B7-1 (CD80) as target for immunotoxin therapy for Hodgkin's disease.
In this preclinical study, the potential applicability of an anti-B7-1 immunotoxin (IT) for the treatment of Hodgkin's disease (HD) was investigated. Immunohistochemical analysis demonstrated strong expression of B7-1 on Hodgkin and Reed-Sternberg (R-S) cells and clear expression on dendritic cells, macrophages and some B-cells in tissues, but not on other tissue cells. Flow cytometric analysis demonstrated that B7-1 was expressed on a few monocytes, but not on CD34+ cells from bone marrow, resting T- or B-cells from peripheral blood or epithelial and endothelial cell lines. An anti-B7-1 immunotoxin containing the anti-B7-1 monoclonal antibody (MAb) B7-24 and saporin as toxin moiety was constructed and showed an affinity similar to that shown by the native MAb. It exhibited strong cytotoxicity against the B7-1+ B-cell line Raji (IC50 10(-11) M), R-S cell lines HDLM2, KM/H2 and L428 and also against a B7-1-transfected epithelial cell line, A431, whose parental line lacks expression of B7-1. In clonogenic assays with Raji cells or KM/H2 cells, a 3- or 4-log kill, respectively, was observed. No cytotoxicity was found against the B7-1- epithelial and endothelial cell lines or against haematopoietic progenitor cells. In conclusion, an anti-B7-1 immunotoxin was developed that had good cytotoxicity against R-S cell lines and that may be used in the elimination of R-S cells in vivo. A concomitant elimination of activated antigen-presenting cells may avoid development of antitoxin and anti-mouse Ig responses and allow repeated administration.
Vooijs
W C
WC
Department of Immuno-haematology, University Hospital Utrecht, The Netherlands.
Otten
H G
HG
van Vliet
M
M
van Dijk
A J
AJ
de Weger
R A
RA
de Boer
M
M
Bohlen
H
H
Bolognesi
A
A
Polito
L
L
de Gast
G C
GC
D000911:Antibodies, Monoclonal / Q000737:chemistry; D018122:B7-1 Antigen / Q000276:immunology* / Q000378:metabolism; D002999:Clone Cells / Q000187:drug effects; D003601:Cytotoxicity Tests, Immunologic; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006689:Hodgkin Disease / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D009504:Neutrophils / Q000276:immunology; D014018:Tissue Distribution; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen