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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

A Novel Glycoengineered Humanized Antibody Targeting DLK1 Exhibits Potent Anti-Tumor Activity in DLK1-Expressing Liver Cancer Cell Xenograft Models †

by
Koji Nakamura
*,
Kota Takahashi
,
Izumi Sakaguchi
‡,
Takumi Satoh
,
Lingyi Zhang
§,
Hiroyuki Yanai
and
Yukihito Tsukumo
*
Chiome Bioscience Inc., 3-12-1 Honmachi Shibuya-ku, Tokyo 151-0071, Japan
*
Authors to whom correspondence should be addressed.
†
This article is a revised and expanded version of a papers entitled “CBA-1205, a novel glycoengineered humanized antibody targeting DLK-1 exhibits potent anti-tumor activity in DLK-1 expressing tumor xenograft models” and “ Synergistic and long-lasing anti-tumor efficacy of CBA-1205, a novel glycoengineered humanized antibody targeting DLK-1, in combination with Lenvatinib in human HCC xenograft models.”, which were presented AACR Annual Meeting 2019, Atlanta, GA, USA, 29 March–3 April 2019, AACR Annual Meeting 2023, Orland, FL, USA, 14–19 April 2023.
‡
Current affiliation: Rena Therapeutics Inc., Shonan Health Innovation Park, 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
§
Current affiliation: Pfizer Japan Inc., 3-22-7, Yoyogi, Shibuya-ku, Tokyo 151-8589, Japan.
Int. J. Mol. Sci. 2024, 25(24), 13627; https://doi.org/10.3390/ijms252413627
Submission received: 23 October 2024 / Revised: 13 December 2024 / Accepted: 17 December 2024 / Published: 19 December 2024
(This article belongs to the Special Issue New Wave of Cancer Therapeutics: Challenges and Opportunities)
Versions Notes

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).
Keywords: Delta-like 1 homolog; CBA-1205; antibody-dependent cellular cytotoxicity; afucosylated antibody; hepatocellular carcinoma Delta-like 1 homolog; CBA-1205; antibody-dependent cellular cytotoxicity; afucosylated antibody; hepatocellular carcinoma

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MDPI and ACS Style

Nakamura, K.; Takahashi, K.; Sakaguchi, I.; Satoh, T.; Zhang, L.; Yanai, H.; Tsukumo, Y. A Novel Glycoengineered Humanized Antibody Targeting DLK1 Exhibits Potent Anti-Tumor Activity in DLK1-Expressing Liver Cancer Cell Xenograft Models. Int. J. Mol. Sci. 2024, 25, 13627. https://doi.org/10.3390/ijms252413627

AMA Style

Nakamura K, Takahashi K, Sakaguchi I, Satoh T, Zhang L, Yanai H, Tsukumo Y. A Novel Glycoengineered Humanized Antibody Targeting DLK1 Exhibits Potent Anti-Tumor Activity in DLK1-Expressing Liver Cancer Cell Xenograft Models. International Journal of Molecular Sciences. 2024; 25(24):13627. https://doi.org/10.3390/ijms252413627

Chicago/Turabian Style

Nakamura, Koji, Kota Takahashi, Izumi Sakaguchi, Takumi Satoh, Lingyi Zhang, Hiroyuki Yanai, and Yukihito Tsukumo. 2024. "A Novel Glycoengineered Humanized Antibody Targeting DLK1 Exhibits Potent Anti-Tumor Activity in DLK1-Expressing Liver Cancer Cell Xenograft Models" International Journal of Molecular Sciences 25, no. 24: 13627. https://doi.org/10.3390/ijms252413627

APA Style

Nakamura, K., Takahashi, K., Sakaguchi, I., Satoh, T., Zhang, L., Yanai, H., & Tsukumo, Y. (2024). A Novel Glycoengineered Humanized Antibody Targeting DLK1 Exhibits Potent Anti-Tumor Activity in DLK1-Expressing Liver Cancer Cell Xenograft Models. International Journal of Molecular Sciences, 25(24), 13627. https://doi.org/10.3390/ijms252413627

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