Summary
The chemokine receptor CCR8 (CC chemokine receptor 8) plays an important role in mediating the recruitment and immunosuppressive function of Treg cells in the tumor microenvironment. IPG7236, the first small molecule antagonist of CCR8 that has entered clinical trials for cancer therapy worldwide, exerts an anti-cancer effect via blocking CCR8-mediated Treg migration and immunosuppression, thereby reversing immunosuppressive microenvironment. Both IPG7236 alone or in combination with PD-1 antibody have shown significant anti-tumor effects in multiple cancer models, including human breast cancer in immune-humanized mouse models. Phase I clinical trials have confirmed its good safety profile and initial efficacy.
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 plays a key role in Treg migration from peripheral to tumor tissue.
￭ CCR8 is crucial for the immunosuppressive function of Treg.
￭ CCR8 antagonist blocks Treg infiltration in tumor tissue and abrogates Treg immunosuppression, thereby boosting anti-cancer immunity.
Key Differentiation
￭ IPG7236 is the first small molecule antagonist of CCR8 in the clinical trial stage worldwide.
￭ The mechanism of action of IPG7236 is strikingly different from that of its competitors, which target CCR8 with monoclonal antibodies with enhanced ADCC function. IPG7236 abrogates Treg-mediated immunosuppression by blocking Treg chemotaxis and immunosuppressive function, whereas the competitors abrogate Treg-mediated immunosuppression by ADCC-mediated depletion of Treg cells.
￭ Given the widespread expression of CCR8 in endothelial cells, epithelial cells, memory CD4+/CD8+ T cells, etc., IPG7236 has a significant safety advantage relative to its competitors.
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.
*P < 0.05, **P < 0.01, compared to vehicle
Clinical trials
￭ Phase indicated no severe (> grade 2) AE during dose escalation from 50 mg to 500 mg, with linear dose-exposure relationship.
￭ The ongoing phase I clinical trial in cancer patients indicated no severe (> grade 2) AE during dose escalation, with preliminary anti-cancer effects.
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.
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