Preclinical studies with the anti-CD19-saporin immunotoxin BU12-SAPORIN for the treatment of human-B-cell tumours

• Published in: British journal of cancer Vol. 72; no. 6; pp. 1373 - 1379
• Main Authors: FLAVELL, D. J, FLAVELL, S. U, BOEHM, D. A, EMERY, L, NOSS, A, LING, N. R, RICHARDSON, P. R, HARDIE, D, WRIGHT, D. H
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.12.1995
• Subjects: Animals; Antibodies, Monoclonal - analysis; Antibodies, Monoclonal - pharmacology; Antigens, CD19 - immunology; Antigens, Neoplasm - immunology; Antineoplastic agents; Antineoplastic Agents - analysis; Antineoplastic Agents - pharmacology; Antineoplastic Agents, Phytogenic - analysis; Antineoplastic Agents, Phytogenic - pharmacology; B-Lymphocytes - metabolism; Biological and medical sciences; Burkitt Lymphoma - drug therapy; Drug Screening Assays, Antitumor; Electrophoresis, Polyacrylamide Gel; Female; General aspects; Humans; Immunotoxins - analysis; Immunotoxins - pharmacology; Leukemia, B-Cell - drug therapy; Leukemia, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Mice, SCID; N-Glycosyl Hydrolases; Neoplasm Proteins - biosynthesis; Neoplasm Transplantation; Pharmacology. Drug treatments; Plant Proteins - analysis; Plant Proteins - pharmacology; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Protein Synthesis Inhibitors - pharmacology; Ribosome Inactivating Proteins, Type 1; Saporins; Sodium Dodecyl Sulfate; Antineoplastic agent; Human; Immunotoxin; Acute; Rodentia; Cytotoxicity; Malignant hemopathy; B-Lymphocyte; Monoclonal antibody; In vitro; Dose activity relation; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Lymphoproliferative syndrome; Animal; Ribosome inactivating protein; Acute lymphocytic leukemia
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.1995.517

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.