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A Novel Glycoengineered Humanized Antibody Targeting DLK1 Exhibits Potent Anti-Tumor Activity in DLK1-Expressing
Koji Nakamura1, Kota Takahashi1, Izumi Sakaguchi1
1Chiome Bioscience Inc., 3-12-1 Honmachi, Shibuya-ku, Tokyo 151-0071, Japan.
Abstract:
Delta-like 1 homolog (DLK1), a non-canonical Notch ligand, is highly expressed in various malignant tumors, especially in hepatocellular carcinoma (HCC). CBA-1205 is an afucosylated humanized antibody against DLK1 with enhanced antibody-dependent cellular cytotoxicity (ADCC). The binding characteristics of CBA-1205 were analyzed by enzyme-linked immunosorbent assay and fluorescence-activated cell sorting assay. The ADCC activity of CBA-1205 was assessed. The anti-tumor efficacy of CBA-1205 was evaluated in xenograft mouse models, and toxicity and toxicokinetic profiles of CBA-1205 were evaluated in cynomolgus monkeys. CBA-1205 selectively bound to DLK1 among the Notch ligands and only to monkey and human DLK1. The binding epitope was between epidermal growth factor-like domains 1 and 2 of DLK1, which are not involved in any known physiological functions. The ADCC activity of CBA-1205 was confirmed using human peripheral blood mononuclear cells as effector cells. CBA-1205 as a single agent and in combination with lenvatinib demonstrated long-lasting anti-tumor efficacy, including tumor regression, in two liver cancer xenograft models. The toxicity and toxicokinetic profiles of CBA-1205 in cynomolgus monkeys were favorable. These findings suggest that CBA-1205 has the potential to be a useful therapeutic option for drug treatment in HCC. A phase 1 study is ongoing in patients with advanced cancers (jRCT2080225288, NCT06636435).
Insights
CBA-1205, an antibody targeting Delta-like 1 homolog (DLK1), shows promise for hepatocellular carcinoma (HCC) treatment. It demonstrated significant anti-tumor effects and favorable safety profiles in preclinical studies, warranting further clinical investigation.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Delta-like 1 homolog (DLK1) is a non-canonical Notch ligand overexpressed in hepatocellular carcinoma (HCC).
- Targeting DLK1 presents a potential therapeutic strategy for HCC and other malignancies.
Purpose of the Study:
- To characterize CBA-1205, an afucosylated humanized antibody targeting DLK1.
- To evaluate the anti-tumor efficacy and safety of CBA-1205 in preclinical models of HCC.
Main Methods:
- Enzyme-linked immunosorbent assay (ELISA) and fluorescence-activated cell sorting (FACS) for binding analysis.
- In vitro assessment of antibody-dependent cellular cytotoxicity (ADCC).
- In vivo evaluation in HCC xenograft mouse models and toxicity studies in cynomolgus monkeys.
Main Results:
- CBA-1205 selectively bound to human and monkey DLK1 at an epitope not involved in physiological functions.
- Enhanced ADCC activity was confirmed using human peripheral blood mononuclear cells.
- CBA-1205 demonstrated significant, long-lasting anti-tumor efficacy, including tumor regression, as a single agent and with lenvatinib.
- Favorable toxicity and toxicokinetic profiles were observed in non-human primates.
Conclusions:
- CBA-1205 exhibits potent anti-tumor activity against HCC via ADCC.
- The favorable preclinical profile suggests CBA-1205 is a promising therapeutic candidate for HCC.
- A Phase 1 clinical trial is currently underway for advanced cancers.
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