IPG7236 for cancer

Summary                      

■The chemokine receptor CCR8 plays an important role in mediating the recruitment of Treg cells to tumor tissue and maintaining the immunosuppressive functions of Treg cells in the tumor microenvironment. IPG7236 is the first small molecule antagonist of CCR8 that has entered clinical trials for cancer therapy worldwide, which exerts an anti-cancer effect via blocking CCR8-mediated Treg migration and immunosuppression, thereby reversing the immunosuppressive microenvironment, and boosting anticancer immunity. Both IPG7236 alone and in combination with PD-1 antibody have shown significant anti-tumor effects in multiple cancer models, including human triple negative breast cancer in immune-humanized mouse models, in preclinical studies. Phase I clinical trials have confirmed its excellent safety profile and preliminary efficacy in multiple cancer types. 

■Phase II clinical trials for cancers with unmet medical needs, including triple negative breast cancer, small cell lung cancer, are currently underway.

Mechanism of Action

■CCR8 is predominantly expressed on tumor-infiltrated Treg cells, while its ligands (e.g., CCL1, CCL18, etc.) are secreted by cancer cells and stromal cells in the tumor microenvironment. 

■CCR8-mediated intracellular signaling plays a key role in Treg migration from peripheral to tumor tissue, and in maintaining the immunosuppressive function of Treg.

■As a potent and specific human CCR8 antagonist, IPG7236 blocks Treg infiltration in tumor tissue and abrogates Treg immunosuppressive functions, thereby boosting anti-cancer immunity. 

Key Differentiation

■IPG7236 is a potent and selective small molecule antagonist of CCR8, and is the leading molecule in clinical trial stage worldwide.

■IPG7236 differentiates itself from the CCR8 antibodies with enhanced ADCC functions by its much better safety profile as unveiled in the clinical trials.

■From MOA perspective, IPG7236 blocks CCR8-mediated Treg recruitment in the tumor tissues and abrogates Treg immunosuppression, thereby boosting anti-cancer immunity. In contrast, the CCR8 ADCC antibodies deplete CCR8-expressing Tregs thereby boosting anticancer immunity.

■Given the widespread expression of CCR8 not only in Treg cells but also in endothelial cells, epithelial cells, memory CD4+/CD8+ T cells, etc., the strategy of blocking the receptor signaling and abrogating the receptor-mediated immunosuppression of Tregs employed by IPG7236 can avoid such side effects caused by the ADCC strategy of depleting CCR8-expressing cells. 

In vivo Properties

■IPG7236 significantly inhibited the growth of multiple tumor types in immune humanized mouse models. 

■As an example shown below, IPG7236 dose-dependently inhibits MDA-MB-231 triple-negative breast cancer growth in an immune humanized mouse model.  

*P < 0.05, ***P < 0.001, ****P < 0.0001, compared to vehicle

■IPG7236 significantly enhances the anti-cancer effect of anti-PD-1 in multiple tumor types.   

■As shown below, IPG7236 synergizes with anti-PD-1 in inhibiting colon (left) and breast cancer (right) growth in immune humanized mouse models.

Clinical trials

■Phase I clinical trials indicated no severe (> grade 2) AE during dose escalation from 50 mg to 500 mg, with linear dose-exposure relationship.

■Phase I clinical trials in cancer patients indicated no severe (> grade 2) AE during dose escalation, with preliminary anti-cancer effects. 

■A transition from Phase I to phase II trial is ongoing.

Publications

■Yong Wu, Jianbei Xi, Yue Li, Zheng Li, Yong Zhang, JianFei Wang, Guo-Huang Fan Discovery of a Potent and Selective CCR8 Small Molecular Antagonist IPG7236 for the Treatment of Cancer. J Med Chem. 2023 Apr 13;66(7): 4548-4564.

IPG7236: First-in-Class Small-Molecule Inhibitor targeting a GPCR for the treatment of IgG4-RD

IPG7236 for IgG4-related disease 

Summary

■IgG4-related disease (IgG4-RD) is a systemic multi-organ fibro-inflammatory disorder, with clinical manifestations including salivary and lacrimal gland enlargement, orbital disease, autoimmune pancreatitis, retroperitoneal fibrosis and tubulointerstitial nephritis. Clinical characterizations include elevation of serum IgG4 level, IgG4-positive plasma cell infiltration, storiform fibrosis, and obliterative phlebitis in affected organs. So far, there are no drugs specifically approved for the treatment of IgG4-RD. Recent studies indicate that plasmacytoid dendritic cells (pDCs) mediate the development of IgG4-RD via the production of IFN-I and interleukin-33 (IL-33). Thus, targeted inhibition of pDC is a disease-modifying therapeutic strategy for IgG4-RD.

■The chemokine receptor CCR8 is highly expressed on pDC and plays a key role in the chemotaxis of pDC to the lesion sites, where the CCR8 ligands, e.g., CCL1, CCL18, etc., are markedly elevated. The CCR8 antagonist potently blocks the activation of pDC and prevents the migration of pDC to the lesion sites, thereby reducing inflammation and fibrosis. Phase I clinical trials have confirmed its excellent safety profile, and with the completion of 6/9 months long term toxicology study, Phase II clinical trial for IgG4-RD is ready to go. 

Mechanism of Action

■CCR8 is highly expressed on the activated pDC in IgG4-RD, and plays a key role in mediating the migration of pDC to the lesion sites, resulting inflammation and fibrosis.

■IPG7236 potently blocks CCR8-mediated chemotaxis of pDC, resulting inflammation resolution and blockade of storiform fibrosis of the affect organs. 

Key Differentiation

■Unlike steroids, which nonspecifically inhibit inflammation, IPG7236 specifically inhibits pDC, the driving cause of IgG4-RD, thereby resulting in inflammation resolution and suppression of tissue fibrosis.

■Compared to the conventional treatment, such as steroids, which cause wide-spectrum of severe side effects, IPG7236 has proven to be a very safe drug with a large safety margin as shown in clinical studies. 

In vivo Properties

■IPG7236 surrogate，IPG0521，significantly inhibited the infiltration of pDC cells in the lesion of autoimmune pancreatitis (AIP), an IgG4-RD animal model. 

■IPG7236 surrogate，IPG0521，significantly inhibited IgG1 deposition in the lesion of autoimmune pancreatitis (AIP), an IgG4-RD animal model. 

■IPG7236 surrogate，IPG0521，significantly inhibited IgG1 deposition in the lesion of autoimmune pancreatitis (AIP), an IgG4-RD animal model. 

■IPG7236-surrogate dose-dependently reduced fibrosis in IgG4-related autoimmune pancreatitis (type I AIP) model. 

Clinical trials

■Phase I clinical trials indicated excellent PK profile with no severe (> grade 2) AE during dose escalation.

■Phase II trial is under preparation.