A novel enediyne‐integrated antibody–drug conjugate shows promising antitumor efficacy against CD30+ lymphomas. Issue 3 (26th January 2018)

• Record Type: Journal Article
• Authors: Wang, Rong; Li, Liang; Zhang, Shenghua; Li, Yi; Wang, Xiaofei; Miao, Qingfang; Zhen, Yongsu
• Is Part Of: Molecular oncology. Volume 12:Issue 3(2018)
• Page Start: 339
• Page End: 355
• Publication Date: 2018-01-26
• Subjects: ADC -- CD30‐targeting -- cytotoxicity -- lymphoma -- therapeutic efficacy; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.12166
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : CD30 is a 120‐kDa type I transmembrane glycoprotein belonging to the tumor necrosis factor receptor superfamily. Overexpression of CD30 has been reported in Hodgkin's lymphoma (HL) and anaplastic large‐cell lymphoma (ALCL). CD30‐targeted treatment with antibody–drug conjugates (ADCs) can lead to promising clinical benefit. Lidamycin (LDM), consisting of an apoprotein LDP and an active enediyne chromophore AE, is a member of the enediyne antibiotic family and one of the most potent antitumor agents. AE and LDP can be dissociated and reconstituted under certain conditions in vitro . LDM is an ideal payload for the preparation of ADCs. In this study, we show the generation, production, and antitumor activity of anti‐CD30‐LDM, a novel ADC which consists of the intact anti‐CD30 antibody and LDM. First, the anti‐CD30‐LDP fusion protein was constructed and expressed in CHO/dhFr − cells. Anti‐CD30‐LDP showed specific and high‐affinity binding to CD30 and could be internalized into target cells. It also exhibited excellent tumor‐targeting capability in vivo . Next, anti‐CD30‐LDM was prepared by assembling the enediyne molecule AE to the fusion protein anti‐CD30‐LDP. Anti‐CD30‐LDM was highly cytotoxic to HL and ALCL cell lines, with IC50 values of 5–50 pm . It can also induce cell apoptosis and G2/M cell cycle arrest. In the Karpas299 xenograft model, the tumor growth was inhibited by 87.76% in mice treated with anti‐CD30‐LDM and with no discernible adverse effects. Taken together, anti‐CD30‐LDM shows attractive tumor‐targeting capability and antitumor efficacy both in vitro and in vivo and could be a promising candidate for the treatment of CD30 + lymphomas. Abstract : We have designed and developed a novel antibody–drug conjugate (ADC), anti‐CD30‐LDM, prepared using DNA recombination and molecular reconstitution. The ADC displays specific affinity and extremely potent cytotoxicity to CD30 overexpressed tumor cells and highly therapeutic efficacy against CD30‐positive tumor model in NOD/SCID mice. Our results suggest that anti‐CD30‐LDM could be a promising candidate for the treatment of CD30 + lymphomas.