Improving tumor targeting and therapeutic potential of Salmonella VNP20009 by displaying cell surface CEA-specific antibodies.
Genetically modified Salmonella typhimurium VNP20009 (VNP) is a useful vehicle for cancer therapy and vaccine development but exhibits limited tumor targeting in vivo. We engineered a novel VNP derivative that expressed carcinoembryonic antigen (CEA)-specific single chain antibody fragments (scFv) on the cell surface to increase tumor-specific targeting. There was significant scFv cell surface display visualized by flow cytometry and confocal microscopy when cells were probed with fluorescently labeled CEA. Atomic force microscopy (AFM) measurements on whole bacteria confirmed binding of unlabeled CEA to the displayed scFv. The modified VNP strain exhibited increased localization in the upper gastrointestinal tract of CEA transgenic mice and accumulated in CEA-expressing tumors. Furthermore, treatment with a single dose of the VNP derivative inhibited growth of MC38CEA tumors and was associated with local accumulation of CD3(+) T cells and CD11b(+) macrophages. The display of antibody fragments on the surface of VNP represents a novel strategy for both targeting CEA-expressing tumors and increasing the immunogenicity of Salmonella-based vaccines for cancer.
Bereta
Michal
M
Department of Immunology, Jagiellonian University Medical School, Krakow, Poland.
Hayhurst
Andrew
A
Gajda
Mariusz
M
Chorobik
Paulina
P
Targosz
Marta
M
Marcinkiewicz
Janusz
J
Kaufman
Howard L
HL
D000230:Adenocarcinoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D000818:Animals; D000912:Antibodies, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D001428:Bacterial Vaccines; D039481:CD11b Antigen / Q000032:analysis; D017252:CD3 Complex / Q000032:analysis; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D041981:Gastrointestinal Tract / Q000382:microbiology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018625:Microscopy, Atomic Force; D018613:Microscopy, Confocal; D012486:Salmonella typhimurium / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology*
D000912:Antibodies, Neoplasm; D001428:Bacterial Vaccines; D039481:CD11b Antigen; D017252:CD3 Complex; D002272:Carcinoembryonic Antigen; C465023:VNP 20009; D014613:Vaccines, Attenuated