Preclinical studies with the anti-CD19-saporin immunotoxin BU12-SAPORIN for the treatment of human-B-cell tumours.
The immunotoxin BU12-SAPORIN was constructed by covalently coupling the single-chain ribosome-inactivating protein saporin to the anti-CD19 monoclonal antibody BU12 via a disulphide linker using the heterobifunctional reagent SPDP. The immunoreactivity and specificity of BU12-SAPORIN was identical to that of unmodified native BU12 antibody. BU12-SAPORIN was selectively cytotoxic in vitro in a dose-dependent manner for the CD19+ human common acute lymphoblastic leukaemia (cALL) cell line NALM-6 but exhibited no toxicity for the CD19- T-cell acute lymphoblastic leukaemia (T-ALL) cell line HSB-2. The survival of severe combined immunodeficient (SCID) mice with disseminated NALM-6 leukaemia was significantly prolonged compared with sham-treated control animals by a course of therapy with BU12-SAPORIN but not with the irrelevant anti-CD7 immunotoxin HB2-SAPORIN. BU12-SAPORIN had no therapeutic effect in SCID mice with disseminated CD19- HSB-2 leukaemia. These preclinical studies have clearly demonstrated the selective cytotoxicity of BU12-SAPORIN for CD19+ target cells both in vitro and in vivo. This, taken together with the lack of expression of the CD19 molecule by any normal life-sustaining tissue and its ubiquitous and homogeneous expression by the majority of cALL and B-NHL cells, provides the rationale for undertaking a phase I trial of systemic therapy with BU12-SAPORIN.
Simon Flavell Leukaemia Research Laboratory, University Department of Pathology, Southampton General Hospital, UK.
D J
DJ
Flavell
S U
SU
Flavell
D A
DA
Boehm
L
L
Emery
A
A
Noss
N R
NR
Ling
P R
PR
Richardson
D
D
Hardie
D H
DH
Wright
D000818:Animals; D000911:Antibodies, Monoclonal / Q000032:analysis / Q000494:pharmacology; D018941:Antigens, CD19 / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000032:analysis / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000032:analysis / Q000494:pharmacology; D001402:B-Lymphocytes / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000188:drug therapy; D004354:Drug Screening Assays, Antitumor; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000032:analysis / Q000494:pharmacology*; D015448:Leukemia, B-Cell / Q000188:drug therapy* / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D009699:N-Glycosyl Hydrolases; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009368:Neoplasm Transplantation; D010940:Plant Proteins / Q000032:analysis / Q000494:pharmacology*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D012967:Sodium Dodecyl Sulfate
D000911:Antibodies, Monoclonal; D018941:Antigens, CD19; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D000922:Immunotoxins; D009363:Neoplasm Proteins; D010940:Plant Proteins; D011500:Protein Synthesis Inhibitors; D054789:Ribosome Inactivating Proteins, Type 1; D012967:Sodium Dodecyl Sulfate; D009699:N-Glycosyl Hydrolases; D000076985:Saporins