【Product for Licensing】A FIC Her2xCD47xCD16a Tri-specific Antibody for Treating Her2 High and Low or Negative Cancers

Project ID：BP-20240705-OR-70

Product Brief Summary

• Product Name: A FIC Her2 x CD47 x CD16a Tri-specific Antibody for Treating Her2^High and Her2^Low or Her2^Negative Cancers
• Modality: Tri-specific Antibody
• Target: Her2 x CD47 x CD16a
• Therapeutic Area: Oncology
• Current Stage: PCC
• Rights Available: China/Global Right
• Collaboration Mode: License out

Background

Immune check-point inhibitor (ICI) such as anti-PD-1 or anti-PD-L1 antibody, which enhances the adaptive immunity via re-energizing exhausted T cells, has become the foundational therapy for many cancers. However, it is efficacious only in 15-30% of the patients.
In order to complement existing immunotherapies and enhance efficacy, a long-acting tri-specific antibody that targets Her2 and CD47 as the primary tumor antigens with CD16a as effector cell engaged was constructed, CD47 is also targeted for enhancing macrophage phagocytosis.

Development Progress:

We have tested this molecule’s ability to kill Her2^high, Her2^low and Her2^neg tumor cell lines with DS8201a (Enhertu®) and Trastuzumab (Herceptin^® ) as the comparator molecules. In the presence of immune cells (hPBMC), the candidate showed superior tumor cell-killing activities to those mediated by DS8201a or Trastuzumab. When combined with 005 (an IL-2-Fc-IFN-α fusion cytokine), the tumor cell-killing activities were dramatically increased.

Notes: 005 is an IL-2-Fc-IFN-a fusion cytokine from the same company

These results suggest that it is feasible to combine two innate immune functions in one molecule to enhance tumor cell-killing activities in the heterogeneous immune environment.

Design and MoAs

• Target Her2+ and/or CD47+ tumor cell with NK cell engager(CD16a) to induce strong ADCC activities;
• Blocking ‘do not eat me’ signal enables macrophage to phagocytose tumor cells;
• Directly inhibits Her2-driven tumor cell proliferation;
• YTE mutations enable longer serum half-life

Molecule Characterizations

• In comparison to Herceptin^®, the candidate stimulates dramatically enhanced macrophage phagocytosis of tumor cells.
• The candidate does not have hemagglutination activities.
• The candidate shows comparable cell internalization to that of Herceptin^®
• The candidate has 7-fold longer serum half-life than that of IgG1 in humanized FcRn mice.

In vitro Activity Study

• The candidate shows less potent direct tumor cell killing activities (ie. in the absence of hPBMC) to that of DS8201a.
• In the presence of hPBMC, candidate exhibits superior anti-tumor activities in Her2^high, Her2^low and Her2^neg cell lines in comparison to DS8201a and Herceptin^®
• In combination with 005 (an IL-2-Fc-IFN-α fusion cytokine), candidate demonstrated dramatically enhanced killing activities in HCC1954 cell line in comparison to each of them alone. The above experiments were repeated in other cell lines, such as HuCC-T1 and PANC-1, with similar results

In vivo Activity Study

• The candidate shows significantly better anti-tumor activity than that of Herceptin^®. CB17 SCID mice were inoculated with human NCI-N87 gastric tumor cells.
• Treatments with PBS, candidate or Herceptin^® were initiated when the mean tumor size reached around 100mm³.
• The candidate or Herceptin^® were given i.p. QW for three weeks and tumor growth was monitored.
• *p<0.05 candidate significantly different from Herceptin^® group.

Conclusions

• In Vitro, the candidate has demonstrated superior anti-tumor activities to DS8201a and Herceptin^® in Her2^high , Her2^low and Her2^neg tumor cells in the presence of human PBMC.
• In Vivo, the candidate shows superior anti-tumor activities to Herceptin^® in NCI-N87 xenograft model, demonstrating tumor cell killing activities by innate immune cells(e.g. NK cells and Macrophages).
• In combination with 005, an immune Fc cytokine fusion, the candidate exhibits dramatically enhanced killing activities towards Her2^high, Her2^low and Her2^neg cancer cell lines, superior to DS8201a and Herceptin^®.
• The candidate exhibits a strong phagocytosis activity without hemagglutination and a 7-fold longer serum half-life than that of IgG1 in humanized FcRn mice.
• The candidate is potentially a strong competitive alternative to or better therapeutic than DS8201a in Her2 targeting cancer indications.

Contact

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