The α-Biased Approach
IL-2 signaling is mediated through receptor complexes containing IL-2Rα (CD25), IL-2Rβ (CD122), and the common γ chain (CD132). Conventional IL-2 can stimulate both effector T cells and regulatory T cells, while excessive systemic exposure can result in dose-limiting toxicities.
Cytokine engineering therefore provides an opportunity to reshape this signaling profile.
IBI363, developed by Innovent Biologics and co-developed globally with Takeda under the R&D code TAK-928, adopts a PD-1/IL-2α-bias bispecific fusion protein design. Rather than eliminating CD25 binding, the molecule retains preferential IL-2Rα engagement while reducing βγ receptor activity.
The rationale is to exploit a biological feature of tumor-reactive T cells: PD-1 and CD25 can be co-expressed on activated tumor-specific T cells. By targeting PD-1-positive cells while retaining IL-2Rα activity, IBI363 is designed to achieve localized, cis-activated IL-2 signaling and preferentially expand and rejuvenate tumor-specific T cells.
The question is whether this molecular design can translate into meaningful clinical benefit.
Emerging Clinical Evidence from 2026 ASCO
Updated data presented at the 2026 ASCO Annual Meeting provide an important perspective.
In a Phase I PoC study of IBI363 monotherapy in advanced immunotherapy-resistant NSCLC, 136 patients received IBI363 across dose levels ranging from 2 μg/kg QW to 4 mg/kg Q3W. The population was heavily pretreated, with 72.1% having received at least two prior lines of therapy.
With a median follow-up of 14.4 months, the most notable findings emerged in patients with squamous NSCLC treated at 3 mg/kg Q3W.
In this cohort:
• Median PFS: 10.1 months
• Median OS: 18.2 months
• 24-month OS rate: 47.8%
These findings are particularly notable in an immunotherapy-resistant population. Nearly half of patients in this cohort remained alive at 24 months, suggesting a durable survival pattern extending beyond the initial response period.
A similar long-term survival signal was observed in EGFR wild-type lung adenocarcinoma.
Among patients receiving IBI363 at 3 mg/kg Q3W:
• Median PFS: 4.2 months
• Median OS: 15.2 months
• 24-month OS rate: 42.7%
The survival benefit was especially pronounced among patients with a history of smoking, where median OS reached 23.4 months compared with 11.5 months in non-smokers.
Together, these data suggest that the potential value of IBI363 may extend beyond short-term tumor response. The sustained OS observed in both squamous and adenocarcinoma populations is consistent with the characteristic “long-tail” pattern increasingly associated with effective immunotherapy.
From Resistant Disease to First-Line Treatment
The development strategy for IBI363 is also moving beyond immunotherapy-resistant disease.
At the 2026 ASCO Annual Meeting, Innovent reported preliminary Phase I PoC data evaluating IBI363 in combination with platinum-based doublet chemotherapy as first-line treatment for advanced NSCLC.
In the dose-optimization stage, the 3→1.5 mg/kg cohort showed:
• ORR: 86.4%
• Confirmed ORR: 81.8%
• DCR: 100%
Importantly, the study enrolled patients with PD-L1 TPS <50%, including both PD-L1-negative and PD-L1-low tumors, a population in which additional therapeutic strategies remain highly relevant. The second stage of the study is evaluating IBI363 plus chemotherapy against pembrolizumab plus chemotherapy across PD-L1 expression levels.
These results provide a complementary perspective: while the monotherapy data highlight the potential for durable benefit in immunotherapy-resistant disease, the first-line combination data demonstrate strong early antitumor activity in previously untreated NSCLC.
Why This Matters
The emerging clinical profile of IBI363 raises an important question for drug development:
Can receptor-biased cytokine signaling translate into a more selective and durable immune response?
The mechanism of IBI363 provides a clear framework for investigating this question.
PD-1 targeting provides cellular localization, while the engineered IL-2 component modulates downstream IL-2 receptor signaling. Rather than treating PD-1 blockade and cytokine stimulation as two independent mechanisms, the PD-1 × IL-2α-bias format is designed to integrate them within the same cellular context.
This makes functional characterization particularly important during candidate evaluation.
An in vitro system that independently captures PD-1 engagement and IL-2 receptor signaling can help researchers investigate whether a PD-1 × IL-2 molecule achieves the intended functional profile.
Evaluating PD-1 × IL-2 Signaling In Vitro
Genomeditech's H_CD25 CD122 CD132 Reporter Jurkat (hPD1 OE) Cell Line (GM-C41979) was developed to support functional evaluation of PD-1 × IL-2 molecules.
The stable clonal Jurkat cell line expresses CD25, CD122, CD132, and PD-1, together with a signal-dependent luciferase reporter system.
This configuration enables researchers to evaluate the functional consequence of PD-1-targeted IL-2 receptor activation in a cellular context containing both components of the intended mechanism.
When a PD-1 × IL-2 fusion protein engages PD-1 and delivers its engineered IL-2 moiety to the IL-2 receptor complex, downstream IL-2 signaling induces reporter activation. The resulting luminescence signal can therefore be used as a quantitative readout for functional activity.
For PD-1 × IL-2 drug development, such a system can support:
• Functional activity assessment
• Dose-response characterization
• Comparison of different IL-2 engineering strategies
• Evaluation of PD-1-targeted cytokine activity
• Mechanism-oriented characterization of candidate molecules
From Molecular Engineering to Clinical Translation
The evolution of PD-1 × IL-2 therapies illustrates an important principle in next-generation immunotherapy: molecular architecture can determine not only receptor engagement, but also the cellular context in which immune activation occurs.
IBI363 represents an α-biased approach designed to combine PD-1 targeting with selective IL-2 receptor activation. The long-term follow-up data presented at ASCO 2026 provide clinical evidence of durable survival in heavily pretreated, immunotherapy-resistant NSCLC, while emerging first-line data indicate strong early antitumor activity when combined with chemotherapy.
As PD-1 × IL-2 programs continue to advance, understanding the relationship between receptor bias, cellular targeting, signaling activity, and clinical response will become increasingly important.
For researchers developing or evaluating next-generation cytokine immunotherapies, robust cell-based functional assays can provide a critical bridge between molecular design and biological activity.
Explore the H_CD25 CD122 CD132 Reporter Jurkat (hPD1 OE) Cell Line (GM-C41979):
https://en.genomeditech.com/cell-line/H_CD25-CD122-CD132-Reporter-Jurkat%28hPD1-OE%29-Cell-Line
References
Zhou, J., Zhang, X., Guo, C., Wang, H., Sun, Y., Liang, X., Chu, Q., Wu, L., Zhou, C., Fang, J., Pan, Y., Cui, J., Huang, Z., Chen, Y., Zhou, C., Liu, X., Yang, Y., Li, N., Zhang, T., & Zhou, H. (2026). First-in-class PD-1/IL-2 α-bias bispecific antibody IBI363 (TAK-928) in patients (pts) with advanced immunotherapy-resistant non–small cell lung cancer (NSCLC): Updated results from a phase I study. Journal of Clinical Oncology, 44(16_suppl), 2618. https://doi.org/10.1200/jco.2026.44.16_suppl.2618
Tu, H., Wang, Y., Liu, H., Huang, D., Ren, P., Ning, F., Shi, X., Liu, B., Yang, H., Wang, L., Feng, H., Liu, C., Zhong, X., Zhang, M., Sun, Y., Gao, A., Zhang, S., Du, J., Ye, J., & Wu, Y. (2026). IBI363 (TAK-928) plus chemotherapy as first-line (1L) treatment for advanced non–small cell lung cancer (NSCLC). Journal of Clinical Oncology, 44(16_suppl), 8586. https://doi.org/10.1200/jco.2026.44.16_suppl.8586
Innovent Biologics. (2026). 2026 ASCO | INNOVeNT presents Long-Term Follow-up results from the POC study of IBI363 (TAK-928) (PD-1/IL-2Α-BiAs Bispecific Fusion Protein), showing robust survival benefits in Advanced Immunotherapy-Resistant Non-Small Cell Lung Cancer. PR Newswire. https://www.prnewswire.com/news-releases/2026-asco--innovent-presents-long-term-follow-up-results-from-the-poc-study-of-ibi363-tak-928-pd-1il-2-bias-bispecific-fusion-protein-showing-robust-survival-benefits-in-advanced-immunotherapy-resistant-non-small-cell-lung-302786450.html
Innovent Biologics. (2026). 2026 ASCO | Innovent Presents Preliminary PoC Data of IBI363 (TAK-928) PD-1/IL-2α-bias bispecific fusion protein) in First-line Advanced NSCLC. PR Newswire. https://www.prnewswire.com/news-releases/2026-asco--innovent-presents-preliminary-poc-data-of-ibi363-tak-928-pd-1il-2-bias-bispecific-fusion-protein-in-first-line-advanced-nsclc-302786452.html
