A defucosylated anti-PD-L1 monoclonal antibody 13-mG2a-f exerts antitumor effects in mouse xenograft models of oral squamous cell carcinoma

Biochemistry and Biophysics Reports

Tomokazu Ohishi¹  Hiroyuki Harada²  Junko Takei²  Manabu Kawada³  Mika K. Kaneko⁴  Yukinari Kato⁴ 

[1] Department of Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan;Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan;Department of Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan;Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, 18-24 Miyamoto, Numazu-shi, Shizuoka, 410-0301, Japan;

关键词: PD-L1;    Monoclonal antibody;    ADCC;    CDC;    Antitumor activity;    Oral cancer;   

DOI  :  

来源: DOAJ

【 摘 要 】

Programmed cell death ligand-1 (PD-L1) is a type I transmembrane glycoprotein expressed on antigen-presenting cells and several tumor cells, including melanoma and lung cancer cells. A strong correlation has been reported between PD-L1 expression in tumor cells and negative prognosis in cancer patients. Previously, we established an anti-PD-L1 monoclonal antibody (mAb), L1Mab-13 (IgG1, kappa), by immunizing mice with PD-L1-overexpressing CHO-K1 cells. L1Mab-13 specifically reacts with endogenous PD-L1 in lung cancer cell lines in flow cytometry and Western blot applications, and stains a plasma membrane-like pattern in lung cancer tissues via immunohistochemical analysis. In this study, we investigated whether L1Mab-13 reacts with oral cancer cell lines and exerts antitumor activities. Because L1Mab-13 lacks antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), we first converted the subclass of L1Mab-13 from IgG1 into IgG2a (13-mG2a), and further produced a defucosylated version (13-mG2a-f) using FUT8-deficient ExpiCHO-S (BINDS-09) cells. Defucosylation of 13-mG2a-f was confirmed using fucose-binding lectins, such as Aleuria aurantia and Pholiota squarrosa lectins. The dissociation constants (KD) for 13-mG2a-f in SAS and HSC-2 oral cancer cells were determined via flow cytometry to be 2.8 × 10−9 M and 4.8 × 10−9 M, respectively, indicating that 13-mG2a-f possesses extremely high binding affinity. In vitro analysis demonstrated that 13-mG2a-f showed moderate ADCC and CDC activities against SAS and HSC-2 oral cancer cells. In vivo analysis revealed that 13-mG2a-f significantly reduced tumor development in SAS and HSC-2 xenografts in comparison to control mouse IgG, even after injection seven days post-tumor inoculation. Taken together, these data demonstrate that treatment with 13-mG2a-f may represent a useful therapy for patients with PD-L1-expressing oral cancers.

【 授权许可】

Unknown