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792 Givastomig, a novel Claudin18.2/4–1BB bispecific antibody, exerts bystander tumor-killing and synergistic anti-tumor activity with therapeutics in 1L/2L treatment for gastric cancer
  1. Xuejun Liu1,
  2. Ke Xu2,
  3. Jane Meng3,
  4. Jie Xia4,
  5. Chenyu Pan2,
  6. Ao Li2,
  7. Zhenhu Li2,
  8. Zhengyi Wang2,
  9. Jaeho Jung4 and
  10. Andrew Zhu2
  1. 1I-Mab Biopharma, San Diego, CA, China
  2. 2I-Mab Biopharma, Shanghai, China
  3. 3I-Mab Bipharma, Beijing, China
  4. 4ABL Bio, Seongnam-si, Republic of Korea
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background Givastomig (TJ-CD4B/ABL111) is a first-in-class bispecific antibody designed to target tumors with a wide range of Claudin 18.2 (CLDN18.2) expression and elicit 4–1BB-mediated T cell activation upon engagement with CLDN18.2-expressing tumor cells. Here we further investigate the mechanism of givastomig and explore its potential in combination with first-line (1L) and second-line (2L) therapeutics for gastric cancer.

Methods The CLDN18.2 expression in formalin-fixed, paraffin-embedded (FFPE) tumors of three human gastric cancer cell lines (MKN-45, MKN-45#14, and MKN-45#18; obtained from Genomeditech) was determined by immunohistochemistry (IHC) staining. The T cell activation and tumor-killing mediated by givastomig were investigated, either alone or in combination with other therapies, using a co-culture system of tumor cells and PBMCs. T cell activation was evaluated by the production of INFg, IL2 and soluble 4–1BB, while tumor-killing was evaluated by the CellTiter-Glo® Assay. Anti-tumor activity and pharmacodynamics effects of the combination treatment were also examined by in vivo gastric cancer patient-derived xenograft (PDX) model.

Results Based on IHC staining, MKN-45, MKN-45#18, and MKN-45#14 exhibited negative (<10% of 1+), low (65% of 1+, no 2+/3+), and moderate (35% of 1+ and 65% of 2+) CLDN18.2 expression, respectively. Givastomig induced T cell activation in a dose and CLDN18.2 expression dependent manner. Givastomig elicited tumor-killing activity against CLDN18.2-positive MKN-45#14 and MKN-45#18 cells but not CLDN18.2-negative MKN-45 cells. Interestingly, bystander tumor-killing was observed in a mixture of MKN-45#14 cells and MKN-45 cells at various ratios in the presence of givastomig. In addition, givastomig-mediated T cell activation and tumor-killing was enhanced in combination with chemotherapies used in 1L or 2L treatment for gastric cancer, including 5-fluorouracil plus oxaliplatin (FOLFOX) and paclitaxel. In a gastric cancer PDX model with moderate CLDN18.2 expression (25–50% of 2+), a triple-combination of givastomig, nivolumab and FOLFOX resulted in better tumor growth inhibition (TGI=40%), accompanied by an increase in tumor-infiltrating T cells, compared to nivolumab plus FOLFOX (TGI=8%).

Conclusions In an in vitro co-culture system that mimics tumor microenvironment, givastomig exerts bystander tumor-killing in which givastomig-mediated T cell activation by CLDN18.2-positive tumor cells leads to the killing of nearby CLDN18.2-negative tumor cells. These results indicate the therapeutic potential of givastomig in the treatment of solid tumors with broad and heterogenous CLDN18.2 expression. The synergistic anti-tumor activity by givastomig in combination with current therapeutics in 1L/2L treatment for gastric cancer, as demonstrated in preclinical studies, warrants further investigation of these combinations in clinics.

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