Antibody-targeted cell fusion.
Membrane fusion has many potential applications in biotechnology. Here we show that antibody-targeted cell fusion can be achieved by engineering a fusogenic viral membrane glycoprotein complex. Three different single-chain antibodies were displayed at the extracellular C terminus of the measles hemagglutinin (H) protein, and combinations of point mutations were introduced to ablate its ability to trigger fusion through the native viral receptors CD46 and SLAM. When coexpressed with the measles fusion (F) protein, using plasmid cotransfection or bicistronic adenoviral vectors, the retargeted H proteins could mediate antibody-targeted cell fusion of receptor-negative or receptor-positive index cells with receptor-positive target cells. Adenoviral expression vectors mediating human epidermal growth factor receptor (EGFR)-targeted cell fusion were potently cytotoxic against EGFR-positive tumor cell lines and showed superior antitumor potency against EGFR-positive tumor xenografts as compared with control adenoviruses expressing native (untargeted) or CD38-targeted H proteins.
Molecular Medicine Program, Mayo Foundation, 200 First St. SW, Rochester, Minnesota 55905, USA.
Takafumi
T
Nakamura
Kah-Whye
KW
Peng
Sompong
S
Vongpunsawad
Mary
M
Harvey
Hiroyuki
H
Mizuguchi
Takao
T
Hayakawa
Roberto
R
Cattaneo
Stephen J
SJ
Russell
D000818:Animals; D000936:Antigen-Antibody Complex / Q000235:genetics / Q000276:immunology*; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000276:immunology; D051916:Membrane Cofactor Protein; D008561:Membrane Fusion / Q000235:genetics / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D015202:Protein Engineering / Q000379:methods; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins / Q000276:immunology; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D016896:Treatment Outcome; D014709:Vero Cells
D000936:Antigen-Antibody Complex; D015703:Antigens, CD; C497857:CD46 protein, human; D006023:Glycoproteins; D007136:Immunoglobulins; C497859:Mcp protein, mouse; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1