Recently, the latest research results of Shanghai JeYou Pharmaceutical Technology Co., Ltd.(hereinafter referred to as "JeYou Pharmaceutical") independently developed an anti-PD1/ IL-2β/γ triple antibody drug (JMB2403) were successfully published in mAbs, an authoritative journal in the field of antibodies. The results reveal the potential differentiated advantages of JMB2403 in tumor treatment.

JMB2403分子            

Research Significance

In the field of cancer immunotherapy, PD-1 inhibitors and IL-2 therapies have long faced the fundamental contradiction of "both efficacy and toxicity." Although PD-1 antibodies have significantly improved the prognosis of some patients, the response rate is limited and drug resistance is prone to development. Although IL-2 has strong anti-tumor activity, it systematically activates Treg cells and endothelial cells and causes serious toxic side effects (such as vascular leak syndrome), and clinical application is limited.

The advent of JMB2403 marks the successful preclinical verification of the world's first trispecific antibody based on the "PD-1 dependent, IL-2R α independent" mechanism, filling the technical gap of "conditional activation" immunotherapy. This study not only broke through the systemic activation bottleneck of traditional "α-free" IL-2 variants, but also pioneered the deep integration of nanobody agonists with targeted delivery, setting a new standard for the next generation of immune cytokine drugs.

Its core position is reflected in:

- Pioneering: For the first time, the triple functional integration of PD-1 targeting +IL-2R βγ dual antagonist + IL-2R α independent was achieved;

- Differentiation: Different from PD-1-IL-2 fusion proteins such as RG6279 and 2149, it adopts a full IgG skeleton + double nanoantibody module, which has better developability and stability.

Main content of the study

Based on the independently developed antibody discovery platform combining phage and yeast display, this study constructed and screened nanoantibodies (sdAbs) against IL-2R β and IL-2R γ, and fused them with humanized anti-PD-1 IgG to finally generate trispecific antibody JMB2403.

SPR analysis showed that JMB2403 has a high affinity for PD-1 (KD=1.8×10 M), which is two orders of magnitude higher than that of JMB2403 for IL-2R βγ (KD=1.23×10 M), which can fully ensure the blocking and targeting of PD-1; at the same time, JMB2403 has a weak affinity for IL-2R αβγ (KD=1.11×10 M), and has weak activation of immunosuppressive cells such as Treg, which can fully exert the anti-tumor activity of effector T. In vitro cell experiments further demonstrated that JMB2403 only activated IL-2-related downstream pSTAT5 signals in activated CD8 T cells expressing PD-1, activated NK cells moderately, and activated Treg cells extremely weakly. In A375 (melanoma) and NCI-H292 (lung cancer) xenograft models, JMB2403 monotherapy achieved approximately 90% complete remission rate, which was significantly better than the PD-1 antibody and patented molecule 2149.

Core Conclusions

1. JMB2403 achieves selective activation of IL-2 signaling in tumor-infiltrating T cells through a PD-1-mediated "cis activation" mechanism, improving the treatment safety window;

2. In the pharmacodynamic model, JMB2403 monotherapy was significantly superior to PD-1 antibody and patented molecule 2149;

3. In cynomolgus monkeys, JMB2403 induced dose-dependent expansion of CD8 T cells, PD-1 CD8 T cells, NK cells and Treg cells, and no IL-2-related toxicities such as vascular leakage and pulmonary edema were observed;

4. The molecule has excellent physical and chemical properties: monomer purity reaches 99.1%, good thermal stability, stable structure after freeze-thaw cycles, and has good development potential.

Differentiated advantages

JMB2403 is currently the only trispecific antibody that achieves the quadrants of "PD-1-dependent +IL-2R α independent binding + IL-2R βγ dual anti-agonist + high stability", bypassing IL-2-based protein transformation difficulties and bottlenecks. It has excellent efficacy, excellent safety and excellent development, and has all the elements to become a "best-in-class" immunotherapy candidate molecule. With the gradual improvement of preclinical data, JMB2403 has a solid foundation for entering Phase I clinical trials and is expected to open a new era of precise immune cytokine therapy within the year.

Article link: https://www.tandfonline.com/doi/full/10.1080/19420862.2026.2709956 

Statement：

1. This information is intended to share research and development progress. It is for medical and health professionals only and is not for advertising purposes. For clinical use, please follow the opinions or guidance of your doctor or other medical and health professionals and follow the drug instructions.

2. JeYou Pharmaceuticals does not recommend any drug or the*utic use.

About JeYou Medicine

Shanghai JeYou Pharmaceutical Technology Co., Ltd. focuses on the "3+1" core treatment areas of cancer, kidney disease, pain, and autoimmunity, focusing on the research and development, manufacturing and commercial transformation of innovative drugs. The company has built a differentiated product matrix with international competitiveness, covering multiple drug types such as mono/dual antibodies, TCE, ADC, small molecule drugs and PROTAC. Currently, there are 40+ internally-developed products/in-house products in a portfolio, and more than 10 have entered the clinical stage. In February 2026, the company's independently developed Class 1 innovative anti-tumor drug Jilemax ® (Socimerose Sulfate Tablets) was approved for marketing by the State Food and Drug Administration.