Antitumor activities of dFv-LDP-AE: An enediyne-energized fusion protein targeting tumor-associated antigen gelatinases

Zhong, Genshen; Wu, Minna; Guo, Xiaofang; Zhang, Shenghua; Qin, Miao; Zhen, Yong‐Su

doi:10.3892/or.2012.1910

Cited by 7 publications

(7 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, targeting therapy against gelatianses might present a potential approach for the treatment of pancreatic cancer. In our previous study, the anti-gelatinases scFv with lidamycin fusion protein dFv-LDP-AE demonstrated potent antitumor efficacy in lung cancer and liver cancer 8 , 9 , it is known that the internalization property for an antibody or its conjugate is very important to maximize it biofunction, so in order to further improve the antitumor efficacy, in this study, an (Arg) 9 penetrating peptide was integrated into the dFv-LDP to generate the dFv-R-LDP fusion protein (Fig. 1 ), after that, the antitumor efficacy of two energized fusion protein dFv-LDP-AE and dFv-R-LDP-AE against pancreatic cancer were evaluated.…”

Section: Discussionmentioning

confidence: 96%

“…It was reported that gelatianses were related with the prognosis and microvessel density (MVD) in patients with pancreatic cancer, and would be a potential target for cancer therapy 6 , 7 . Antibody against gelatinases had been developed and the conjugation of scFv against gelatinases with lidamycin already showed potent antitumor efficacy in several kinds of cancer types, such as lung cancer, hepatoma 5 , 8 , 9 . In this study, the antitumor efficacy of scFv-based fusion protein against gelatianses conjugated with lidamycin was investigated in pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

An arginine-rich cell penetrating peptide contained anti-gelatinase scFv-LDM fusion protein shows potent antitumor efficacy in pancreatic cancer

Zhong

Yang

et al. 2018

J. Cancer

View full text Add to dashboard Cite

Pancreatic cancer (PC) is one of the most dangerous cancers with less than 5% survival rate in 5 years. This study was to evaluate the antitumor activities of dFv-LDP-AE and dFv-R-LDP-AE, two energized fusion protein targeting gelatinases, on pancreatic cancer. The fusion protein dFv-LDP-AE consists of two tandem anti-gelatianses scFv and an enediyne antibiotic lidamycin (LDM) for receptor binding and cell killing. To improve the penetration capability, the fusion protein dFv-LDP-AE was integrated with an arginine-rich cell penetrating peptide (Arg)9 and then generated the fusion protein dFv-R-LDP-AE. The current study demonstrated that dFv-LDP and dFv-R-LDP had high affinity with the antigen gelatinases and PC cells, the integration of (Arg)9 could increase the penetration rate of fusion protein in SW-1990 and PANC-1 cells. After enediyne-energized with chromophore of lidamycin, the energized fusion protein dFv-LDP-AE and dFv-R-LDP-AE showed potent cytotoxicity to PC cells and could induced the robust cell apoptosis and necrosis in vitro. Western blot showed that dFv-R-LDP-AE could increase PARP cleavage, and inhibited the expression of VEGF, Cyclin D1, Cox-2 and Bcl-2 in SW-1990 and PANC-1 cells. In vivo, at a tolerated dosage, dFv-LDP, dFv-LDP-AE and dFv-R-LDP-AE inhibited tumor growth by 20.42%, 56.31% (P < 0.01, compared to that of control) and 74.2% (P < 0.05, compared to that of dFv-LDP-AE) in pancreatic cancer SW-1990 xenografted mice, respectively. Moreover, the results of in vivo optical imaging showed that fusion protein dFv-R-LDP displayed prominent accumulation in the tumor in SW-1990 xenografted mice and Capan-2 orthotopic transplanted mice. These results showed that dFv-R-LDP-AE possessed potent antitumor efficacy on PC, which indicating it could be a promising candidate for targeting therapy of PC.

show abstract

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

An arginine-rich cell penetrating peptide contained anti-gelatinase scFv-LDM fusion protein shows potent antitumor efficacy in pancreatic cancer

Zhong

Yang

et al. 2018

J. Cancer

View full text Add to dashboard Cite

show abstract

“…The apoprotein and the chromophore may be detached and reassembled under certain conditions (6,15). Taking advantage of the targeting property of antibodies or antibody fragments, types of chimeric fusion proteins, composed of antibody fragments and apoprotein, were created and then reassembled with the detached chromophore (6–9). In the present study, two fusion proteins CDR3-LDP and CDR3-LDP-CDR3, composed of a heavy-chain CDR3 domain fused with the lidamycin apoprotein, were designed.…”

Section: Discussionmentioning

confidence: 99%

Small antibody fusion proteins with complementarity-determining regions and lidamycin for tumor targeting therapy

Zhong

Guo

et al. 2013

Oncology Letters

Self Cite

View full text Add to dashboard Cite

Gelatinases are overexpressed in several types of maligancies and tumor stromal cells. Lidamycin is an enediyne antitumor antibiotic, which is composed of an apoprotein (LDP) and an active chromophore (AE). It is known that the heavy-chain complementarity-determining region-3 (CDR3) domain of scFv is important in antibody affinity. The aim of this study was to prepare the enediyne-energized fusion proteins with a heavy-chain CDR3 domain of anti-gelatinases scFv and lidamycin, and to evaluate their antitumor efficiency. Fusion proteins comprising the CDR3 domain and the lidamycin apoprotein were generated, and ELISA, immunofluorescence and FACS were used to analyze the binding of the fusion protein with antigen gelatinases. The purified fusion proteins were assembled with the lidamycin chromophore, and the antitumor effects were evaluated in vitro and in vivo. It was found that the CDR3-LDP and CDR3-LDP-CDR3 fusion proteins demonstrated high affinity towards antigen gelatinases. Following stimulation of CDR3-LDP with enediyne, the results of MTT showed potent cytotoxicity towards tumor cells; the IC50 values of CDR3-LDP-AE to HepG2 and Bel-7402 tumor cells were 1.05×10−11 and 6.6×10−14 M, respectively. In addition, CDR3-LDP-AE displayed a potent antitumor effect in H22 cell xenografts in mice; the combination of CDR3-LDP (10 mg/kg) and CDR3-LDP-AE (0.25 and 0.5 mg/kg) revealed that the tumor inhibitory rates were 85.2 and 92.7%, respectively (P<0.05 compared with CDR3-LDP-AE). In conclusion, these results suggest that the CDR3-LDP fusion protein and its analog CDR3-LDP-AE may both be promising candidates for tumor targeting therapy.

show abstract

“…After cell attachment, the FITC-labeled HSA, FITC-labeled DF-HSA or/and TMR-dextran were added at a final concentration of 1 mg/ml and incubated for another 0 to 5 h at 37°C. The experimental operation of FITC labeling protein was performed as the described protocol [ 49 ]. At the end of the incubation period, cells were washed three times in cold PBS and then immediately fixed in 4% paraformaldehyde for 15 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

A recombinantly tailored β-defensin that displays intensive macropinocytosis-mediated uptake exerting potent efficacy against K-Ras mutant pancreatic cancer

Shang

Sheng

et al. 2016

Oncotarget

Self Cite

View full text Add to dashboard Cite

K-Ras mutant pancreatic cancer cells display intensive macropinocytosis, indicating that this process may be exploited in the design of anticancer targeted therapies. In this study, we constructed a macropinocytosis-oriented recombinantly tailored defensin (DF-HSA) which consists of human β-defensin-2 (DF) and human serum albumin (HSA). The macropinocytosis intensity and cytotoxicity of DF-HSA were investigated in K-Ras mutant MIA PaCa-2 cells and wild-type BxPC-3 cells. As found, the DF-HSA uptake in MIA PaCa-2 cells was much higher than that in wild-type BxPC-3 cells. Correspondingly, the cytotoxicity of DF-HSA to MIA PaCa-2 cells was more potent than that to BxPC-3 cells. In addition, the cytotoxicity of DF-HSA was much stronger than that of β-defensin HBD2. DF-HSA suppressed cancer cell proliferation and induced mitochondrial pathway apoptosis. Notably, DF-HSA significantly inhibited the growth of human pancreatic carcinoma MIA PaCa-2 xenograft in athymic mice at well tolerated dose. By in vivo imaging, DF-HSA displayed a prominent accumulation in the tumor. The study indicates that the recombinantly tailored β-defensin can intensively enter into the K-Ras mutant pancreatic cancer cells through macropinocytosis-mediated process and exert potent therapeutic efficacy against the pancreatic carcinoma xenograft. The novel format of β-defensin may play an active role in macropinocytosis-mediated targeting therapy.

show abstract

Antitumor activities of dFv-LDP-AE: An enediyne-energized fusion protein targeting tumor-associated antigen gelatinases

Cited by 7 publications

References 18 publications

An arginine-rich cell penetrating peptide contained anti-gelatinase scFv-LDM fusion protein shows potent antitumor efficacy in pancreatic cancer

An arginine-rich cell penetrating peptide contained anti-gelatinase scFv-LDM fusion protein shows potent antitumor efficacy in pancreatic cancer

Small antibody fusion proteins with complementarity-determining regions and lidamycin for tumor targeting therapy

A recombinantly tailored β-defensin that displays intensive macropinocytosis-mediated uptake exerting potent efficacy against K-Ras mutant pancreatic cancer

Contact Info

Product

Resources

About