65.2%) compared to the control group (10.8%), which consisted of 113 patients treated only with intramuscular injections of 60 mg of long-acting octreotide every 4 weeks. Additionally, the response rate for the Lutetium Lu 177 Dotatate group was 18%, markedly higher than the 3% observed in the control group. From: DOI: 10.1056/NEJMoa1607427Based on this, at the end of 2017, the U.S. FDA approved Lutetium Dotatate LU-177 for the treatment of patients with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Due to its targeted nature and relatively low systemic toxicity, this therapy has received widespread attention and application in the field of precision medicine. In October 2017, Novartis acquired the French innovative pharmaceutical company Advanced Accelerator Applications for $3.9 billion to build and expand its radioligand therapy platform. In 2018, Novartis invested an additional $2.1 billion to acquire the biopharmaceutical company Endocyte, securing several more radiopharmaceutical candidates. Through these acquisitions, Novartis has established and extended its radioligand therapy platform, comprising multiple marketed products: Lutathera (177Lu-DOTATATE) and 68Ga-Edotreotide, as well as several products in development: 177Lu-PSMA-617, 177Lu-PSMA-R2, 177Lu-NeoB, 177Lu-FF58, 225Ac-PSMA-617, etc. Furthermore, Lanreotide Acetate is a non-selective somatostatin receptor (SSTRs) antagonist that was first approved for marketing in 2002 for the treatment of acromegaly. Its investigational indications include gastroenteropancreatic neuroendocrine tumors. 68Ga-Edotreotide is a non-selective SSTRs antagonist product developed by Advanced Accelerator Applications. It is a radioactive diagnostic agent used in PET scans to detect somatostatin receptor-positive neuroendocrine tumors in both adult and pediatric patients. Other related R&D pipelinesMisoprostol is a medication primarily used to reduce the risk of stomach ulcers in users of non-steroidal anti-inflammatory drugs (NSAIDs). Its mechanism of action involves stimulating prostaglandin receptors in the stomach, enhancing gastric protection against acidic substances, and reducing gastric acid secretion, thereby protecting the gastric mucosa from damage. Additionally, Misoprostol is used for various medical applications: in the field of gynecology, it can be used to manage early miscarriage, prevent postpartum hemorrhage, and perform abortion surgery during early pregnancy. When Misoprostol acts on prostaglandin receptors in the uterus and cervix, it increases the strength and frequency of uterine contractions and decreases cervical tension, thus playing a key role in the management of miscarriage. ONO-4578, developed by Ono Pharmaceutical, is a highly selective antagonist of the EP4 receptor and is currently being studied for its safety and efficacy as monotherapy and in combination with nivolumab in patients with advanced or metastatic solid tumors, including gastric cancer. Based on the results of a Phase 1 clinical study, ONO-4578 has demonstrated good tolerability and certain antitumor activity. YY-001 and HTL-0039732 are selective EP4 receptor antagonists developed by Shanghai Yu Yao and Sosei Group, respectively, and are currently involved in clinical studies for various solid tumors, including gastric cancer. BMS-986340 is an IgG1 subtype monoclonal antibody product targeting CCR8, originally researched and developed by BMS. This drug possesses enhanced non-fucosylated (NF) Fc region features. As the CCR8 receptor is a chemokine receptor expressed on the surface of regulatory T cells (Tregs) and participates in the regulation of the immune system, BMS-986340 has been engineered to specifically bind CCR8. Due to its non-fucosylated Fc segment, it enhances effector functions against target cells. This optimization enables BMS-986340 to effectively deplete regulatory T cells (Tregs), which may modulate the immune response for treating diseases associated with excessive immunosuppression or dysfunctional Tregs. Currently, clinical trials for various solid tumors, including gastric cancer, are underway involving BMS-986340. FPI-2059 is a small molecule radiopharmaceutical that targets the Neurotensin Receptor 1 (NTSR1). This receptor is overexpressed in a variety of solid tumors, including pancreatic ductal adenocarcinoma, colorectal cancer, head and neck squamous cell carcinoma, gastric cancer, Ewing sarcoma, and neuroendocrine-differentiated prostate cancer. FPI-2059 is developed based on compounds previously known as IPN-1087 and 3BP-227. These compounds have been studied as beta-emitting radiopharmaceuticals in researcher-initiated studies and phase I clinical trials. In 2021, Fusion Pharmaceuticals acquired this asset and transformed it into an alpha-emitting radiopharmaceutical, labeled with Actinium-225. Concurrently, FPI-2058 is a diagnostic analog of FPI-2059, replacing Actinium-225 with Indium-111 as the radioactive isotope for medical imaging and diagnostic purposes. This targeted radiopharmaceutical design aims to achieve precise targeted therapy and diagnosis for the aforementioned types of tumors. TT-4 is a selective A2B receptor antagonist developed by Tarus Therapeutics that is currently in phase 1/2 clinical development. The trial aims to evaluate its therapeutic effect in patients with various advanced solid tumors, including gastric cancer. 177Lu-PP-F11N is a radioactive drug complex that combines PP-F11N (a gastrin analog) with the beta-emitting radioactive isotope Lutetium-177. This drug exhibits potential antitumor activity and may be used as an agent for single-photon emission computerized tomography (SPECT) imaging. After intravenous injection, PP-F11N specifically binds to the Cholecystokinin-2 Receptor (CCK2R). This allows visualization of the tumor cells expressing the CCK-2 receptor using nuclear medicine imaging techniques. Additionally, the Lutetium-177 radioactive isotope delivers cytotoxic doses of beta-radiation to the tumor cells expressing the CCK-2 receptor, providing targeted destruction of these cells. As the CCK-2 receptor is widely expressed in various types of tumor cells, 177Lu-PP-F11N has the potential for the treatment of these specific types of tumors and offers targeted imaging for personalized, precise cancer diagnosis and therapy.