Abstract 1535: CBA-1205, a novel glycoengineered humanized antibody targeting DLK-1 exhibits potent anti-tumor activity in DLK-1 expressing tumor xenograft models

Abstract

Abstract Delta-like 1 homolog (DLK-1) is a type I transmembrane protein with 6 tandem EGF-like motifs in extracellular region. In fetal development, DLK-1 is expressed at high levels in undifferentiated, highly proliferative tissues, such as, liver, kidney, skeletal muscle and brain. In the fetal liver, it has reported that DLK-1 positive hepatoblasts have a differentiation capability toward hepatocyte and cholangiocyte in vitro. In adult tissues, its expression is restricted in tissues such as adrenal grand and hypophysis. On the other hand, overexpression of DLK-1 in cancers have been reported in several cancer types, such as hepatocellular carcinoma (HCC), neuroblastoma, rhabdomyosarcoma, small cell lung carcinoma, myelodysplastic syndrome. Interestingly, the expression of DLK-1 is overlapped with other hepatic progenitor cell markers such as EpCAM in HCC and DLK-1 has been suggested to be a marker of cancer stem cells in HCC. According to these selective expressions of DLK-1 in cancer tissues as well as cancer stem cells in HCC, DLK-1 is supposed to be a potential target for antibody-based therapy. CBA-1205 is a novel humanized antibody (IgG1/κ) targeting DLK-1 which was glycol-engineered by GlymaxX® to potentiate antibody-dependent cellular cytotoxicity (ADCC) activity. The purpose of this study is to evaluate the anti-tumor activity of CBA-1205 in multiple human cancer cell lines in vitro and xenograft models in vivo. In vitro, CBA-1205 showed potent ADCC activity in several DLK-1 positive human cancer cell lines for different cancer types. In vivo, CBA-1205 exhibited potent anti-tumor activity in several human cancer xenograft mouse models. In a Hep3B HCC xenograft model, we evaluated dose-dependent efficacy of CBA-1205 at a dose of 0.1, 0.3, 1, 3 and 10 mg/kg by the intraperitoneally injection. The tumor growth was inhibited in a dose-dependent manner and the inhibition rate at the dose of ≥ 1 mg/kg was more than 90% compared to isotype human IgG1 control. At 10 mg/kg, CBA-1205 treatment resulted in tumor regression in all mice and 4 complete tumor elimination out of 8 mice was observed. Single injection of 10 mg/kg CBA-1205 induced tumor apoptosis and reduced the CD31 positive tumor micro vessel at 24 and 48 h after the treatment. Similar anti-tumor activity of CBA-1205 was exhibited in other xenograft model of HCC-derived HepG2 and neuroblastoma-derived SK-N-FI, BE2-C and Kelly. In conclusion, we demonstrated that a novel glycoengineered humanized anti-DLK-1 antibody, CBA-1205, exerts potent anti-tumor activity in vitro and in vivo in multiple models and could be a novel treatment option for DLK-1 expressing cancer such as HCC. First-in-human Phase I study of CBA-1205 is planned to be initiated in Q1 2020. Citation Format: Koji Nakamura, Kota Takahashi, Izumi Sakaguchi, Zhang Lingyi, Hiroyuki Yanai, Toru Kanke. CBA-1205, a novel glycoengineered humanized antibody targeting DLK-1 exhibits potent anti-tumor activity in DLK-1 expressing tumor xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1535.