IPG1094 in tumor: Macrophage Migration Inhibitory Factor (MIF) is known to be upregulated in various types of cancer and plays a crucial role in the differentiation and infiltration of MDSCs. This ultimately leads to immunosuppression in pancreatic, melanoma, multiple myeloma, glioblastoma, and breast cancer. Consequently, MIF is considered a promising therapeutic target for tumor treatment. IPG1094 suppresses tumor exosome-induced MDSC proliferation in vitro and demonstrates remarkable antitumor effects in animal models of multiple cancers and multiple myeloma.
IPG1094 in autoimmune disease: MIF serves as a crucial regulator of innate immunity. It is released in response to various stimuli, including infections, cytokines, and variations in glucocorticoid levels. MIF exerts both paracrine and endocrine effects, leading to the production of multiple proinflammatory cytokines, downregulation of p53 expression, and promotion of leukocyte survival. Numerous studies have observed elevated levels of MIF are present in patients diagnosed with autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. Consequently, MIF represents a potential therapeutic target for treating autoimmune diseases. In the context of therapeutic intervention, IPG1094 demonstrates downregulation of TNF-α, IL-6, and other proinflammatory cytokines, effectively attenuating the pathogenesis and progression of experimental autoimmune encephalomyelitis (EAE), imiquimod-induced psoriasis (IMQ), and MRL/lpr SLE murine models. The potential of IPG1094 in treating autoimmune diseases is currently being investigated in clinical.
IPG1094 in tumor indication
Mechanism of Action
￭Inhibits the formation of tumor exosome-induced myeloid-derived suppressor cells (MDSCs).
￭IPG1094 is a pioneering small-molecule MIF inhibitor with remarkable antitumor efficacy.
In vivo Properties
￭IPG1094 demonstrated significant antitumor activity as a single agent in a mouse multiple myeloma model on NCG mice.
The tumor burden in the multiple myeloma model on NCG mice
*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, compared to the vehicle group
IPG1094 in autoimmune disease
Mechanism of Action
￭In the state of autoimmune diseases, MIF overexpression on monocytes/macrophages inhibits p53. As a result, macrophages cannot transform from M1 type to M2 type. With the continuous activation of M1 type macrophages, a large number of inflammatory factors cause the continuous amplification of inflammation, resulting in tissue and organ damage and autoimmune diseases.
￭IPG1094 can inhibit the tautomerase activity of MIF, alter the spatial conformation of the MIF protein, block the binding of MIF to its receptor CD74, remove the inhibition of MIF-CD74 on p53, and up-regulate the level of p53 in M1-type macrophages. This promotes the transformation of M1-type macrophages (inflammatory) to M2-type macrophages (anti-inflammatory) and ultimately leads to their apoptosis, which helps eliminate inflammation and promote tissue repair.
￭ IPG1094 is the first clinical-phase MIF inhibitor, demonstrating promising data with favourable pharmacokinetic (PK) properties and high safety window in the clinic.
￭ MIF regulates upstream signals of innate immunity; therefore, targeting MIF could have the potential efficacy superior to other single cytokine inhibitors. Preclinical data of IPG1094 have verified its effectiveness in multiple autoimmune disease models.
In vitro and In vivo Properties
￭IPG1094 demonstrates potent inhibition of MIF tautomerase activation, with a pIC50 value ranging from 6.00 to 6.29.
￭IPG1094 exhibits a dose-dependent attenuation of the clinical score in the experimental autoimmune encephalomyelitis (EAE) murine model.
￭IPG1094 dose-dependently inhibits psoriasis-like pathology in the imiquimod (IMQ) murine model.
Jia et al, the tautomerase activity of tumor exosomal MIF is crucial to promoting pancreatic cancer progression via modulating MDSC differentiation. Cancer Immunology Research (in press)