CCR8 is predominantly expressed on tumor-infiltrated Treg cells, while its ligands (e.g., CCL1, CCL18) are produced by cancer cells and stromal cells in the tumor microenvironment. CCR8 plays a key role in Treg migration from peripheral to tumor tissue and is critical for the immunosuppressive function of Treg. IPG0521 blocks CCR8-mediated Treg chemotaxis and immunosuppression, thereby boosting anti-cancer immunity. CCR8 is also observed to be prominently expressed on plasmacytoid dendritic cells (pDC); IPG0521 treatment reduced pDC infiltration in autoimmune pancreatic IgG4-related disease (IgG4RD) and alleviated the disease severity; therefore, IPPG0521 holds a great promise to treated IgG4 RD.
IPG0521 in tumor indication: CCR8 is highly expressed on the surface of most tumor-infiltrated Treg cells, which are responsible for their recruitment, activation and/or suppressive capacity. Targeted inhibition of CCR8 is a potential therapeutic strategy against cancer. IPG0521 is a CCR8-specific antibody that exhibits cross-reactive with CCR8 in human, mouse, rat, dog, and monkey species. It demonstrates excellent antitumor efficacy in preclinical models by abolishing Treg immunosuppression through blocking CCL1-CCR8 signal, which improves CD8+ T cells and NK cells cytotoxicity, enhances antigen processing and presentation of DC, enhances the antitumor potential of neutrophils and significantly reduced M-MDSC and TAM in murine syngeneic liver cancer. Unlike other clinical phase competitors with enhanced ADCC functionality, IPG0521 primarily blocks CCR8-mediated signals, potentially minimizing toxic side effects associated with CCR8 expression in normal human tissues. See More
IPG0521 in IgG4-RD: In the Poly (I:C)-induced MRL/MpJ mouse model that mimics human IgG4-related disease (IgG4-RD), CCR8 also highly expressed on the surface of pDC. IPG0521 effectively inhibits the infiltration of pDC cells into inflammatory lesions, reduces the expression of IFN-α and IL-33, suppresses plasmablast generation, and mitigates fibro-inflammatory responses in various organs, including the pancreas, salivary gland, and endocranium. With its potential therapeutic benefits, IPG0521 holds promise as a first-in-class agent for the treatment of IgG4-related disease (IgG4-RD). See More
Furthermore, IPG0521 exhibits long-term stability, high solubility, and good tolerability in both rats and cynomolgus monkeys. Currently, IPG0521 has progressed to the stage of investigational new drug (IND) filing.
IPG0521 in tumor
Mechanism of Action
￭"Abolished CCL1 mediated Treg's immunosuppression."
￭"Improved CD8+ T cell and NK cell cytotoxicity."
￭"Enhanced DC antigen processing and presentation."
￭"Reduced M-MDSC and TAM in liver cancer."
￭"Increased the antitumor potential of neutrophils."
￭ IPG0521 exhibits a strong binding affinity to CCR8 in various species, including humans, mice, rats, dogs, and cynomolgus monkeys. Therefore, the effectiveness and safety of IPG0521 in a preclinical setting can be fully assessed and assured before it proceeds to clinical trials.
￭ Unlike assets with enhanced ADCC functionality from other competitors, IPG0521 displays an antitumor effect primarily by blocking CCR8-mediated signals, which further ensures safety in clinical.
In vitro and In vivo Properties
￭ IPG0521 has high binding affinity against CCR8 in humans, mice, rats, dogs, and cynomolgus monkeys.
￭ IPG0521 has a strong inhibition effect on CCL1-CCR8 signaling demonstrated through Calcium mobilization and Tango Assays.
￭ IPG0521 reduced Tregs immunosuppression by inhibiting CCR8+ Tregs chemotaxis.
￭ IPG0521 abolished CCL1-mediated Tregs immunosuppression by targeting CTLA4 and LAG3.
￭ IPG0521 promotes tumor-infiltrated CD8+ T cell proliferation.
￭ IPG0521 demonstrates significant single-agent antitumor activity in the H22 syngeneic model.
Ordinary one-way ANOVA, * P < 0.05, ** P < 0.01,*** P < 0.001, compared to mIgG2a.
￭ IPG0521 promotes immunoreactivity in H22 liver cancer mice.
Tian et al, CCR8 antagonist antibody eliminates immunosuppression of Tregs to promote an antitumor immune response in liver cancer micro-environment (under review).
IPG0521 in IgG4-RD: In the MRL/MpJ mouse model, induced by Poly (I:C) to mimic human IgG4-related autoimmune pancreatitis (AIP), CCR8 has been observed to be prominently expressed on the plasmacytoid dendritic cells (pDCs). IPG0521 demonstrates significant inhibition of pDC infiltration into the inflamed pancreas. Additionally, it effectively reduces the expression of IFN-α and IL-33, suppresses the generation of plasmablast, and mitigates fibro-inflammatory responses in multiple organs, such as the pancreas, salivary gland, and endocranium. With its potential therapeutic advantages, IPG0521 exhibits promising prospects as a pioneering therapeutic agent for the treatment of IgG4-RD.
Mechanism of Action
￭ Abnormal pDCs, Th2, and Treg cells are associated with the immunopathogenesis of IgG4RD.
￭ Chronic fibroinflammatory responses depend on the activating pDCs, which produce high levels of IFN-α and IL-33.
￭ 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 primarily reduces the infiltration of pDCs, Tregs, and Th2 cells, while downregulating the expression of IFN-α and IL-33 in lesion sites, attenuating disease pathogenesis.
￭ IPG0521 effectively blocks the infiltration of pDC cells in the pancreas and other affected tissues, thereby inhibiting the abnormal activation of the immune response at lesion sites.
￭IPG0521 shows better target selectivity and safety compared with current clinical drugs, such as corticosteroids.
In vivo Properties
￭ IPG0521 reduces the infiltration of pDC cells and attenuates fibrosis in the inflamed pancreases of Poly (I:C) induced AIP mouse model.