B-cell restricted saporin immunotoxins: activity against B-cell lines and chronic lymphocytic leukemia cells.
B cell-restricted immunotoxins were constructed by conjugating anti-B monoclonal antibodies to saporin, the major ribosome inactivating protein from the seeds of the plant Saponaria officinalis. HD37-SAP is directed against CD19, the broadest B cell-specific determinant. HD39-SAP and HD6-SAP recognize two different epitopes on the CD22 molecule, an antigen present on the cell surface of B cells at late stages of differentiation. All three immunotoxins inhibited DNA synthesis and protein synthesis in target B lymphoma cells with a dose-related effect, in short incubation times and in the absence of potentiators. A clonogenic assay demonstrated that all immunotoxins could eliminate more than two logs of clonogenic malignant B cells with a two-hour incubation at concentrations not toxic to cells not bearing target antigens. The immunotoxin activity was evaluated by DNA synthesis inhibition in fresh B-chronic lymphocytic leukemia cells (B-CLL) stimulated to proliferate by incubation with an antibody specific for the receptor of C3b complement component (CR1) plus B cell growth factor. B-CLL cell DNA synthesis was actively inhibited by treatment at low immunotoxin concentration without need of potentiators. Immunotoxins exerted their effect also in whole blood of CLL patients under conditions achievable in vivo. We conclude that B cell-restricted immunotoxins HD37-SAP, HD39-SAP, and HD6-SAP are good candidates for in vivo therapy of B-cell malignancies.
Bregni
M
M
Division of Medical Oncology, Istituto Nazionale Tumori, Milano, Italy.
Siena
S
S
Formosa
A
A
Lappi
D A
DA
Martineau
D
D
Malavasi
F
F
Dorken
B
B
Bonadonna
G
G
Gianni
A M
AM
D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015703:Antigens, CD; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D015815:Cell Adhesion Molecules; D004273:DNA, Neoplasm / Q000096:biosynthesis; D006801:Humans; D000922:Immunotoxins / Q000633:toxicity*; D066298:In Vitro Techniques; D037102:Lectins; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000628:therapy; D008213:Lymphocyte Activation; D009699:N-Glycosyl Hydrolases; D010940:Plant Proteins / Q000008:administration & dosage*; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D051918:Sialic Acid Binding Ig-like Lectin 2; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte; C497867:CD22 protein, human; D015815:Cell Adhesion Molecules; D004273:DNA, Neoplasm; D000922:Immunotoxins; D037102:Lectins; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D051918:Sialic Acid Binding Ig-like Lectin 2; D009699:N-Glycosyl Hydrolases; D000076985:Saporins