Abstract 5242: Rationally designing a radionuclide drug conjugate for heterogeneous genomically stable gastric cancer

Abstract

Abstract Background: Gastric cancer (GC) is one of common malignant tumors with a 5-year survival rate less than 10% for patients in advanced stages. Genomically stable gastric cancer (GSGC), featuring the worst prognosis of four subtypes of GC based on its molecular characteristics, receives limited benefits from recently approved HER2-targeted antibody drug conjugates (ADCs) due to the lack and heterogeneity of tumoral HER2 expression. Currently, radionuclide drug conjugates (RDCs) have attracted great attention in targeted therapy, owing to its unique advantages of radiation-associated direct DNA damages and relatively long radiation distances. These unique advantages enable RDCs to efficiently and broadly ablate both cancer cells and cancer-associated stromal cells in heterogeneous tumor microenvironment without being internalized by target cells, featuring a novel and more efficient “bystander killing” effect than linker-cleavable ADCs. Here, a RDC was developed by rationally screening GSGC-targeting antibodies and radionuclides for targeted treatment of GSGCs. Meanwhile, the “bystander killing” effect of the RDC will be quantitatively determined and compared with conventional linker-cleavable ADCs. Results: First, ICAM1 was identified as a more preferable molecular target relatively to HER2 in human GSGCs via flow cytometric analyses. Next, a RDC was constructed by covalently conjugating anti-ICAM1 antibody with radionuclide 131I via indogen chemistry. 131I, the RDC warhead emitting β-particles with an emission range of approximately 0.8 mm, is a clinically-used radionuclide with FDA approval for treating several tumors. Then, the half maximum inhibitory concentrations (IC50s) of constructed 131I conjugated ICAM1 antibody (131I-ICAM1) was evaluated in human GSGC cell lines. Its inherent bystander killing effect was validated by measuring the viability of ICAM1 negative cells co-incubated with ICAM1 positive cells in the treatment of 131I-ICAM1, in comparison with ADC of the same target. Ultimately, the anti-tumor efficacy of 131I-ICAM1 was verified in heterogeneous GSGC models. Simultaneously, the histopathological damages to normal organs by 131I-ICAM1 was minimized by optimizing its dose. Conclusions: In this study, we constructed a rationally designed 131I-ICAM1 by conjugating ICAM-1 antibody and clinical available radionuclide 131I and investigated the intrinsic bystander killing effect of this RDC in ablating heterogeneous GSGCs. Our research explored the potential of 131I-ICAM1 as a promising targeted therapeutic candidate for treating heterogeneous GSGCs. Citation Format: Le Yang, Rui Xu, Peng Guo, Heqing Yi, Xiangdong Cheng. Rationally designing a radionuclide drug conjugate for heterogeneous genomically stable 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 5242.