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Potent killing of HBV-related hepatocellular carcinoma by a chimeric protein of anti-HBsAg single-chain antibody and truncated Bid

Author:
Yan, Bo, Ouyang, Qing, Zhao, Zhining, Cao, Feng, Wang, Tao, Jia, Xiaofei, Meng, Yanling, Jiang, Shuai, Liu, Jiayun, Chen, Rui, Jia, Lintao, Zhang, Rui, Wen, Weihong, Jin, Boquan, Chen, Siyi, Zhao, Jing, Yang, Angang
Source:
Biomaterials 2013 v.34 no.20 pp. 4880-4889
ISSN:
0142-9612
Subject:
Hepatitis B virus, antibodies, anticarcinogenic activity, apoptosis, chimerism, growth retardation, hemagglutinins, hepatitis B antigens, hepatoma, humans, image analysis, influenza, inhibitory concentration 50, surface antigens, therapeutics
Abstract:
Targeted therapy is needed for hepatitis B virus (HBV)-mediated hepatocellular carcinoma (HCC) which shows overexpression of HBV surface antigen (HBsAg). We previously developed scFv15, a human single-chain antibody against HBsAg. Here we tested the strategic feasibility of scFv15-mediated delivery of apoptotic effectors for HBsAg-targeted HCC therapy and application of HA2 motif of influenza hemagglutinin to enhance endosome escape and antitumor effect. A class of HBsAg-targeted immunoproapoptotic molecule was generated by sequentially fusing scFv15, the furin-cleavable motif from diphtheria toxin (Fdt), HA2 and a truncated apoptotic protein Bid (tBid). The resulting scFv15-Fdt-HA2-tBid was prokaryotically expressed and functionally characterized for HBsAg-binding capacity, endosome escape activity and antitumor effect as compared with scFv15-Fdt-tBid. Both scFv15-Fdt-HA2-tBid and scFv15-Fdt-tBid retained affinity and specificity for HBsAg, and bound and selectively killed HBsAg-positive HCC cells via apoptosis. Notably, the IC₅₀ of scFv15-Fdt-HA2-tBid in HBsAg-positive PLC/PRF/5 cells was 10 times lower than that of scFv15-Fdt-tBid. In vivo imaging of antitumor activity demonstrated 95% growth inhibition of orthotopic HCC by scFv15-Fdt-HA2-tBid compared with 75% suppression by scFv15-Fdt-tBid. This study represents an extended application of the immunoproapoptotic strategy in the treatment of HBsAg-positive HCC and shows significant potential of HA2 as a functional enhancer for endosome-encapsulated antibody-conjugates.
Agid:
905154