Synthesis and evaluation of homocamptothecin antibody-drug conjugates for cancer treatment

Yalong Li; Zhiyang Cheng; Wei Zhou; Lei Wang; Xiaomei Li; Guangxin Xia; Wei Lu; Shulei Zhu

doi:10.1016/j.ejmech.2024.116899

Synthesis and evaluation of homocamptothecin antibody-drug conjugates for cancer treatment

Eur J Med Chem. 2024 Dec 5:279:116899. doi: 10.1016/j.ejmech.2024.116899. Epub 2024 Sep 21.

Authors

Yalong Li¹, Zhiyang Cheng², Wei Zhou³, Lei Wang¹, Xiaomei Li¹, Guangxin Xia⁴, Wei Lu⁵, Shulei Zhu⁶

Affiliations

¹ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, PR China.
² Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, PR China; Central Research Institute, Shanghai Pharmaceuticals Holding Company Limited, Shanghai, 201203, PR China.
³ Central Research Institute, Shanghai Pharmaceuticals Holding Company Limited, Shanghai, 201203, PR China.
⁴ Central Research Institute, Shanghai Pharmaceuticals Holding Company Limited, Shanghai, 201203, PR China. Electronic address: [email protected].
⁵ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, PR China. Electronic address: [email protected].
⁶ Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, PR China. Electronic address: [email protected].

PMID: 39321689
DOI: 10.1016/j.ejmech.2024.116899

Abstract

As an emerging tumor therapeutic strategy, antibody-drug conjugates (ADCs) overcome the high toxicity of traditional small molecule chemotherapy and improve the targeting of treatment. In this study, we successfully constructed a novel ADC, Tras-16b, for the first time using homocamptothecin 16b as the payload. Tras-16b, at a dose of 3 mg/kg, exhibited comparable anti-tumor activity to Enhertu and demonstrated an enhanced safety profile in the NCI-N87 xenograft model. Notably, this is the first ADC developed based on homocamptothecin, marking a significant advancement with promising prospects for the structural modification of camptothecin ADCs.

Keywords: Antibody-drug conjugates (ADCs); Cancer treatment; Homocamptothecin.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Camptothecin* / analogs & derivatives
Camptothecin* / chemical synthesis
Camptothecin* / chemistry
Camptothecin* / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Female
Humans
Immunoconjugates* / chemistry
Immunoconjugates* / pharmacology
Mice
Mice, Inbred BALB C
Mice, Nude
Molecular Structure
Structure-Activity Relationship

Substances

Camptothecin
Immunoconjugates
homocamptothecin
Antineoplastic Agents