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 language | English |
|---|---|
| Pages (from-to) | 872-879 |
| Number of pages | 8 |
| Journal | British Journal of Haematology |
| Volume | 92 |
| Issue number | 4 |
| Publication status | Published - 1996 |
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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 journal › Article
}
TY - JOUR
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.
AB - 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.
KW - CD30 antigen
KW - Hodgkin's disease
KW - Immunotoxins
KW - Monoclonal antibodies
KW - Ribosome-inactivating proteins
UR - http://www.scopus.com/inward/record.url?scp=0029880032&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0029880032&partnerID=8YFLogxK
M3 - Article
C2 - 8616080
AN - SCOPUS:0029880032
VL - 92
SP - 872
EP - 879
JO - British Journal of Haematology
JF - British Journal of Haematology
SN - 0007-1048
IS - 4
ER -