VEGF kinoid vaccine, a therapeutic approach against tumor angiogenesis and metastases.
Tumor growth depends on blood supply, requiring the development of new vessels, and vascular endothelial growth factor (VEGF) plays a central role in neoangiogenic processes. For this reason, VEGF represents a target for the development of new therapeutic antiangiogenic molecules. Clinical trials using anti-VEGF mAbs such as bevacizumab have validated the efficacy of this therapeutic approach but have also revealed adverse effects. Here we report that a VEGF-derived immunogen, consisting of a heterocomplex of a murine (m)VEGF and keyhole limpet hemocyanin, called "mVEGF kinoid," triggered a strong Ab immune response in mice. The anti-VEGF Abs inhibited both the proliferation of human umbilical vein endothelial cells cultured in the presence of mVEGF and the binding of mVEGF to its receptor-2 Flk-1. In mVEGF kinoid-immunized BALB/c mice challenged with syngeneic CT26 colorectal tumor cells, the number and size of lung metastases were significantly decreased. In human (h)VEGF kinoid-immunized BALB/c mice, high levels of serum Abs to hVEGF were present, and purified IgG from these mice decreased by > or =50% the tumor growth of human A673 rhabdomyosarcoma cells and HT29 colon carcinoma xenografted in Swiss nude and NOD/SCID mice, respectively. Tumor cell growth inhibition was similar to that observed in mice receiving therapeutic doses of bevacizumab. These experiments suggest that a therapeutic vaccine containing VEGF kinoid may represent a strategy for safely combating VEGF-dependent neovascularization and metastases occurring in malignant tumors.
Rad
Farhad Haghighi
FH
INSERM U602 Microenvironnement et Physiopathologie de la Différenciation, Hôpital Paul Brousse, 12 Avenue Paul Vaillant Couturier, F-94807 Villejuif, France.
Le Buanec
Hélène
H
Paturance
Sébastien
S
Larcier
Patrick
P
Genne
Philippe
P
Ryffel
Bernhard
B
Bensussan
Armand
A
Bizzini
Bernard
B
Gallo
Robert C
RC
Zagury
Daniel
D
Uzan
Georges
G
D000818:Animals; D000906:Antibodies / Q000302:isolation & purification; D000917:Antibody Formation / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000473:pathology; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007106:Immune Sera; D007114:Immunization; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000517:prevention & control; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000517:prevention & control*; D017239:Paclitaxel / Q000627:therapeutic use; D012208:Rhabdomyosarcoma / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D000906:Antibodies; D019496:Cancer Vaccines; D007106:Immune Sera; D042461:Vascular Endothelial Growth Factor A; D017239:Paclitaxel