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

Br J Cancer. 1995 Dec;72(6):1373-9. doi: 10.1038/bjc.1995.517.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / analysis
  • Antibodies, Monoclonal / pharmacology
  • Antigens, CD19 / immunology
  • Antigens, Neoplasm / immunology
  • Antineoplastic Agents / analysis
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents, Phytogenic / analysis
  • Antineoplastic Agents, Phytogenic / pharmacology
  • B-Lymphocytes / metabolism
  • Burkitt Lymphoma / drug therapy
  • Drug Screening Assays, Antitumor
  • Electrophoresis, Polyacrylamide Gel
  • Female
  • Humans
  • Immunotoxins / analysis
  • Immunotoxins / pharmacology*
  • Leukemia, B-Cell / drug therapy*
  • Leukemia, B-Cell / metabolism
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred ICR
  • Mice, SCID
  • N-Glycosyl Hydrolases*
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Transplantation
  • 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

Substances

  • Antibodies, Monoclonal
  • Antigens, CD19
  • Antigens, Neoplasm
  • Antineoplastic Agents
  • Antineoplastic Agents, Phytogenic
  • Immunotoxins
  • Neoplasm Proteins
  • Plant Proteins
  • Protein Synthesis Inhibitors
  • Ribosome Inactivating Proteins, Type 1
  • Sodium Dodecyl Sulfate
  • N-Glycosyl Hydrolases
  • Saporins