IPG1094 in 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 infiltration, and inhibits tumor growth. IPG1094 is the global leader as MIF tautomerase inhibitor, which is currently in clinical trials for cancer. The phase I clinical trial completed in Australia has proved to be incredibly safe, with a reasonable DMPK profile. Phase II clinical trial for long cancer brain metastasis is underway and is pending for expanding to other cancer indications. 

Mechanism of Action

■ MIF is abnormally up-regulated in most tumor cells, while its receptor, CD74, is exclusively expressed in myeloid cells.

■ As a component of tumor-derived exosomes, MIF plays a key role in disturbing myeloid cell differentiation via binding to CD74 and triggering intracellular signaling, resulting in blockade of myeloid cell differentiation and the subsequent accumulation of MDSCs in not only the bone marrow and second lymphoid organs, but in tumor tissues as well.

■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, thereby lifting the suppression of MDSC on CD8+ T cell activation and proliferation, resulting in elevated antitumor immunity. 

Key Differentiation

■ IPG1094 is the first selective MIF tautomerase inhibitor targeting MDSC in clinical trial stages worldwide.

■ IPG1094 is a cell membrane penetrable compound, which is able to hit its target that is localized in intracellular vesicles or exosomes.

■ IPG1094 is a brain penetrable compound, which is especially efficacious for primary and secondary 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, co-incubation with murine pancreatic cancer-derived exosomes enhances MDSC-mediated immunosuppression 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.

■ Pilot clinical studies on glioblastoma and lung cancer brain metastases indicate that IPG1094 treatment resulted in significant reduction of tumor size, marked revoking of brain edema, and profound amelioration of brain tumor-associated symptoms, including fatigue, nausea, headache, etc., associated with a dramatically prolonged progress-free survival (PFS).    

■ Phase II trials in lung cancer brain metastases as the first indication are underway.  

IPG1094 in ischemic stroke

Summary: 

Stroke is a leading cause of death worldwide, with a global prevalence of over 68 million. Ischemic strokes account for 80% of stroke cases. The macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine activated in response to ischemia. MIF is found in many types of cells, such as lymphocytes, neutrophils, endothelial cells, and neuronal cells. MIF has been reported to be markedly elevated in the stroke patients, and the expression levels of MIF mRNA and protein are upregulated during acute phase of stroke. The recent clinical research demonstrates that serum MIF level positively correlates to the severity of neurological function (by using NIHSS score) and also infarct volume in acute ischemic stroke patients, indicating that MIF is involved in the pathology of cerebral ischemia.

Increasing lines of evidence show a crucial character of MIF in mediating ischemic brain injury. MIF increases BBB permeability under ischemic attack. Furthermore, MIF exacerbates cerebromicrovascular endothelial cell death, neuronal cell death and neurological deficits in the MCAo rodent model. On the other hand, administration of MIF antagonist produces protective effects against BBB permeability, infarction and neurological deficits following ischemic injury. These studies provide the pathological mechanism of MIF in ischemic stroke and MIF may be a good drug target for the therapy of the stroke.

Mechanism of Action

■Myeloid-derived MIF drives RIPK1-mediated cerebromicrovascular endothelial cell death to exacerbate ischemic brain injury 

■MIF, which is upregulated in the course of ischemic stroke, enhances blood-brain-barrier permeability, thereby contributing to cerebral edema.

■ As a cytokine that sits on the top of inflammation cascades, MIF plays a key role in neuroinflammation during ischemic brain injury.

■ Thus, the MIF inhibitor IPG1094 is able to attenuate post ischemic stroke brain injury, and promote recovery.  

Key Differentiation

■ IPG1094 is the first selective MIF tautomerase inhibitor that is potentially able to modify the pathology of ischemic stroke.

■ Unlike other therapies, IPG1094 is multifunctional, not only attenuating cerebral edema, but also eliminating inflammation, thereby promoting post-stroke recovery.

In vivo Properties

■IPG094 significantly reduced infarction and improved behavioral deficits in MCAO mice, asserting its therapeutic potential for ischemic stroke. 

Clinical studies 

■ Phase I clinical trial in health volunteers has been completed, showing excellent PK and safety profile.

■ With the completion of a 6/9 months pre-clinical toxicity study showing no additional toxicity versus 28-day tox, phase II clinical trial for ischemic stroke will be initiated once IND is approved. 

IPG1094 in 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 to exacerbate inflammation. The tautomerase activity of MIF is responsible for its biological functions. Thus, targeted inhibition of MIF tautomerase is a disease-modifying strategy for autoimmune diseases. IPG1094 is the global leader in MIF tautomerase inhibition currently in clinical trials. The phase I clinical trial has proved to have good safety and a reasonable DMPK profile. With the IND approvals by the US FDA and China CDE, the phase II trial for Lupus nephritis is underway and is ready to expand to other disease indications. 

Mechanism of Action

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

■MIF triggers the CD44/CD74 receptor complex and the CXCR2 and CXCR4 chemokine receptors, resulting in the production of more inflammatory cytokines. 

■ As an endogenous inhibiting molecule of p53, whose elevation triggers the transition of macrophages from “M1” to “M2”and eventually apoptosis, MIF plays a key role in maintaining macrophages in“M1”phenotype. MIF plays the above roles through its tautomerase activity; thus, inhibition of MIF tautomerase activity is a disease-modifying strategy for autoimmune diseases. 

Key Differentiation

■ IPG1094 is the first selective MIF tautomerase inhibitor in clinical trial stages worldwide.

■ IPG1094 is a brain penetrable compound, which is especially efficacious for primary and secondary brain tumors.

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

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.