Abstract 5732: DXC020, a novel anti-CD54 antibody conjugate with a functional linker, exhibits potent anti-tumor efficacy

Intercellular adhesion molecule-1 (ICAM-1, CD54) is a transmembrane glycoprotein of the immunoglobulin superfamily and involved in intercellular adhesion during inflammatory injury, viral infection, and tumorigenesis. The overexpression of CD54 is associated with the aggressiveness of liver cancer, non-small cell lung cancer, triple-negative breast cancer, melanoma, oral squamous cell carcinoma, and pancreatic cancer. Moreover, CD54’s role in immune cell adhesion implies that targeting this molecule could potentially enhance the immune response against cancer cells. The identification of CD54 as a candidate gene in prostate tumors exposed to chronic cisplatin administration highlights its potential as a therapeutic target in cancer, including liver cancer. These properties make CD54 a promising target for the development of antibody-drug conjugates (ADCs) and other targeted therapies in hepatocellular carcinoma (HCC) and other malignancies. Through preliminary screening, several monoclonal mouse-derived antibodies with a strong affinity for CD54 were identified. To prevent the human body from developing a human anti-mouse antibody response (HAMA), these antibodies were subjected to a process of mutation and back-mutation to humanization. This meticulous engineering resulted in humanized antibodies with affinities comparable to their murine counterparts, with a dissociation constant (KD) in the pM range. Endocytosis experiments demonstrated that these humanized antibodies effectively internalized within tumor cells, a crucial property for the efficacy of antibody-based therapies. These antibodies were then conjugated with both tubulysin based and CPT-payloads to create series of ADCs. In vitro cytotoxicity assays revealed that many of the ADCs exhibit potent cytotoxicity against a range of cancer cell lines, including non-small cell lung cancer, prostate cancer, breast cancer, liver cancer, and bile duct cancer. In vivo studies using cell-derived xenograft (CDX) models demonstrated that a single, low-dose administration of a CD54-ADC candidate, DXC020, can significantly inhibit tumor growth and even induce tumor regression in cases such as non-small cell lung cancer. These promising results indicated that CD54-ADCs could become a viable candidate for targeted therapy against tumors expressing CD54, offering a new frontier in the treatment of various cancers, in particular for hepatocellular or hepatobiliary carcinoma, which still remains a global health challenge. The successful humanization of the antibodies, their effective internalization in tumor cells, and the robust cytotoxicity of the resulting DXC020 both in vitro and in vivo models, position the CD54-ADC as a promising candidate in further clinical study. Citation Format: Xingyan Jiang, Tianyu Zhou, Junxiang Jia, Huihui Guo, Yuanyuan Huang, Hangbo Ye, Lingli Zhang, Jun Zheng, Lu Bai, Wenjun Li, Binbin Chen, Qingliang Yang, Robert Zhao. DXC020, a novel anti-CD54 antibody conjugate with a functional linker, exhibits potent anti-tumor efficacy [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 5732.