1560P - Osemitamab (TST001): An ADCC enhanced humanized anti-CLDN18.2 mab, demonstrated improved efficacy in combination with anti-PD-L1/PD-1 mab and oxaliplatin/5-FU in preclinical tumor models

Background

Osemitamab (TST001) is a best-in-class humanized antibody with improved CLDN18.2 binding affinity and ADCC activity. Here, we evaluated the dynamics of on-treatment PD-L1 expression on the tumor cells in both in vivo tumor models and in vitro tumor cells and studied preclinical efficacy of the combination of Osemitamab and anti-PD-L1/PD-1 mAb +/- oxaliplatin/5-FU (Oxa/5-FU) in both CLDN18.2+/PD-L1+ and CLDN18.2+/PD-L1- tumor models.

Methods

For in vitro cell assay, we co-cultured the CLDN18.2-expressing GC cells w/wo human PBMC and 30 μg/ml Osemitamab for 72hr, and then transferred the supernatant to the matched tumor cells for another 72hr incubation. PD-L1 expression on the tumor cells was detected by using FACS analysis. The mouse with CLDN18.2-expressing tumors were injected intraperitoneally with Osemitamab or in combination with anti-PD-L1/PD-1 mAbs twice a week and injected intravenously with oxa/5-FU weekly in in vivo efficacy studies. CLDN18.2 and PD-L1 expression on the tumors was detected by using IHC analysis.

Results

We found that in the presence of human immune cells, PD-L1 expression on the CLDN18.2-expressing GC cells in vitro and tumors in vivo was upregulated after Osemitamab treatment. In two CLDN18.2+/PD-L1+ mouse syngeneic models, Osemitamab combined with Atezolizumab exhibited significantly higher tumor growth inhibition (TGI) than the single agents. Furthermore, in the same tumor model, the triplet [Osemitamab in combination with anti-mouse PD-1 (RMP1-14) + Oxa/5-FU] showed even better TGI than the doublet [Osemitamab + Oxa/5-FU or RMP1-14 + Oxa/5-FU]. Additionally, in a CLDN18.2+/PD-L1- GC PDX model with human PBMC reconstruction on B-NSG-hIL-15 mice, the Osemitamab in combination with Oxa/5-FU was also superior to either Oxa/5-FU or Oxa/5-FU + nivolumab.

Conclusions

PD-L1 upregulation after Osemitamab treatment provides a rationale for combination of Osemitamab and anti-PD-L1/PD-1 mAb. And the potential synergistic effect of Osemitamab and GC standard of care (SoC: anti-PD-1 mAb + Oxa/5-FU) in preclinical tumor models supports Osemitamab in combination with SoC chemotherapy +/- nivolumab in G/GEJ patients.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Suzhou Transcenta Therapeutics Co., Ltd.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.