IPG0521 in cancer
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.
￭ 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.
￭ IND application
￭ 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
IPG0521 in IgG4-RD
￭ 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 elevated serum IgG4 level, IgG4-positive plasma cell infiltration, storiform fibrosis, and obliterative phlebitis in affected organs. There is no disease modifying therapy for this disease, and novel treatments are desperately needed.
￭ Although the etiology of IgG4-RD remains unclear, aberrant activation of plasmacytoid dendritic cells（pDCs）is considered a driving cause of the disease. We found for the first time that CCR8 is predominantly expressed on the surface of pDCs and plays a role in pDC activation and chemotaxis. Thus, CCR8 antagonism is a potential therapeutic strategy for IgG4-RD.
￭ In the IgG4-RD mouse model (Poly (I:C)-induced MRL/MpJ mouse model that mimics human IgG4-RD, we found that CCR8 was highly expressed on the surface of pDC and is responsible for the infiltration of pDC cells into inflammatory lesions. IPG0521 blocks pDC migration towards the lesion site, down-regulates IFN- and IL-33, which play a key role in fibrosis and B cell activation, resulting in inflammation resolution and blockade of fibrosis.
Mechanism of Action
￭ CCR8 is specifically expressed in pDC cells that play a key role in the pathogenesis of IgG4-RD.
￭ Activation of pDCs, which produce high levels of IFN-α and IL-33, is responsible for the chronic fibroinflammatory responses in IgG4-RD.
￭ IFN-α can induce the expression of various inflammatory cytokines, while IL-33 promotes the production of Th2-associated cytokines (e.g., IL-4) and regulates the activity of plasma cells, resulting in gland inflammation and fibrosis.
￭ IPG0521 blocks pDC migration towards the lesion site, down-regulates IFN- and IL-33, which play a key role in fibrosis and B cell activation, resulting in inflammation resolution and blockade of fibrosis.
￭ IPG0521 is the only CCR8 antagonist antibody used for the treatment of IgG4-RD.
Unlike steroids that temporally reduce inflammation with severe side effects, IPG0521 is a disease-modifying agent without significant side effects at the therapeutic dosage.
In vivo Properties
￭ IPG0521 dose-dependently reduced pDCs in the pancreatic tissue of f IgG4-related autoimmune pancreatitis (type I AIP) model.
￭ IPG0521 dose-dependently reduced fibrosis in IgG4-related autoimmune pancreatitis (type I AIP) model.
￭ IPG0521 dose-dependently reduced B cell infiltration in the pancreatic tissue of fibrosis in the IgG4-related autoimmune pancreatitis (type I AIP) model.
￭ IND application.