Anti-CD30 (BER-H2) immunotoxins containing the type-1 ribosome-inactivating proteins momordin and PAP-S (pokeweed antiviral protein from seeds) display powerful antitumour activity against CD30+ tumour cells in vitro and in SCID mice

Adelmo Terenzi, Andrea Bolognesi, Laura Pasqualucci, Leonardo Flenghi, Stefano Pileri, Harald Stein, Kadin Marshall, Barbara Bigerna, Letizia Polito, Pier Luigi Tazzari, Massimo F. Martelli, Fiorenzo Stirpe, Brunangelo Falini

Research output: Contribution to journalArticle

Abstract

The anti-CD30 immunotoxin (IT) Ber-H2/ saporin is effective in patients with refractory Hodgkin's disease. However, responses are short and partial, one of the main reasons being the inability to repeal IT doses because of formation of human antibodies against the murine antibody and/or the toxin. To overcome this problem, we constructed two new anti-CD30 ITs by covalently linking the mouse monoclonal antibody Ber-H2 to the type 1 ribosome-inactivating proteins (RIPs) momordin (MOM) and pokeweed antiviral protein from seeds (PAP-S), which do not cross-react with each other or with saporin. Both ITs inhibited protein synthesis by Hodgkin's disease and anaplastic large-cell lymphoma (ALCL)-derived CD30+ target cell lines with a very high efficiency (IC50 ranging from <5 × 10-13 M to 2-75 × 10-11 M, as RIP). In a SCID mouse model of xenografted CD30+ human ALCL, a 3d treatment with non-toxic doses of Ber-H2/MOM (50% LD50), started 24h after transplantation, prevented tumour development in about 40% of the animals and significantly delayed tumour growth rate in the others. Main toxicity signs in mice and rabbits were a dose-related increase of serum transaminases (AST and ALT) and creatine phosphokinase (CPK). LD50 (as RIP) in Swiss mice was 7 mg/kg for Ber-H2/MOM and 0-45 mg/kg for Ber-H2/PAP-S. Sequential administration of two anti-CD30 ITs (Ber-H2/MOM and Ber-H2/saporin) was well tolerated and did not result in formation of antibodies cross-reacting with the two plant toxins. The results presented in this paper suggest that, in the future, sequential administration of anti-CD30 humanized antibodies linked to antigenically distinct type 1 RIPs (saporln, MOM, PAP-S) should be feasible.

Original languageEnglish
Pages (from-to)872-879
Number of pages8
JournalBritish Journal of Haematology
Volume92
Issue number4
Publication statusPublished - 1996

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Type 1 Ribosome Inactivating Proteins
Immunotoxins
SCID Mice
Seeds
Ribosome Inactivating Proteins
Anaplastic Large-Cell Lymphoma
Lethal Dose 50
Neoplasms
Hodgkin Disease
Antibody Formation
Antibodies, Monoclonal, Humanized
Creatine Kinase
Transaminases
Inhibitory Concentration 50
Transplantation
Monoclonal Antibodies
In Vitro Techniques
momordin
pokeweed antiviral protein
Rabbits

Keywords

  • CD30 antigen
  • Hodgkin's disease
  • Immunotoxins
  • Monoclonal antibodies
  • Ribosome-inactivating proteins

ASJC Scopus subject areas

  • Hematology

Cite this

Anti-CD30 (BER-H2) immunotoxins containing the type-1 ribosome-inactivating proteins momordin and PAP-S (pokeweed antiviral protein from seeds) display powerful antitumour activity against CD30+ tumour cells in vitro and in SCID mice. / Terenzi, Adelmo; Bolognesi, Andrea; Pasqualucci, Laura; Flenghi, Leonardo; Pileri, Stefano; Stein, Harald; Marshall, Kadin; Bigerna, Barbara; Polito, Letizia; Tazzari, Pier Luigi; Martelli, Massimo F.; Stirpe, Fiorenzo; Falini, Brunangelo.

In: British Journal of Haematology, Vol. 92, No. 4, 1996, p. 872-879.

Research output: Contribution to journalArticle

Terenzi, A, Bolognesi, A, Pasqualucci, L, Flenghi, L, Pileri, S, Stein, H, Marshall, K, Bigerna, B, Polito, L, Tazzari, PL, Martelli, MF, Stirpe, F & Falini, B 1996, 'Anti-CD30 (BER-H2) immunotoxins containing the type-1 ribosome-inactivating proteins momordin and PAP-S (pokeweed antiviral protein from seeds) display powerful antitumour activity against CD30+ tumour cells in vitro and in SCID mice', British Journal of Haematology, vol. 92, no. 4, pp. 872-879.
Terenzi, Adelmo ; Bolognesi, Andrea ; Pasqualucci, Laura ; Flenghi, Leonardo ; Pileri, Stefano ; Stein, Harald ; Marshall, Kadin ; Bigerna, Barbara ; Polito, Letizia ; Tazzari, Pier Luigi ; Martelli, Massimo F. ; Stirpe, Fiorenzo ; Falini, Brunangelo. / Anti-CD30 (BER-H2) immunotoxins containing the type-1 ribosome-inactivating proteins momordin and PAP-S (pokeweed antiviral protein from seeds) display powerful antitumour activity against CD30+ tumour cells in vitro and in SCID mice. In: British Journal of Haematology. 1996 ; Vol. 92, No. 4. pp. 872-879.
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abstract = "The anti-CD30 immunotoxin (IT) Ber-H2/ saporin is effective in patients with refractory Hodgkin's disease. However, responses are short and partial, one of the main reasons being the inability to repeal IT doses because of formation of human antibodies against the murine antibody and/or the toxin. To overcome this problem, we constructed two new anti-CD30 ITs by covalently linking the mouse monoclonal antibody Ber-H2 to the type 1 ribosome-inactivating proteins (RIPs) momordin (MOM) and pokeweed antiviral protein from seeds (PAP-S), which do not cross-react with each other or with saporin. Both ITs inhibited protein synthesis by Hodgkin's disease and anaplastic large-cell lymphoma (ALCL)-derived CD30+ target cell lines with a very high efficiency (IC50 ranging from <5 × 10-13 M to 2-75 × 10-11 M, as RIP). In a SCID mouse model of xenografted CD30+ human ALCL, a 3d treatment with non-toxic doses of Ber-H2/MOM (50{\%} LD50), started 24h after transplantation, prevented tumour development in about 40{\%} of the animals and significantly delayed tumour growth rate in the others. Main toxicity signs in mice and rabbits were a dose-related increase of serum transaminases (AST and ALT) and creatine phosphokinase (CPK). LD50 (as RIP) in Swiss mice was 7 mg/kg for Ber-H2/MOM and 0-45 mg/kg for Ber-H2/PAP-S. Sequential administration of two anti-CD30 ITs (Ber-H2/MOM and Ber-H2/saporin) was well tolerated and did not result in formation of antibodies cross-reacting with the two plant toxins. The results presented in this paper suggest that, in the future, sequential administration of anti-CD30 humanized antibodies linked to antigenically distinct type 1 RIPs (saporln, MOM, PAP-S) should be feasible.",
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T1 - Anti-CD30 (BER-H2) immunotoxins containing the type-1 ribosome-inactivating proteins momordin and PAP-S (pokeweed antiviral protein from seeds) display powerful antitumour activity against CD30+ tumour cells in vitro and in SCID mice

AU - Terenzi, Adelmo

AU - Bolognesi, Andrea

AU - Pasqualucci, Laura

AU - Flenghi, Leonardo

AU - Pileri, Stefano

AU - Stein, Harald

AU - Marshall, Kadin

AU - Bigerna, Barbara

AU - Polito, Letizia

AU - Tazzari, Pier Luigi

AU - Martelli, Massimo F.

AU - Stirpe, Fiorenzo

AU - Falini, Brunangelo

PY - 1996

Y1 - 1996

N2 - The anti-CD30 immunotoxin (IT) Ber-H2/ saporin is effective in patients with refractory Hodgkin's disease. However, responses are short and partial, one of the main reasons being the inability to repeal IT doses because of formation of human antibodies against the murine antibody and/or the toxin. To overcome this problem, we constructed two new anti-CD30 ITs by covalently linking the mouse monoclonal antibody Ber-H2 to the type 1 ribosome-inactivating proteins (RIPs) momordin (MOM) and pokeweed antiviral protein from seeds (PAP-S), which do not cross-react with each other or with saporin. Both ITs inhibited protein synthesis by Hodgkin's disease and anaplastic large-cell lymphoma (ALCL)-derived CD30+ target cell lines with a very high efficiency (IC50 ranging from <5 × 10-13 M to 2-75 × 10-11 M, as RIP). In a SCID mouse model of xenografted CD30+ human ALCL, a 3d treatment with non-toxic doses of Ber-H2/MOM (50% LD50), started 24h after transplantation, prevented tumour development in about 40% of the animals and significantly delayed tumour growth rate in the others. Main toxicity signs in mice and rabbits were a dose-related increase of serum transaminases (AST and ALT) and creatine phosphokinase (CPK). LD50 (as RIP) in Swiss mice was 7 mg/kg for Ber-H2/MOM and 0-45 mg/kg for Ber-H2/PAP-S. Sequential administration of two anti-CD30 ITs (Ber-H2/MOM and Ber-H2/saporin) was well tolerated and did not result in formation of antibodies cross-reacting with the two plant toxins. The results presented in this paper suggest that, in the future, sequential administration of anti-CD30 humanized antibodies linked to antigenically distinct type 1 RIPs (saporln, MOM, PAP-S) should be feasible.

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