TianGang Yinuo Submits IPO Prospectus Highlighting αTIGIT-IL2, a Novel TIGIT/IL-2 Bispecific Fusion Protein for Overcoming Immune Checkpoint Inhibitor Resistance

    TregCells as the core regulators of immune homeostasis,Present in tumors“Double-edged sword”Characteristics: On the one hand, it maintains the body's defense against autoimmune attacks, and on the other hand, it does so by secretingIL-10、TGF-βand expressionCTLA-4、TIGITEqual molecules, potent inhibitory effectTCell Function, Construction of ImmunosuppressionTME。Currently TargetingTregCell therapy strategies face many bottlenecks:SystemicClearTregCells may trigger severe autoimmune reactions。AndLow DoseIL-2Priority AmplificationTregCells, while high doses can activate effector cells, the toxicity is significant.。

Recently,Hefei TG ImmunoPharma Co., Ltd.《Nature Communications》Developed a fusion antibodyTIGITMonoclonal Antibodies andIL-2Immune CytokinesαTIGIT-IL2, through precise targeting of tumor infiltrationTregCells and induce their“Fragilization”，Simultaneously mobilizing neutrophils andCD8⁺TCells Build Potent Anti-Tumor Immune Network, for OvercomingICBDrug resistance provides a new strategy.

One:αTIGIT-IL2Precision Targeting of Tumor InfiltrationTregCells, Exhibiting Potent Tumor-Inhibiting Activity

    αTIGIT-IL2Through Anti-TIGITSingle-chain variable region (scFv) andIL-2The fusion design,αTIGIT-IL2Compared with miceTIGITThe binding affinity with the parent antibody13G6Equivalent, while retaining the fullIL-2Bioactivity,STAT5Phosphorylation Activation Capability and RecombinationIL-2Consistent。

In vivo and in vitro experiments have confirmed,αTIGIT-IL2Mainly combined with tumor infiltrationTregCells, this targeting mainly relies onTregHighly Expressed in CellsCD25（IL-2High-affinity receptorαChain), rather thanTIGITOrCD122`, Block`CD25Can significantly reduce its binding efficiency。10μg/DoseαTIGIT-IL2InMC38Can be achieved in colorectal cancer models70%Tumor Growth Inhibition Rate Above (TGI), and does not cause liver and lung tissue damage, serumALT/ASTNo significant increase in level, better thanαPD1-IL2And TraditionalIL-2Treatment.

InMelanoma (B16F10）Center，αTIGIT-IL2Effectively InhibitPD-1Growth of inhibitor-resistant tumors,TGISignificantly higher thanαPD1-IL2。：At the same timeLow Dose (10μg/Dose) can significantly reduceColorectal Cancer (MC38）Tumor volume, prolonging the survival period of tumor-bearing mice。

 Two:αTIGIT-IL2InductionTregCell Fragilization, Breaking Immune Suppression

    αTIGIT-IL2The core mechanism lies in reshaping tumor infiltrationTregThe functional phenotype of cells, making them from“Potent Inhibitory Type”Transform into“Fragile Type”（fragile-like）：αTIGIT-IL2After treatment, tumor infiltrationTregKey inhibitory molecules of cells (Foxp3、CTLA-4、CD39、IL-10) was significantly down-regulated, and in vitro experiments confirmed its effect onCD4⁺RoutineTCell (Tconv) The ability to inhibit proliferation decreases50%Above。AndVulnerabilityTregHigh Cell ExpressionIFN-γ、TNFPro-inflammatory factors, which can further activate effector immune cells, establishing an inflammatoryTME。

 In additionαTIGIT-IL2To the spleenTregCells showed no significant inhibitory effect; instead, their function was slightly enhanced, suggesting that their regulation is tumor microenvironment-specific. This specificity depends on the high expression in tumor regions.CD155（TIGITLigand), MissingCD155Cannot induceTregCell fragility.Through single-cellRNASequencing (scRNA-seq) Analysis,αTIGIT-IL2Post-treatment tumor infiltrationTregCells are categorized into4A subpopulation, with high expressionIfng、TnfThe fragile subgroup (cluster3) The proportion significantly increased, and this subset is enriched in pathways such as lymphocyte activation and pro-inflammatory cytokine production, further confirmingTregCell functional reprogramming.

Three:IFN-γMediating Neutrophil Reprogramming, StrengtheningCD8⁺TCellular Anti-Tumor Function

Mechanism analysis shows,TregCell &CD4⁺TconvCells inαTIGIT-IL2Secrete a large amount of chemokines under the influence, significantly promoting neutrophil infiltration into tumors.。High Expression of Tumor-Infiltrating NeutrophilsMHCIMolecular andCD80、IL-15and other co-stimulatory molecules, which cross-present tumor-associated antigens (TAA) is enhanced, effectively activatingOVASpecificityCD8⁺TCell Proliferation。

Multiplex immunohistochemistry shows,αTIGIT-IL2After processing,Ly6G⁺Neutrophils andCD8⁺TThe spatial distance of cells within the tumor is significantly shortened, and the frequency of intercellular communication increases.At the same timeTumor InfiltrationCD8⁺TCellularKi67⁺Proliferation ratio increased,IFN-γ、TNF-αIncreased secretion, early effect subset (PD-1⁺Tim-3⁻) and memory precursor subpopulation (CD25⁺) The proportion has increased significantly。NeutralizationIFN-γFully ReversibleαTIGIT-IL2The anti-tumor effect, while blocking neutrophil reprogramming andCD8⁺TCell Activation, ConfirmedIFN-γIs connectedTregThe key hub of fragility and downstream immune activation.

 Four:αTIGIT-IL2UnitedPD-1Inhibitor OvercomeTNBCImmune Treatment Resistance

AnalysisTNBCSingle-cell sequencing data from patients revealed that,ICBTumor Infiltration in Non-RespondersTregHigh Cell ExpressionFOXP3、TIGIT、CTLA4Such as inhibitors, the functional scores were significantly higher than those of responders, and the function was further enhanced after treatment, suggestingTregCells are the key drivers of drug resistance.InEO771TNBCIn the model,αTIGIT-IL2Monotherapy achieves partial tumor control, withPD-1After the combination of inhibitors, the tumor volume decreased.75%，2/5Complete Tumor Regression Achieved in Mice。

After the tumor-bearing mice were cured by combined therapy, they were re-inoculated.EO771Cells can completely inhibit tumor growth, confirming the induction of long-term antitumor immune memory.。MechanismDisplayαTIGIT-IL2Treatment can upregulate tumor cellsPD-L2Expression,PD-L2AndPD-1The combination may compensatePD-L1The inadequacy of blockade, therefore, withPD-1Inhibitor Combination RatioPD-L1The combination of inhibitors is more effective.

SummaryThought

    αTIGIT-IL2Achieving Anti-Tumor Breakthrough Through Dual Mechanisms:On the one hand, precise targeting of tumor infiltrationTregCells, inducing their fragility to relieve immunosuppression。On the other hand, with the help ofIFN-γDrive Neutrophil Reprogramming, StrengthenCD8⁺TAntigen-specific killing function of cells.

FutureNeed to be confirmed in clinical specimensαTIGIT-IL2To PersonTregRegulatory Effects and Safety of Cells。At the same timeSearch for PredictionsαTIGIT-IL2Biomarkers of treatment response (such asTregCellTIGIT/CD25Expression Level,CD155Expression Level)。

    Wang, T., Xu, Y., Zhang, Z. et al. αTIGIT-IL2 achieves tumor regression by promoting tumor-infiltrating regulatory T cell fragility in mouse models. Nat Commun 16, 9223 (2025). https://doi.org/10.1038/s41467-025-64296-z