Abstract 4553: DXC004A, a novel EGFR antibody-tubulysin analog conjugate demonstrated potential to broaden therapeutic opportunities for non-small cell lung cancer
Authors: Xiaobo Cai, Min Cao, Huihui Guo, Qingliang Yang, Yongxiang Chen, Xiangfei Kong, Yong Du, Zhicang Ye, Zhixiang Guo, Lingli Zhang, Lu Bai, Junxiang Jia, Yunxia Zheng, Wei Zheng, Jun Zheng, Wenjun Li, Yuanyuan Huang, Zhongliang Fan, Binbin Chen, Meng Dai, Robert Y. Zhao
Journal: Cancer Research (2024)

Abstract EGFR is a member of the epidermal growth factor receptor (HER) family, and the over-expression of EGFR plays an important role in the growth and progression of various tumors, including non-small cell lung cancer. Monoclonal EGFR antibodies, such as cetuximab and panitumumab, have proven efficacy in various types of cancer. However, treatment with the anti-EGFR agents can be associated with toxicities of the skin, nails, hair, and eyes. Nimotuzumab (Nimo) is the first humanized monoclonal antibody targeting EGFR and has been granted approval for use in squamous cell carcinoma of head and neck (SCCHN), glioma and nasopharyngeal cancer in different countries. In contrast to cetuximab, Nimotuzumab is distinguished by achieving higher or similar complete remission rate (CRR) or overall remission rate (ORR) of the primary tumor in clinical applications but much less toxicity, resulting in a better safety profile, which has been attributed to its about 10-fold lower affinity. Paclitaxel combined with cisplatin is the first-line chemotherapy regimen for non-small cell lung cancer. A phase 2 clinical trial has confirmed that Nimotuzumab combined with concurrent chemoradiation therapy (radiation concurrent with docetaxel and cisplatin, CCRT) was well tolerated for locally advanced squamous cell lung cancer. However, the combination strategy of Nimo-CCRT has only demonstrated similar OS and PFS to those in the CCRT group. DXC004A is an ADC drug targeting EGFR, in which a Nimotuzumab derivative and a Tubulysin B analog is conjugated by a functional linker. DXC004A is in phase I clinical trial and has demonstrated clinical activity in advanced non-small cell lung cancers and good tolerability. In vitro and in vivo results had confirmed that DXC004A monotherapy had better anti-tumor activity than the combination of Nimotuzumab and Tubulysin analog in HCC827 cell lines with high EGFR expression. Meanwhile, a single injection of low-dose DXC004 (2.5 mg/kg) in HCC827 xenograft model showed very good durable anti-tumor effect. Moreover, the combination of DXC004A with Cisplatin exhibited significantly better activities than that of Nimo-CCRT combination, DXC004A or cisplatin alone, in vitro and in vivo, which might solve the predicament of poor efficacy of Nimo-CCRT combination therapy. This synergy results suggested that DXC004A plus cisplatin would possibly be a new adjuvant therapy for non-small cell lung cancer in further clinical studies. Citation Format: Xiaobo Cai, Min Cao, Huihui Guo, Qingliang Yang, Yongxiang Chen, Xiangfei Kong, Yong Du, Zhicang Ye, Zhixiang Guo, Lingli Zhang, Lu Bai, Junxiang Jia, Yunxia Zheng, Wei Zheng, Jun Zheng, Wenjun Li, Yuanyuan Huang, Zhongliang Fan, Binbin Chen, Meng Dai, Robert Y. Zhao. DXC004A, a novel EGFR antibody-tubulysin analog conjugate demonstrated potential to broaden therapeutic opportunities for non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4553.