Abstract 2862: Cetuximab-Triptolide conjugate suppresses growth of EGFR-overexpressing lung cancers through targeting RNA polymerase II

Triptolide (TPL), a natural compound isolated from a traditional Chinese medicine Thunder God Vine, exhibits strong anticancer activities; however, its clinical use is limited by low water-solubility and high systemic toxicity. To overcome these disadvantages, we developed a novel antibody drug conjugate (ADC) to specifically delivered TPL to cancer cells overexpressing EGFR which is frequently found in many types of human cancers including 70% of non-small cell lung cancers (NSCLC). The ADC is made by conjugation of TPL to Cetuximab, a clinically available anti-EGFR monoclonal antibody, via lysine residues of the antibody. Biochemical analysis showed that the average of drug-to-antibody ratio (DAR) of Cet-TPL is about 5, and the conjugation has little effect on the solubility and binding affinity of Cetuximab. The antitumor efficacy and toxicity of Cet-TPL were assessed and compared to that of TPL, Cetuximab, and a combination of these two. And the results demonstrated that Cet-TPL drastically suppresses in vitro proliferation and in vivo growth of these EGFR-overexpressing cancers including A549 and H1299 NSCLC cell lines, and two NSCLC patient-derived xenografts (PDXs); and SCC6 head-neck cancer cell line, while it did not significantly inhibit the proliferation and growth of NSCLC H520 that barely expresses EGFR. Furthermore, immunofluorescent analysis revealed that Cet-TPL is effectively transported into lysosomes of cancer cells that overexpress EGFR proteins, spared cells that don9t express EGFR. Similar to TPL, which inhibits RNA polymerase II (Pol II) mediated transcription, Cet-TPL can also effectively target Pol II and significantly induce apoptosis in these EGFR-overexpressing cancers. Compared to Triptolide, Cetuximab, or their combinations, Cet-TPL displays higher target-specific cytotoxicity against EGFR-expressed cancers and much lower in vivo systematic toxicity. In addition, Cet-TPL efficiently suppresses activated EGFR pathway in SCC6 cancer cells. Taken together, Cet-TPL represents a potent targeted therapeutic agent against EGFR-overexpressing NSCLC and other cancers. Citation Format: Keqiang Zhang, Yuelong Ma, Yuming Guo, Ting Sun, Jun Wu, David Horne, Dan Raz. Cetuximab-Triptolide conjugate suppresses growth of EGFR-overexpressing lung cancers through targeting RNA polymerase II [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2862.