Target is a novel GPCR (currently undisclosed) expressed in particular in immune cells. Activated by its endogenous ligands, which are produced in the inflammatory niche, it functions as a chemo-attractant receptor, mediating the migration of inflammatory cells to the inflammatory sites. Single nucleotide polymorphisms (SNPs) of the GPCR, which lead to elevated expression on target cells, have been identified to be associated with several inflammatory and autoimmune diseases. IPG11406, a highly potent small molecule antagonist of the GPCR target, is a typical disease-modifying compound which effectively blocks the target-mediated activation and chemotaxis of inflammatory cells, resulting in complete inflammation resolution. Pre-clinical safety assessments indicate its excellent safety profile and exceptional efficacy in multiple autoimmune disease models, including systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis. INDs covering several autoimmune diseases have been approved by both FDA and NMPA in 2023, and Phase I clinical trial is currently being advanced.
Mechanism of Action
￭ Viral infections or SNPs lead to elevated expression of the GPCR target on aberrantly activated dendritic cells, macrophages, T cells, and B cells.
￭ The receptor ligands (currently undisclosed) are produced by inflammatory cells in the inflammatory sites, mediating the chemotaxis of the target GPCR-expressing immune cells to the inflammatory sites.
￭ IPG11406 potently blocks the target GPCR-mediated chemotaxis of the immune cells, resulting in complete inflammation resolution.
￭ Unlike the biologics currently in the clinic, such as antibodies against TNF, IL-17, and IL-23 that neutralize the specific inflammatory cytokines without removing the inflammatory cells in the lesion, IPG11406 efficiently eradicates inflammatory cells in the lesion, resulting in complete inflammation resolution. Thus, IPG11406 is a disease-modifying agent for autoimmune diseases.
￭ Unlike kinase inhibitors that are used for the treatment of autoimmune diseases, such as JAK inhibitors, which cause severe side effects via non-specifically blocking the intracellular signaling pathways, IPG11406 specifically blocks the target GPCR-mediated chemotaxis of inflammatory cells, with a large safety margin (over 150 fold safety window).
In vivo Properties
￭ IPG11406 markedly eradicates inflammatory cells in the lesion of several autoimmune disease models, including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease, resulting in complete inflammation resolution and attenuation of pathologies.
￭ As an example, IPG11406 treatment of spontaneous IBD mouse model（Il10-/- mice）results in the eradication of Th1 cells in the colon tissues.
￭ As an example, IPG11406 treatment of spontaneous IBD mouse model（Il10-/- mice）resulted in the eradication of CD11b+ inflammatory cells in the colon tissues.
￭ As an example, IPG11406 reversed the aberrantly up-regulated genes related to inflammation in the colon tissue of Il10-/- mice.
￭ As an example, IPG11406 treatment of spontaneous lupus nephritis mouse model (MRL/Lpr) resulted in complete normalization of urinary protein.
￭ As an example, IPG11406 treatment of spontaneous lupus nephritis mouse model (MRL/Lpr) resulted in the eradication of activated macrophages in the kidney.
￭ Phase I clinical trial in health volunteers is ongoing.