▎WuXi AppTec Content Team Report

On August 12, the official website of the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) announced,AstraZeneca's申报的1类新药注射用AZD7798获批临床，拟开发治疗Moderate to Severe Crohn's DiseaseAccording to the official website of AstraZeneca and public information,AZD7798It is a humanized monoclonal antibody targeting T-cell subsets, which can deplete CCR9-positive lymphocytes and is under development for the treatment of Crohn's disease.The product is currently in Phase 2 clinical trials internationally, and this is the first time it has been approved for an IND in China.

Screenshot source:CDE Official Website

According to literature reports, C-C chemokine receptor 9 (CCR9) is a G protein-coupled receptor discovered in 1996. It is expressed on the cell membranes of dendritic cells, neutrophils, lymphocytes, mononuclear macrophages, and vascular endothelial cells. However, for three years after the discovery of CCR9, its ligand remained unidentified, leading it to be temporarily termed an "orphan receptor." It was not until 1999 that CCL25 was found to bind exclusively and specifically to CCR9.CCR9/CCL25 Signaling Pathway Is Involved in the Regulation of the Occurrence and Development of Various Diseases, including cardiovascular diseases, hepatitis, arthritis, inflammatory bowel disease, asthma, etc.

Studies show that CCR9/CCL25 is the key axis for recruiting lymphocytes to the small intestine, representing a potential therapeutic target for Crohn's disease (CD).CCR9/CCL25 Interaction Regulates Inflammatory Immune Responses in the Intestinal Mucosa by Balancing Different Dendritic Cell Subsets。

AZD7798 is a potential "first-in-class" treatment for Crohn's disease.class”Monoclonal antibody that depletes CCR9+ lymphocytes. According toClinicalTrialsOfficial website, researchers are conducting aPhase 2a Study (AMALTHEA）, aimed to evaluate AZD7798 treatmentModerate to Severe Crohn's DiseaseEfficacy and safety.

It is worth mentioning that monitoring the depletion and repletion of CCR9+ cells in the blood is simple, but it is difficult in major tissues (small intestine, mesenteric lymph nodes) and requires invasive surgery for access. Understanding the pharmacodynamics of AZD7798 in the gut is crucial to guiding further clinical development. To meet this need, the researchers also developed aCCR9-specific PET tracer, capable of repeatedly quantifying CCR9 expression in the gutOngoing research will evaluate the impact of AZD7798 on the depletion/repletion of CCR9+ cells in the gut, providing critical data to support the clinical development program.

Although research on the functions of CCR9/CCL25 in inflammatory diseases is gradually deepening, the understanding of CCR9/CCL25 is becoming more comprehensive.However, research on the mechanism of CCR9/CCL25 in inflammatory diseases is mostly limited to theoretical foundations and still requires more clinical application validation. This AstraZeneca productThe approval of AZD7798 for clinical use also signifies further progress in clinical research within this field.

[1] Official of the Center for Drug Evaluation, National Medical Products Administration of ChinaWebsite. Retrieved Aug 12, 2024, from https://www.cde.org.cn/main/xxgk/listpage/da6efd086c099b7fc949121166f0130c

[2] AstraZeneca Official Website. From https://www.astrazeneca.com/our-therapy-areas/pipeline.html

[3]J MacKay. et al. （2024）P014 First-time-in-human visualisation of CCR9 expression in the gut by positron emission tomography. Journal of Crohn's and Colitis. doi:https://doi.org/10.1093/ecco-jcc/jjad212.0144

[4]Xue Wu.et al. (2021) The Roles of CCR9/CCL25 in Inflammation and Inflammation-Associated Diseases.Front Cell Dev Biol.doi: 10.3389/fcell.2021.686548