Antitumor activity of anti-CD30 immunotoxin (Ber-H2/saporin) in vitro and in severe combined immunodeficiency disease mice xenografted with human CD30+ anaplastic large-cell lymphoma

Laura Pasqualucci, Mariusz Wasik, Beverly A. Teicher, Leonardo Flenghi, Andrea Bolognesi, Fiorenzo Stirpe, Letizia Polito, Brunangelo Falini, Marshall E. Kadin

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80 Scopus citations

Abstract

To develop a novel adjunctive therapy for CD30 (Ki-1)+ anaplastic large- cell lymphoma (ALCL), we investigated in preclinical studies the antitumor activity of an immunotoxin (IT) constructed by coupling the plant ribosome- inactivating protein saporin (SO6) to the monoclonal antibody (MoAb) Ber-H2 that is directed against the CD30 molecule, a new member of the tumor necrosis factor receptor (TNFR) superfamily. The activity of Ber-H2/SO6 IT was tested both in vitro against the CD30+ ALCL-derived cell line JB6 and in vivo using our severe combined immunodeficiency disease (SCID) mouse model of human xenografted CD30+ ALCL. In vitro, the Ber-H2/SO6 IT was selectively and highly toxic to the JB6 cell line [50% inhibiting concentration (IC50), 3.23 x 10-12 mol/L as SO6]. In vivo, a 3-day treatment with nontoxic doses of Ber-H2/SO6 (50% of LD50) induced lasting complete remissions (CR) in 80% of mice when started 24 hours after tumor transplantation. In contrast, injection of the IT at later stages of tumor growth (mice bearing subcutaneous tumors of 40- to 60-mm3 volume), induced CR in only 6 of 21 (approximately 30%) mice and significantly delayed tumor growth rate (P < .01). This finding suggests that maximum effect of the anti-CD30 IT is observed when tumor cell burden is small. Persistent tumors from IT-treated mice consisted of CD30+ cells, thus excluding the possibility that selection of CD30-negative mutant clones during IT therapy was responsible for resistance to treatment. We conclude that Ber-H2/SO6 IT is an effective agent against CD30+ ALCL growing in SCID mice, suggesting its possible role as adjuvant therapy in patients with CD30+ ALCL refractory to standard treatments.

Original languageEnglish
Pages (from-to)2139-2146
Number of pages8
JournalBlood
Volume85
Issue number8
DOIs
StatePublished - Apr 15 1995

Keywords

  • Animals
  • Antibodies, Monoclonal/immunology
  • Child
  • Drug Administration Schedule
  • Drug Evaluation, Preclinical
  • Female
  • Humans
  • Immunotoxins/therapeutic use
  • Ki-1 Antigen/immunology
  • Lymphoma, Large-Cell, Anaplastic/drug therapy
  • Male
  • Mice
  • Mice, SCID
  • N-Glycosyl Hydrolases
  • Neoplasm Transplantation
  • Plant Proteins/therapeutic use
  • Ribosome Inactivating Proteins, Type 1
  • Saporins
  • Specific Pathogen-Free Organisms
  • Tumor Cells, Cultured

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