Pseudomonas exotoxin-based immunotoxins containing the antibody LL2 or LL2-Fab' induce regression of subcutaneous human B-cell lymphoma in mice.
We have produced immunotoxins using LL2, a monoclonal antibody which binds to human B-cell lymphomas and which, in a radioiodinated form, induced responses in lymphoma patients (D.M. Goldberg et al., J. Clin. Oncol., 9: 548-564, 1991). We have coupled LL2 to Lys-PE38KDEL, a derivative of Pseudomonas exotoxin (PE) which does not bind to the PE receptor. LL2-PE38KDEL was cytotoxic toward several Burkitt's lymphoma lines, with 50% inhibitory concentration values ranging from 2 to 6 ng/ml (10-30 pM). Another immunotoxin, LL2-Fab'-PE38KDEL, was produced by chemically coupling the Fab' fragment of LL2 to Lys-PE38KDEL. LL2-Fab'-PE38KDEL also was cytotoxic toward the Burkitt's cells, with a 50% inhibitory concentration of 1-2 ng/ml (13-24 PM). The antibody LL2 alone had no cytotoxicity toward the malignant cells, and excess LL2 prevented the cytotoxicity of LL2-PE38KDEL and LL2-Fab'-PE38KDEL. Control immunotoxins UPC-10-PE38KDEL and Mu-9-Fab'-PE38KDEL were not cytotoxic. LL2-PE38KDEL and LL2-Fab'-PE38KDEL bound to cells with 50% and 17% of the affinity of LL2, respectively. Both immunotoxins, but not UPC-10-PE38KDEL, prevented the development of CA-46 tumors in nude mice. LL2-PE38KDEL and LL2-Fab'-PE38KDEL, but not the control immunotoxins, led to complete regressions of measurable s.c. CA-46 tumors in nude mice, when given at 50% and 35% of the 50% lethal dose, respectively. LL2 alone significantly retarded the growth of CA-46 tumors but did not cause complete tumor regressions. Immunotoxins containing derivatives of Pseudomonas exotoxin can be targeted to human B-cell lymphoma and merit further study as potential therapeutic agents.
Kreitman
R J
RJ
Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892.
Hansen
H J
HJ
Jones
A L
AL
FitzGerald
D J
DJ
Goldenberg
D M
DM
Pastan
I
I
D036002:ADP Ribose Transferases; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000627:therapeutic use; D001427:Bacterial Toxins; D001835:Body Weight / Q000187:drug effects; D004334:Drug Administration Schedule; D005098:Exotoxins / Q000378:metabolism / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism / Q000627:therapeutic use*; D000922:Immunotoxins / Q000378:metabolism / Q000627:therapeutic use*; D016393:Lymphoma, B-Cell / Q000378:metabolism / Q000532:radiotherapy / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D012878:Skin Neoplasms / Q000378:metabolism / Q000532:radiotherapy / Q000628:therapy*; D014407:Tumor Cells, Cultured; D037521:Virulence Factors; D014916:Whole-Body Irradiation; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins; D005098:Exotoxins; D007140:Immunoglobulin Fab Fragments; D000922:Immunotoxins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C095913:bectumomab