Details

Autor(en) / Beteiligte

• Mao, Yurong
• Wei, Ding
• Fu, Fengqing
• Wang, Huihui
• Sun, Ziyu
• Huang, Ziyi
• Wang, Yan
• Zhang, Guangbo
• Zhang, Xueguang
• Jiang, Biao
• Chen, Hongli

Titel

Development of a MMAE-based antibody-drug conjugate targeting B7–H3 for glioblastoma

Ist Teil von

• European journal of medicinal chemistry, 2023-09, Vol.257, p.115489-115489, Article 115489

Ort / Verlag

France: Elsevier Masson SAS

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• B7–H3 (immunoregulatory protein B7-homologue 3) is overexpressed in many cancer cells with limited expression in normal tissues, considered to be a promising target for tumor therapeutics. Clinical trials of antibody-drug conjugates (ADCs) against different targets for glioblastoma have been investigated and showed potent efficacies. In this study, we developed a homogeneous ADC 401-4 with a drug-to-antibody ratio (DAR) of 4, which was prepared by conjugation of Monomethyl auristatin E (MMAE) to a humanized anti-B7-H3 mAb 401, through a divinylsulfonamide-mediated disulfide re-bridging approach. In vitro studies, 401-4 displayed specific killing against B7–H3-expressing tumors and was more effective in cells with higher levels of B7–H3 for different glioblastoma cells. 401-4 was furthered labeled with Cy5.5 to yield a fluorescent conjugate 401-4-Cy5.5. The in vivo imaging studies showed that the conjugate accumulated in tumor regions and exhibited the ability to target-specific delivery. In addition, significant antitumor activities for 401-4 was observed against U87-derived tumor xenografts in a dose dependent manner. [Display omitted] •A homogeneous ADC 401-4 with DAR of 4 targeting B7–H3 was prepared.•ADC 401-4 was more effective in cells with higher levels of B7–H3 for different glioblastoma cells.•Fluorescently labeled conjugate 401-4-Cy5.5 showed that the conjugate accumulated in tumor regions.•In vivo 401-4 exhibited significant antitumor activities against tumor xenografts in a dose dependent manner.