Summary

The chemokine receptor CCR8 (CC chemokine receptor 8) is predominantly expressed on the surface of tumor-infiltrating Treg cells and plays an important role not only in mediating the recruitment of Treg cells to the tumor center but also in the immunosuppressive activity of Treg cells in the tumor microenvironment. IPG0521 is a potent CCR8 antagonist with mild ADCC activity, which exerts an anti-tumor effect by blocking Treg migration from peripheral to tumor tissue, and abrogating Treg immunosuppressive function, thereby boosting anti-cancer immunity. IPG0521 synergizes with anti-PD-1 in cancer therapy, and is potentially efficacious to anti-PD1 ineffective or resistant cancer types. GLP safety assessment indicates its excellent safety profile.

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 critical for the immunosuppressive function of Treg.

￭ IPG0521 blocks Treg infiltration in tumor tissue and abrogates Treg immunosuppression, thereby boosting anti-cancer immunity.

Key Differentiation

￭ IPG0521 is the only CCR8 monoclonal antibody worldwide that cross-reacts with five species, including mouse, rat, dog, monkey, and human, with high affinity.  

￭ The mechanism of action of IPG0521 is strikingly different from its competitors which target CCR8 with monoclonal antibodies with enhanced ADCC function. IPG0521 abrogates Treg-mediated immunosuppression by blocking Treg chemotaxis and immunosuppressive function with mild ADCC activity, whereas the competitors abrogate Treg-mediated immunosuppression by enhanced ADCC-mediated depletion of Treg cells. Given the widespread expression of CCR8 in endothelial cells, epithelial cells, memory CD4+/CD8+ T cells, etc., IPG0521 has a significant safety advantage relative to its competitors.

In vitro Properties

￭ IPG0521 bound to CCR8 with high affinity from five different species.

In vivo properties

￭ IPG0521 significantly inhibited the growth of multiple cancer types in syngeneic mouse models.

￭ As an example, IPG0521 dose-dependently inhibited the growth of murine liver cancer, with complete inhibition of tumor growth at the dose of 10 mg/kg.  

                  Ordinary one-way ANOVA, * P < 0.05, ** P < 0.01, *** P < 0.001, compared to mIgG2a.

￭ As an example, RNAseq results indicated that IPG0521 robustly enhanced anti-cancer immunity in the murine liver cancer model.

￭ As an example, single-cell RNAseq results indicated that IPG0521 increased the ratio of lower immunosuppressive Treg cells and decreased the ratio of higher immunosuppressive Treg cells, leading to a reduction of Treg immunosuppression. 

￭ As an example, single-cell RNAseq results indicated that IPG0521 increased CD8+ T cell proliferation, leading to enhanced cytotoxicity. 

￭ As an example, single-cell RNAseq results indicated that IPG0521 increased the ratio of perforin-positive NK cells, leading to enhanced cytotoxicity. 

Current status

￭ IND application

Publications

￭ Binle Tian, Zhilong Wang, Na Wang, Xuebing Jia, Yuanyuan Zhang, Jingyi Zhou, Wen Zhang, Zheng Li, Junli Xue, JianFei Wang, Guo-Huang Fan, Qi Li. CCR8 antagonistic antibody abolishes immunosuppression of regulatory T cells and modulates antitumor immune micro-environment in Liver Cancer. Cancer Res, in submission