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Updated: Jan 7, 2026
Genetic Encoding of a Non-Canonical Amino Acid for the Generation of Antibody-Drug Conjugates Through a Fast Bioorthogonal Reaction
Published on: September 14, 2018
Utilización de un sustrato de tetrapéptido de elastasa como agente de enlace para conjugados de fármacos de
Lingli Gao1, Hanrui Wei1, Junyi Zhang1
1Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Tiantan Xili No. 1, Beijing 100050, China.
Abstract:
Disialoganglioside GD2 (GD2) is highly expressed in several tumors. While anti-GD2 antibodies and GD2-based antibody-drug conjugates (ADCs) have shown some therapeutic efficacy, their activity requires enhancement. Elastase, abundant in tumor microenvironment, has substrates that can serve as ADC linkers. Here, we constructed an anti-GD2 ADC by conjugating the anti-GD2 antibody Hu3F8 to the payload monomethyl auristatin E (MMAE) via an elastase-cleavable tetrapeptide linker (BMOA). Hu3F8 was produced using a 293F expression system, and its specific binding to GD2-positive cells was confirmed. The cytotoxicity of the ADCs was evaluated in both GD2-positive and GD2-negative tumor cell lines with or without elastase and its antitumor effects were investigated. It showed GD2-dependent cytotoxicity, with a significantly decreased IC50 in GD2-positive cells upon elastase addition, while no cytotoxicity was observed in GD2-negative cells. Additionally, Hu3F8-BMOA-MMAE induced significant cell cycle arrest and apoptosis in GD2-positive cells, with stronger effects in the presence of elastase. In M21 melanoma mouse models, Hu3F8-BMOA-MMAE achieved an obvious tumor inhibition rate compared to the control. These findings demonstrate that utilizing a neutrophil elastase tetrapeptide substrate as a linker in anti-GD2 ADCs is a potential strategy for the therapy of GD2-positive tumors.
