Strong humoral response elicited by a DNA vaccine targeting gastrin-releasing peptide with optimized adjuvants inhibits murine prostate carcinoma growth in vivo.
Previous studies demonstrated that the elevated expression and receptor binding of gastrin-releasing peptide (GRP) in various types of cancer suggest that GRP might be a putative target for immunotherapy in neoplastic diseases. DNA vaccine for hormone/growth factor immune deprivation represents a feasible and attractive approach for cancer treatment; nevertheless, there is still a need to increase the potency of the DNA vaccine. Here, based on six copies of the B cell epitope GRP(18-27) in a linear alignment as an immunogen, we designed several anti-GRP DNA vaccines containing different combinations of immunoadjuvants, such as HSP65, tetanus toxoid(830-844) (T), pan HLA-DR-binding epitope (PADRE) (P), and mycobacterial HSP70(407-426) (M), on a backbone of pCR3.1 plasmid vector with eight 5'-GACGTT-3' CpG motifs and the VEGF183 signal peptide (VS). The effects of these immunoadjuvants in enhancing GRP-specific humoral immune response were then evaluated by comparing the respective immunogenicity and antitumor effects. Immunization of mice with pCR3.1-VS-HSP65-TP-GRP6-M2 elicited much higher levels of specific anti-GRP antibodies and more effectively inhibited the growth of a GRP-dependent tumor RM-1 in vivo. Interestingly, plasmids encoding for 2HSP70(407-426), but not the one with 1 or 3HSP70(407-426) showed stronger immune stimulatory potential as well as impressive antitumor activity, suggesting that 2HSP70(407-426) is an efficient molecular adjuvant for developing self-epitope vaccines. The highly immunogenic, potent anti-tumorigenic and antiangiogenesis activities of the anti-GRP DNA vaccine offered a novel immunotherapeutic approach in the treatment of GRP-dependent tumors and their complications.
Lu
Yong
Y
Minigene Pharmacy Laboratory, Biopharmaceutical College, China Pharmaceutical University, Nanjing, People's Republic of China.
Mekoo
Didier J L
DJ
Ouyang
Kedong
K
Hu
Xiangbing
X
Liu
Yanhua
Y
Lin
Ming
M
Jin
Liang
L
Cao
Rongyue
R
Li
Taiming
T
Zhang
Yankai
Y
Fan
Hao
H
Liu
Jingjing
J
D000276:Adjuvants, Immunologic / Q000235:genetics / Q000627:therapeutic use*; D000818:Animals; D015153:Blotting, Western; D019496:Cancer Vaccines / Q000235:genetics / Q000627:therapeutic use*; D049109:Cell Proliferation; D002846:Chromatography, Affinity; D004797:Enzyme-Linked Immunosorbent Assay; D019886:Gastrin-Releasing Peptide / Q000276:immunology*; D006360:Heat-Shock Proteins / Q000235:genetics; D056724:Immunity, Humoral; D007114:Immunization; D017780:Malaria Vaccines / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D019444:Vaccines, DNA / Q000235:genetics / Q000627:therapeutic use*
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D006360:Heat-Shock Proteins; D017780:Malaria Vaccines; C401223:PADRE 45; D019444:Vaccines, DNA; D019886:Gastrin-Releasing Peptide