Antitumor effects of an engineered and energized fusion protein consisting of an anti-CD20 scFv fragment and lidamycin |
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Authors: | Hong Fang QingFang Miao ShengHua Zhang Xin Cheng DongSheng Xiong YongSu Zhen |
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Institution: | Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. |
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Abstract: | Antibody-based fusion proteins are the next generation of antibody therapies for cancer and other diseases. CD20 antigen,
which is overexpressed on cell membranes in nearly 95% of cases of B-cell Non-Hodgkin’s Lymphoma, is an attractive target
for the therapy of B-lymphoid malignancies. Lidamycin (LDM) is a potent enediyne-containing antitumor antibiotic that now
has entered phase II clinical trials. In this study, we prepared an engineered fusion protein, scFv-LDP, consisting of an
anti-CD20 scFv fragment and the apoprotein LDP of LDM using DNA recombination. After purification and refolding, scFv-LDP
was found to bind specifically to CD20-positive lymphoma cells using ELISA and indirect immunofluorescent cytochemical staining
assays. The energized fusion protein scFv-LDP-AE was obtained using molecular reconstitution of the active chromophore AE
of LDM and scFv-LDP. MTT assay revealed potent cytotoxicity of scFv-LDP-AE to CD20-positive Raji and Daudi cells, with IC50 values of 1.21×10−11 and 6.24×10−11 mol L−1, respectively. An in vivo subcutaneous xenograft model of CD20-positive B cell lymphoma in BALB/c (nu/nu) mice was also utilized. Drugs were given
intravenously on day 14 and 21 after tumor transplantation. In terms of maximal tolerated doses, scFv-LDP-AE at 0.3 mg kg−1 suppressed tumor growth by 79.3%, and LDM at 0.05 mg kg−1 by 68.6% (P<0.05). Results suggested scFv-LDP-AE could be a potential candidate for tumor-targeting therapy. |
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