【Product for Licensing】A Highly Differentiated IL-2- Fc-IFN-α Fusion Protein for Cancer Combination Therapies

Project ID：BP-20240705-OR-71

Product Brief Summary

• Product Name: A Highly Differentiated IL-2- Fc-IFN-α Fusion Protein for Cancer Combination Therapies
• Modality: Fusion Protein
• Target: IL-2 x IFN-α
• Therapeutic Area: Oncology
• Current Stage: PCC
• Rights Available: China/Global Right
• Collaboration Mode: License out

Background

Both IL-2 and IFN-α were approved as the first two immunotherapies, those who responded have long-term survival benefits. However, the severe toxicity especially in high doses prohibited their broad use in oncology.
Recently, there has been strong interest in modifying these two cytokines in the effort to reduce the toxicity and enhance the activity such as enhancing the binding of IL-2 to the intermediate affinity β/γ receptors and reducing the binding of IL-2 to high-affinity α/β/γ receptors.

Development Progress:
Here we have developed a long-acting novel IL-2-Fc-IFN-α fusion molecule termed candidate that has mutations to reduce the toxicity effects of IL-2 and IFN-α and prolong its serum half-life.
The candidate has demonstrated potent tumor cell-killing activities in multiple cancer cell lines. When combined with 004 (a Her2-CD47-CD16a tri-specific antibody) in vitro, the tumor cell-killing activities were dramatically increased. A preliminary in vivo study demonstrated efficacies in the syngeneic mouse tumor model.

These results suggest that this fusion cytokine molecule can potentially be used in monotherapy or combination therapies with antibodies targeting PD-1 or PD-L1.

The features and characterizations of candidate

• A novel Fc cytokine (IL-2 and IFN-α) fusions protein.
• Mutations to increase IL-2β/γ receptor binding for stronger cytotoxicity, reduce IFN-α activity for less toxicity, reduce FcγR binding for less ADCC activity and enhance FcRn binding for longer serum half-life.
• The candidate shows significantly increased affinity to IL-2Rα, IL-2Rβ, IFN-αR2 and human FcRn
• The candidate stimulated a 10-fold higher CTLL-2 cell proliferation than that of wild type IL-2.
• The candidate activates and expands NK and CD8⁺ T cells with a minimal Treg expansion.

In Vitro Activity Study

• The candidate shows less potent direct tumor cell killing activities (in the absence of hPBMC) than that of WT IFN-α.
• The candidate shows better tumor cell killing activities than that of WT IL-2 in the presence of hPBMC.
• In combination with 004, the tumor cell-killing activities were dramatically increased in HCC1954 cell line. Similar results were obtained with other cell lines such as MDA-MB-231, NCI-N87 and MDA-MB-468.

Notes：004 is a Her2-CD47-CD16a tri-specific antibody from the same company

In Vivo Activity Study

• MC38 tumor cells were seeded in syngeneic C57BL6 mice. Treatments with candidate or PBS by i.p. were carried out once the mean tumor size reached ~ 80mm³. The candidate was given at a dose of 145 μg/mouse every week for 3 weeks.
• p<0.05,*p<0.01 the candidate group significantly different from PBS group.
• The in vivo assays to demonstrate efficacy and safety are ongoing.

Summary & Conclusion

• The candidate enhances IL-2β/γ receptor binding, activates and expands NK and CD8⁺T cells while reduces the expansion of Treg cells.
• Although the candidate shows higher binding affinity to IFN-αR2, the bioactivities in inhibiting tumor cell growth were significantly reduced compared to WT IFN-α.
• The candidate shows less potent direct tumor cell killing activities (in the absence of hPBMC) than that of WT IFN-α in multiple tumor cell lines.
• The candidate demonstrates better tumor cell killing activities than that of WT IL-2 in the presence of hPBMC in multiple tumor cell lines.
• Safety evaluations are currently ongoing both in vivo and in vitro.
• The candidate represents a highly differentiated immunomodulating therapeutic candidate with unique PK properties and reduced toxicity, suitable for use in immuno-combination therapies, especially with tumor-targeting antibodies or checkpoint inhibitors.

Contact

• If interested, please contact DrugTimes BD Team at BD@drugtimes.cn. Many thanks!