Abstract 5072: A novel antibody drug conjugateengineered for chromosome instable gastric cancer

Abstract

Abstract Gastric cancer (GC) ranks the fifth common cancer worldwide. Patients with GC suffer from a low 5-y survival rate due to the lack of effective treatments. Based on the genomic and molecular characteristics of GC, the Cancer Genome Atlas (TCGA) classified GC into four molecular subtypes: microsatellite-instable (MSI), Epstein-Barr virus-positive (EBV), chromosomal-instable (CIN), and genomically stable (GS). CIN tumors usually occur at gastroesophageal junction and normally belong to intestinal type of Lauren classification, which are characterized by DNA anueploidy, abnormal chromosomal copy numbers, and the frequent mutation of gene TP53, leading to chromosomal instability. CIN represents the most prevalent GC subtype (>50%) with a poor prognosis, highlighting a significant and unmet medical need for developing effective CIN-targeted therapeutics. Antibody drug conjugates (ADCs) are a new class of targeted therapeutics, composed of a humanized monoclonal antibody and small molecular cytotoxic drugs via chemical linkers. In this study, we designed and engineered a novel ADC targeting chromosome instable gastric cancer (CINGC). We first explored intercellular adhesion molecule-1 (ICAM1) as a novel molecular target for CINGC by characterizing its overexpression levels in a panel of human GINGC cell lines. ICAM1 is a cell surface transmembrane glycoprotein with functions of regulating cell-cell adhesion, signaling, and transendothelial migration of leukocytes to sites of inflammation. Many malignant tumors including GC were found to aberrantly overexpress ICAM1 on the surfaces of tumor cells. The high overexpression of ICAM1 on CINGC cells was validated by using flow cytometry (FCM) quantitatively and immunofluorescence (IF) staining qualitatively. To correlate it with clinically relevant GC tumor tissues, immunohistochemical (IHC) staining of ICAM1 was then conducted to determine the high expression of tumor tissue compared with para cancer tissue. The antigen-mediated endocytosis of ICAM1 monoclonal antibody was further detected by FCM quantitatively and IF visually. All the results showed that ICAM1 was an promising molecular target for CINGC, therefore, it was selected to engineer CINGC-targeted ADCs. We engineered a panel of ADC formulations with different linkers and cytotoxic payloads. We identified an optimal ADC formulation for CINGC by screening their cytotoxicity against CINGC cells in vitro in comparison with first line chemodrugs including 5-FU and oxaliplatin, which efficacy was validated by measuring its inhibitory activity on tumor growth, progression and metastasis via CINGC xenograft models. In conclusion, a novel ICAM1 ADC was designed and engineered to selectively recognize and ablate CINGC cells in vitro and in vivo. Our engineered new ADC offers the possibility of improving the clinical outcome and life quality of CINGC patients and expanding the scope of clinical use of drugs. Citation Format: Xinyan Wang, Li Yuan, Xiaoqing Guan, Shili Yao, Bing Zhu, Chun Liu, Tong Yang, Peng Guo, Jiangjiang Qin, Xiangdong Cheng. A novel antibody drug conjugateengineered for chromosome instable gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5072.