TY - JOUR
T1 - 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
AU - Pasqualucci, Laura
AU - Wasik, Mariusz
AU - Teicher, Beverly A.
AU - Flenghi, Leonardo
AU - Bolognesi, Andrea
AU - Stirpe, Fiorenzo
AU - Polito, Letizia
AU - Falini, Brunangelo
AU - Kadin, Marshall E.
PY - 1995/4/15
Y1 - 1995/4/15
N2 - 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.
AB - 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.
KW - Animals
KW - Antibodies, Monoclonal/immunology
KW - Child
KW - Drug Administration Schedule
KW - Drug Evaluation, Preclinical
KW - Female
KW - Humans
KW - Immunotoxins/therapeutic use
KW - Ki-1 Antigen/immunology
KW - Lymphoma, Large-Cell, Anaplastic/drug therapy
KW - Male
KW - Mice
KW - Mice, SCID
KW - N-Glycosyl Hydrolases
KW - Neoplasm Transplantation
KW - Plant Proteins/therapeutic use
KW - Ribosome Inactivating Proteins, Type 1
KW - Saporins
KW - Specific Pathogen-Free Organisms
KW - Tumor Cells, Cultured
UR - http://www.scopus.com/inward/record.url?scp=0028926611&partnerID=8YFLogxK
U2 - 10.1182/blood.v85.8.2139.bloodjournal8582139
DO - 10.1182/blood.v85.8.2139.bloodjournal8582139
M3 - Article
C2 - 7718885
AN - SCOPUS:0028926611
SN - 0006-4971
VL - 85
SP - 2139
EP - 2146
JO - Blood
JF - Blood
IS - 8
ER -