Abstract B127: Novel anti-CD147 antibody DS-1471a exerts antitumor effect in hepatocellular carcinoma Patient Derived Xenograft models and its efficacy correlates with the expression of CD147

Abstract

Abstract Background: CD147 is an immunoglobulin-like receptor that is highly expressed in various cancers and involved in the growth, metastasis, and activation of inflammatory pathways via interactions with various functional molecules, such as integrins, CD44, and monocarboxylate transporters. Through screening of CD147-targeting antibodies with antitumor efficacy, we developed a novel humanized IgG4-formatted monoclonal anti-CD147 antibody, DS-1471a. Our previous studies revealed this antibody showed potent antitumor efficacy superior to standard of care drugs in various cell line xenograft mouse models such as hepatocellular carcinoma (HCC), pancreatic invasive ductal adenocarcinoma, and chronic myelogenous leukemia. In this study, we further examined antitumor efficacy and biomarker expression in 18 patient derived xenograft (PDX) models established from HCC patients. Methods: DS-1471a or vehicle was administered intravenously once per week at 10 mg/kg doses in HCC-PDX models and tumor volumes were measured every 2 or 3 days. After tumors were harvested, samples were analyzed by simple western blotting (sWB, capillary based western blotting system) and immunohistochemistry (IHC). H-scores were calculated from IHC results and correlation between H-score, protein expression by sWB, and tumor growth inhibition (TGI) ratio were examined. Results: Seven out of 18 PDX models showed over 50% TGI with DS-1471a treatment in comparison to vehicle, regardless of gender, tumor grade, and hepatitis virus type. Protein expression analysis by sWB showed good correlation of several biomarker candidates with efficacy of DS-1471a. Among the biomarker candidates tested, CD147, the DS-1471a target molecule, showed the strongest correlation with efficacy (r = 0.78). SMAD4, which regulates the downstream signaling of the CD147 complex, and FBXO22, reported to contribute to CD147 degradation, also showed good correlation with DS-1471a efficacy (r = 0.66 and r = 0.77, respectively). By both sWB and IHC analysis, all PDX models showed negative or weak KLF5 expression, another biomarker candidate for DS-1471a that is known to be a suppressor for SMAD signaling pathway. A clear correlation between CD147 H-score and TGI was observed (r= 0.74) in these patient derived PDX models. Correlation between CD147 H-score and protein expression levels by sWB was also observed (r = 0.71). Of note, all PDX models showed moderate to high expression of CD147. Conclusion: These pre-clinical study results suggest DS-1471a may be potentially beneficial for HCC treatment. In addition, our results show correlation of DS-1471a efficacy with expression of CD147. Further studies are needed to further understand the full potential benefit of DS-1471a in clinical trials. Citation Format: Hiroshi Yuita, Ryuichi Nakamura, Jun Tsukada, Hideo Yukinaga, Huynh The Hung, Keisuke Fukuchi. Novel anti-CD147 antibody DS-1471a exerts antitumor effect in hepatocellular carcinoma Patient Derived Xenograft models and its efficacy correlates with the expression of CD147 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B127.