Abstract 7290: Targeting APP with GENA-119B31: A novel approach to overcoming immune checkpoint inhibitor resistance in cancer immunotherapy

Abstract Immunotherapy has profoundly transformed the treatment of advanced cancers, leading to improved clinical outcomes. Despite these successes, many patients remain unresponsive to immune checkpoint inhibitors (ICI). Consequently, there is an urgent need for novel treatments for patients who fail to respond to ICI or develop resistance. We previously identified amyloid precursor protein (APP), a type I transmembrane protein present in T cells. APP interacts with the novel immune checkpoint protein contactin 4 (CNTN4), expressed in tumor cells, and plays a central role in mediating CNTN4’s immunosuppressive signal to T cells. Moreover, profiling APP expression in tumor-infiltrating T cells from NSCLC patients treated with anti-PD-1 and chemotherapy, we observed that CD8+ Teff cells of non-responding (SD) patients predominantly exhibited elevated APP levels, while those of responding (PR) patients manifested higher levels of IFNG and PDCD1. Here, we present the in vitro and in vivo efficacy of GENA-119B31, a humanized monoclonal antibody targeting APP. GENA-119B31 binds strongly to human APP at both protein and cellular levels and effectively blocks the interaction between CNTN4 and APP. The in vitro biological activities of GENA-119B31 were evaluated using co-culture conditions with CD4+ or CD8+ T cells and A549 human cancer cells engineered to overexpress OKT3 and CNTN4. GENA-119B31 treatment demonstrated promising T cell-mediated cytotoxicity. For the in vivo study, we established CNTN4-overexpressing murine cancer cell lines (CT26/Cntn4 and Pan02/Cntn4) due to the low CNTN4 expression in mouse cells compared to human cells. This allowed for more clinically relevant conditions in efficacy assessment. GENA-119B31 showed strong anti-tumor activity in the CT26/Cntn4 syngeneic liver metastasis murine model, which has been internally confirmed to be resistant to anti-PD-1 therapy and closely mirrors clinical outcomes. The efficacy was demonstrated by a marked reduction in metastatic nodules and a decrease in hepatic damage markers in serum. In our previous study using human cancer TMA slides, pancreatic cancer, known for its resistance to ICIs, was identified as having high CNTN4 expression. In the Pan02/Cntn4 syngeneic subcutaneous murine model, GENA-119B31 showed significant anti-tumor activity, with reductions in tumor volume and weight, whereas no such effects were observed in the Pan02 WT model, which has low CNTN4 expression. These findings indicate that GENA-119B31’s anti-tumor activity is mediated through the APP/CNTN4 axis, with CNTN4 expression potentially serving as a biomarker for therapeutic response. This study confirms the potential of APP as a target for cancer immunotherapy through the use of the anti-APP antibody GENA-119B31. Our findings provide preclinical evidence supporting GENA-119B31 as a promising novel therapeutic strategy. Citation Format: Mi Young Cha, Kitae Park, Hyunuk Kim, Hyunkyung Yu, Bu-Nam Jeon, Jiyeong Lee, Youngeun Ha, Sang-Moo Park, Gyeongyeon Kim, Suah Choi, Han-Sol Kim, Hyonam Kim, Sang-Gyun Kim, Hansoo Park. Targeting APP with GENA-119B31: A novel approach to overcoming immune checkpoint inhibitor resistance in cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7290.