Summary                      

￭  IPG7236 is a first-in-class, orally administered, small-molecule antagonist of the chemokine receptor CCR8, establishing it as the global leader in this novel class of cancer immunotherapies. 

￭  IPG7236 is uniquely positioned with a dual-application strategy, targeting immunosuppressive regulatory T cells (Tregs) in oncology and pathogenic plasmacytoid dendritic cells (pDCs) in the autoimmune condition IgG4-Related Disease (IgG4-RD). 

￭  Developed with a novel chemical structure possessing superior druggability and high selectivity, IPG7236 has demonstrated a significant safety advantage over competing antibody-based approaches in clinical trials. 

￭  As the most advanced oral CCR8 antagonist in development, IPG7236 is poised to unlock the immune system's potential against solid tumors and provide a transformative new therapy for a rare disease with high unmet need.

IPG7236 in Oncology

Mechanism of Action

￭ CCR8 is predominantly expressed on tumor-infiltrating Tregs, which are a primary driver of immunosuppression within the tumor microenvironment. These Tregs prevent the body’s natural antitumor immune response. 

￭  IPG7236 works by selectively blocking the CCL1-CCR8 signaling pathway, which disrupts the recruitment of these immunosuppressive Tregs to the tumor site. 

￭ This alleviates the immunosuppressive shield, enhancing the infiltration and activity of tumor-killing CD8+ T cells and enabling the immune system to effectively recognize and attack cancer cells.

Key Differentiation

￭ Oral Small-Molecule Advantage: IPG7236's oral administration provides significant advantages over large-molecule antibody competitors in terms of manufacturing cost, distribution, and patient compliance.

￭ Novel Mechanism of Action (Signaling Blockade vs. Cell Depletion): Unlike competing ADCC-enhanced antibodies that deplete all CCR8-expressing cells (including healthy ones), IPG7236 selectively blocks Treg function without causing widespread cell death. This targeted mechanism is anticipated to deliver a significantly superior safety profile by avoiding on-target, off-tumor toxicity.

￭ Superior Safety Profile: In the ongoing Phase 1/2a clinical trial, IPG7236 has been escalated up to 1000 mg BID without any drug-related Serious Adverse Events (SAEs) observed, highlighting its excellent tolerability.

￭ Synergy with PD-1 Inhibitors: Pre-clinical data demonstrates a strong synergistic effect with anti-PD-1 antibodies, positioning IPG7236 as a promising therapy to overcome resistance to current checkpoint inhibitors.

Current Development & Status

￭ Phase 1 (Healthy Subjects): An initial Phase 1 trial in healthy subjects in Australia demonstrated that IPG7236 is well-tolerated, with linear pharmacokinetics supporting its development.

￭ Phase 1/2a MRCT (Ongoing): A multi-center clinical trial for advanced solid tumors is ongoing in the U.S. and China (initiated in 2022). The study is evaluating IPG7236 as both a monotherapy and in combination with the anti-PD-1 antibody toripalimab. Completion is expected in the first half of 2026.

￭ Next Steps: A Phase 1b/2a trial is planned to initiate in 2026 to evaluate IPG7236 in combination with an anti-PD-1 therapy for patients with triple-negative breast cancer (TNBC).

In vivo Properties

￭ Tumor Microenvironment Modulation: In a humanized breast cancer model, IPG7236 treatment caused a significant, dose-dependent decrease in tumor-infiltrating Tregs and a corresponding dose-dependent increase in tumor-killing CD8+ T cells.

￭ Monotherapy Antitumor Activity: IPG7236 demonstrated potent, dose-dependent inhibition of tumor growth as a monotherapy in the same humanized mouse model.

￭ Synergistic Efficacy with Anti-PD-1: In a combination study, IPG7236 (TGI of 47.2%) together with a PD-1 antibody resulted in a significantly enhanced anti-cancer effect (TGI of 73.8%), while the PD-1 antibody alone showed no significant effect.

IPG7236 in IgG4-RD

Mechanism of Action

￭ In IgG4-RD, CCR8 is predominantly expressed on pathogenic plasmacytoid dendritic cells (pDCs). These pDCs migrate to affected organs and produce inflammatory signals (IFN-I, IL-33) that drive the Th2 immune response, fibrosis, and production of pathogenic IgG4 antibodies. 

￭ IPG7236 is designed to block this CCR8-mediated pDC migration, thereby reducing their accumulation at lesion sites. This action breaks the chronic inflammatory cycle, alleviates inflammation and fibrosis, and helps restore normal immune tolerance.

Key Differentiation

￭ Addressing High Unmet Need: Current first-line therapy for IgG4-RD is glucocorticoids, which are associated with significant long-term side effects. IPG7236 offers the potential for a novel, targeted, oral therapy for a condition with no approved drugs.

￭ Targeted Oral Therapy: As a specific, oral small molecule, IPG7236 could provide a more precise and convenient treatment option compared to the broad immunosuppression of steroids or the use of B-cell depleting biologics like rituximab.

￭ Vast Untapped Market Potential: IgG4-RD represents an orphan disease with a growing patient population and a clear need for safer, more effective treatments. According to F&S, the global market for IgG4-RD is expected to reach US$431.0 million by 2035.

Current Development & Status

￭ Strong Safety Foundation: The favorable safety and tolerability profile demonstrated in the ongoing oncology trials provides a strong foundation for its development in the IgG4-RD patient population.

￭ Regulatory Milestone: IPG7236 received IND approval from the FDA for IgG4-RD in 2024.

￭ Next Steps: A Phase 2 clinical trial for IgG4-RD is planned to commence in the U.S. and China in 2026, with a target for NDA submission in 2028.

In vivo Properties

Using a surrogate anti-CCR8 antibody (IPG0521) in a mouse model of IgG4-RD, treatment resulted in significant, dose-dependent therapeutic effects:

￮ Reduced Organ Damage: Markedly reduced immune cell infiltration, parenchymal destruction, and fibrosis in the pancreas.

￮ Downregulated Key Cytokines: Significantly downregulated the expression of pro-inflammatory and pro-fibrotic cytokines, including IL-6, IL-1β, IFN-γ, and TGF-β, in affected salivary glands.

Publications

• Journal of Medicinal Chemistry: "Discovery of a Potent and Selective CCR8 Small Molecular Antagonist IPG7236 for the Treatment of Cancer.”

• 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.