Genor Biopharma Co. Ltd participated at the 38th Annual Meeting of The Society for Immunotherapy of Cancer, 2023, in San Diego, shared two posters for two programs: Generation of an innovative BsAb targeting CCR8/CTLA-4, Development of a tri-specific antibody targeting PD-1/CTLA-4/TIGIT.
- GBD201 (CCR8/CTLA-4): SITC2023 Abstract#491
BACKGROUD: CTLA-4-expressing regulatory T cells (Tregs) are abundantly present in tumor tissues and suppress anti-tumor responses. Currently approved CTLA-4 inhibitors, such as ipilimumab, induce severe irAEs, which limited their use. Therefore, next-generation of CTLA-4 inhibitors with reduced toxicity and increased efficacy is highly demanded, given the fact that CTLA-4 inhibition has showed unique advantages in inducing immune memory response and prolonging anti-tumor activity.
SIGNIFICANCE: CCR8 is recently found to be predominantly expressed on intra-tumor Tregs but little on peripheral Tregs or activated Tconv. Anti-CCR8 antibodies have been shown significant anti-tumor activity in pre-clinical studies. We have hypothesized that a strong anti-CCR8 arm may provide preferential inhibition of CTLA-4 on CCR8+CTLA-4+ intra-tumor Tregs and have synergistic effects on Tregs in TME. Therefore, we have developed a novel BsAb, GBD201, targeting CCR8/CTLA-4. The innovative bsAb exhibited potent depletion of intra-tumor Tregs but spared peripheral Tregs and Tconv. In hCCR8/hCTLA-4 mice, GBD201 showed better efficacy and safety profile compared to ipilimumab.
Click here to download the full "CCR8/CTLA-4 Bispecic Antibody" poster
- GBD209 (PD-1/CTLA-4/TIGIT): SITC2023 Abstract#492
BACKGROUD: Immune checkpoint inhibitors (ICIs) such as anti-PD-1/PD-L1 and anti-CTLA-4 antibodies have achieved enormous success in cancer treatment. However, only a subset of patients shows clinical responses. The combination of CTLA-4 and PD-1 blockers have increased response rates in patients, but severe immune related adverse events (irAEs) have limited their use. TIGIT is another inhibitory receptor, and often co-expressed with PD-1 on tumor-infiltrating CD8+ cytotoxic T cells, which may also provide important negative signals. Several anti-TIGIT blocking antibodies have shown encouraging anti-tumor activity in clinical studies when combined with PD-1/PD-L1 blockers. We have recently generated a tri-specific antibody, GBD209, targeting PD-1/CTLA-4/TIGIT and by fine tuning and balancing the potency of each arm.
SIGNIFICANCE: GBD209 has excellent anti-tumor efficacy by synergistically blocking PD-1, TIGIT, and CTLA4 pathways on T cells. To reduce the potential toxicity caused by CTLA4 inhibition, GBD209 was designed to only partially block the interactions of CTLA4 with it’s ligands CD80/CD86, and the blockade was highly dependent on the expression PD-1, reducing peripheral toxicity. GBD209 exhibited better efficacy than PD-1/CTLA-4 bsAb as well as the combination therapy of anti-PD-1, CTLA-4, and TIGIT antibodies in animal model. In vivo arthritis model in hPD-1/hPD-L1/hCTLA-4/hTIGIT KI mice showed GBD209 had at least 15-fold better tolerance compared to Ipilimumab. Thus, GBD209 may represent a next generation of check point inhibitor with good safety profile for cancer treatment.
Click here to download the full content of the "PD-1/CTLA-4/TIGIT Tri-specific Antibody" poster
