| Targets |
IBI363 targets two distinct pathways within the immune system. The first is the PD-1/PD-L1 immune checkpoint axis. By binding to PD-1 on the surface of exhausted T cells, IBI363 prevents tumor cells from engaging PD-L1, thereby reactivating the cytotoxic activity of CD8+ T cells. The second is the IL-2 receptor complex. Through its engineered IL-2alpha-biased cytokine arm, IBI363 preferentially binds to the trimeric IL-2 receptor (IL-2Ralphabetagamma) found on effector T cells (Teffs) rather than the dimeric receptor (IL-2Rbetagamma) found on Tregs and NK cells. This selective engagement promotes the proliferation and survival of tumor-specific T cells while minimizing the activation of immunosuppressive Tregs.
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| ln Vitro |
The in vitro activity of IBI363 is characterized by its ability to stimulate T cell proliferation and cytokine production. In cell-based assays, treatment of human peripheral blood mononuclear cells (PBMCs) with IBI363 leads to a significant increase in the proliferation of CD8+ and CD4+ effector T cells, as measured by CFSE dilution or Ki-67 expression. It also enhances the secretion of effector cytokines such as interferon-gamma (IFN-gamma) and granzyme B. Importantly, compared to wild-type IL-2, IBI363 induces minimal expansion of regulatory T cells (Tregs) and shows reduced activation of NK cells, confirming its alpha-bias selectivity and improved safety profile. The PD-1 blockade component is confirmed by its ability to restore T cell function in mixed lymphocyte reactions (MLRs).
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| ln Vivo |
IBI363 has shown robust in vivo activity in preclinical models, leading to FDA Fast Track Designation for squamous NSCLC. In syngeneic mouse tumor models, treatment with IBI363 results in superior tumor growth inhibition (TGI) compared to anti-PD-1 monotherapy or IL-2 monotherapy. A Phase 1 trial reported a 50% objective response rate (ORR) and an 88.9% disease control rate (DCR) at a 3 mg/kg dose. The median progression-free survival (PFS) at this dose was not reached. Notably, it has shown clinical benefit in patients who have previously progressed on anti-PD-(L)1 therapy, a population with high unmet need. Responses have been observed in PD-L1 low and negative tumors, indicating a novel mechanism overcoming primary resistance to checkpoint inhibitors.
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| Enzyme Assay |
In vitro binding studies confirm the dual-targeting nature of IBI363. Surface Plasmon Resonance (SPR) or Bio-Layer Interferometry (BLI) is used to measure the binding affinity of IBI363 to its targets. In a typical assay, recombinant human PD-1 protein is immobilized on a sensor chip. IBI363 is flowed over the chip at increasing concentrations (e.g., 0.1 nM to 500 nM) in running buffer (PBS, 0.05% Tween-20). The association and dissociation rates are recorded, and the equilibrium dissociation constant (KD) is calculated. This is repeated for the IL-2 receptor alpha (CD25) subunit. Affinities in the low nanomolar range are expected. For functional binding, a ligand blockade assay involves incubating PD-1 expressing cells with IBI363, followed by the addition of recombinant PD-L1. The reduction in PD-L1 binding is measured by flow cytometry.
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| Cell Assay |
In vitro cell-based activity is assessed using primary human T cells. For IL-2 signaling, CD8+ T cells are isolated from healthy donor PBMCs. Cells are labeled with CellTrace Violet (CTV) and plated in anti-CD3 antibody-coated plates. They are then treated with serial dilutions of IBI363 or controls (PBS, anti-PD-1, IL-2) for 5-7 days. Proliferation is quantified by flow cytometry CTV dilution. Activation markers (CD25, CD69, CD44) and differentiation markers (Granzyme B, Perforin) are measured by flow cytometry. Cytokine levels (IFN-gamma, TNF-alpha, IL-10) in the supernatant are measured by ELISA. The alpha-bias selectivity is demonstrated by simultaneously measuring proliferation of CD8+ Teff vs. CD4+CD25hiFoxP3+ Tregs in the same culture. IBI363 should show a high Teff/Treg ratio compared to wild-type IL-2.
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| Animal Protocol |
The most robust in vivo data for IBI363 is derived from human clinical trials (Phase 1, NCT05460767). The protocol for this open-label, multicenter study enrolled patients with advanced solid tumors. Patients receive IBI363 via intravenous infusion at various dose levels (e.g., 0.3, 1.0, 1.5, 3.0 mg/kg). Primary endpoints include safety, tolerability, and the determination of the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Secondary endpoints include objective response rate (ORR) assessed by RECIST v1.1, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Blood samples are collected for pharmacokinetic (PK) analysis (concentration of IBI363) and pharmacodynamic (PD) analysis (e.g., T cell subsets, cytokine levels). In preclinical models, IBI363 is administered to mice bearing syngeneic tumors (e.g., MC38, CT26).
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| ADME/Pharmacokinetics |
IBI363 is a protein therapeutic (bispecific antibody fusion protein), and its PK properties are characteristic of monoclonal antibodies. Following intravenous administration, it is expected to have a slow clearance (low CL), a small volume of distribution (Vd), and a long terminal half-life (t1/2) of several days (approximately 4-7 days). This supports a dosing schedule of every 2 or 3 weeks. The bispecific nature may slightly alter its distribution compared to a standard monoclonal antibody, but it remains largely confined to the vascular space. Phase 1 trial results have been used to characterize its PK profile, showing a dose-proportional increase in exposure (Cmax and AUC) over the dose range of 1-3 mg/kg, which supports the selection of the 3 mg/kg dose for further clinical development.
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| Toxicity/Toxicokinetics |
The safety profile is manageable, with most treatment-related adverse events (TRAEs) being mild to moderate. In the Phase 1 trial, grade 3 or higher TRAEs occurred in 20.1% of patients. The most common TRAEs included arthralgia (joint pain), anemia, hyperthyroidism, hypothyroidism, and rash. Unlike traditional high-dose IL-2 therapy, no vascular leak syndrome (VLS) or severe capillary leak has been reported, confirming the alpha-bias design successfully mitigates this historically dose-limiting toxicity.
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| References | |
| Additional Infomation |
IBI363 has received Fast Track Designation from the FDA for the treatment of patients with squamous non-small cell lung cancer (NSCLC) after prior anti-PD-(L)1 therapy and platinum-based chemotherapy. It has also received Breakthrough Therapy Designation from China's NMPA. It is being developed by Innovent Biologics. The mechanism of action combines PD-1 checkpoint blockade with an alpha-bias IL-2 that preferentially activates CD8+ T cells over Tregs, representing a novel approach to overcome resistance to immunotherapy. The recommended Phase 2 dose (RP2D) is 3.0 mg/kg administered intravenously once every 3 weeks.
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| Appearance |
Typically exists as solids at room temperature
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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