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

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

doi:10.1016/j.ejmech.2023.115489

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

Eur J Med Chem. 2023 Sep 5:257:115489. doi: 10.1016/j.ejmech.2023.115489. Epub 2023 May 20.

Authors

Yurong Mao¹, Ding Wei¹, Fengqing Fu², Huihui Wang¹, Ziyu Sun¹, Ziyi Huang³, Yan Wang⁴, Guangbo Zhang³, Xueguang Zhang⁵, Biao Jiang⁶, Hongli Chen⁷

Affiliations

¹ Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
² Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, NO.178 Ganjiang Road, Suzhou, 215000, China; State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, China.
³ Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, NO.178 Ganjiang Road, Suzhou, 215000, China.
⁴ State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, China; Department of Clinical Pharmacology, The First Affiliated Hospital of Soochow University, NO.899 Pinghai Road, Suzhou, 215006, China.
⁵ Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, NO.178 Ganjiang Road, Suzhou, 215000, China; State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, China; Suzhou Bright Scistar Antibody Biotech. Co., Ltd, Block 7, NO.17 ChangPing Road, Suzhou, 215152, China. Electronic address: xueguangzh@126.com.
⁶ Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Shanghai Clinical Research and Trial Center, Shanghai, 201210, China. Electronic address: jiangbiao@shanghaitech.edu.cn.
⁷ Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Shanghai Clinical Research and Trial Center, Shanghai, 201210, China. Electronic address: chenhl@shanghaitech.edu.cn.

PMID: 37235999
DOI: 10.1016/j.ejmech.2023.115489

Abstract

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.

Keywords: Antibody-drug conjugates; B7-H3; Glioblastoma; In vivo imaging.

MeSH terms

Cell Line, Tumor
Glioblastoma* / drug therapy
Humans
Immunoconjugates* / pharmacology
Immunoconjugates* / therapeutic use
Xenograft Model Antitumor Assays

Substances

CY5.5 cyanine dye
Immunoconjugates
monomethyl auristatin E
CD276 protein, human