IPG1094 for cancer 

Summary: 

Macrophage Migration Inhibitory Factor (MIF) is known to be upregulated in various types of cancer and, as a component of tumor-derived exosomes, plays a crucial role in the differentiation and infiltration of myeloid derived suppressor cells (MDSCs)， the major immunosuppressive cells in the tumor microenvironment. The tautomerase activity of MIF is responsible for its biological functions, and targeted inhibition of MIF tautomerase activity reduces MDSC, enhances CD8+ T cell proliferation and infiltration, thereby suppressing tumor growth. IPG1094 is so far the most selective and potent MIF tautomerase inhibitor, which is currently in clinical trials for cancer. The completed phase I clinical trial has proven its excellent safety and reasonable DMPK profiles. Phase II clinical trial for brain metastatic cancer is underway and is pending for expanding to other cancer types. 

Mechanism of Action

■MIF, a natural inhibitor of P53, is aberrantly expressed in most tumor cells, while its receptor, CD74, is exclusively expressed in myeloid cells.  

■As a component of tumor exosomes, MIF plays a key role in disturbing myeloid cell differentiation via binding to CD74 receptor complex and triggering intracellular signaling, resulting in disturbance of myeloid cell differentiation and the subsequent accumulation of MDSCs in the bone marrow, second lymphoid organs, and tumor tissues. 

■MIF possesses thio-protein oxidoreductase and tautomerase activities, and the latter has proven to be crucial for its biological functions. Targeted inhibition of MIF tautomerase activity reduces MDSC, enhances CD8+ T cell infiltration, and prevents tumor growth. 

■IPG1094 is a selective and potent MIF tautomerase inhibitor, which exerts anti-cancer effects via suppressing MDSC. 

Key Differentiation

■IPG1094 is the leading inhibitor of MIF tautomerase in clinical trial stage worldwide.

■With its excellent cell membrane penetration property, IPG1094 is able to hit its target that is localized in intracellular vesicles or exosomes. 

■As an excellent brain penetrable compound, IPG1094 is exceptionally efficacious on primary and metastatic brain tumors.

■Phase I clinical trial indicates a large safety margin and excellent pharmacokinetic (PK) properties. 

In vitro properties 

■IPG1094 abrogates murine pancreatic cancer-derived exosome-induced MDSC.

■In the MDSC and CD8+ T cell co-culture system, addition of murine pancreatic cancer-derived exosomes enhances MDSC-mediated suppression on CD8+ T cell proliferation, which is blocked by IPG1094.

In vivo Properties

■IPG1094 dose-dependently inhibits the growth of multiple tumor types in both syngeneic and immune-humanized mouse models. 

■As an example shown below, IPG1094 dose-dependently inhibits multiple myeloma growth.

Ordinary two -way ANOVA, * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001

compared to Vehicle, N = 8 in each group.

Clinical studies 

■Phase I clinical trial indicated no severe (> grade 2) AE during dose escalation from 100 mg to 1200 mg, with linear dose-exposure relationship. 

■Phase II trials on primary brain tumors and brain metastases are underway.  

IPG1094 for autoimmune diseases 

Summary: 

As an inflammatory cytokine sitting on the top of inflammation cascades, MIF is critically involved in chronic inflammation in autoimmune diseases. The single nucleotide polymorphism (SNP) of MIF has been shown to be associated with multiple autoimmune diseases. MIF is up-regulated in the activated macrophages, and is postulated to play a role in the maintenance of macrophage in the M1 phenotype, the major cell type that produces pro-inflammatory cytokines to activate T cells, B cells and dendritic cells in the course of inflammation, via, at least in part, inhibiting intracellular p53. The tautomerase activity of MIF is responsible for its biological functions. Thus, targeted inhibition of MIF tautomerase is a disease-modifying strategy for inflammatory/autoimmune diseases. IPG1094 is the global leader in MIF tautomerase inhibition currently in clinical trials. The phase I clinical trial has completed, pending for phase II trials in autoimmune diseases. 

Mechanism of Action

■In autoimmune diseases, the single nucleotide polymorphism (SNP) of MIF results in a marked elevation of MIF. 

■MIF binds to CD74 receptor complex in myeloid cells, which induces intracellular signaling leading to inhibition of p53, the latter plays a role in maintaining macrophages in the “M1” phenotype. The tautomerase domain is essential for MIF binding to its receptor complex.  

■It is postulated that IPG1094 inhibits the tautomerase activity of MIF, resulting in conformational change of MIF and the subsequent interacting with its receptor complex, and eventually the apoptosis of the activated macrophages.   

Key Differentiation

■IPG1094 is the first molecule specifically targeting M1 macrophages, leading to the apoptosis of M1 macrophages, and the subsequent inflammatory resolution.

■IPG1094 is much safer than the existing autoimmune disease therapies, with a large safety margin and excellent pharmacokinetic (PK) properties as indicated in clinical trials. 

In vivo Properties

■IPG094 dose-dependently reduces pathologies in multiple autoimmune disease mouse models. 

■As an example shown below, IPG1094 dose-dependently inhibits psoriasis-like pathology in the imiquimod (IMQ)-induced psoriasis mouse models.

Clinical studies 

■Phase I clinical trial indicated no severe (> grade 2) AE during dose escalation from 100 mg to 1200 mg, with linear dose-exposure relationship.

■With the completion of a 6/9 months pre-clinical toxicity study showing no additional toxicity versus 28-day tox, and with IND approvals for psoriasis, SLE, multiple sclerosis, etc., phase II clinical trials are ready to go.