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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
- Source :
- British journal of haematology. 92(4)
- Publication Year :
- 1996
-
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 repeat 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 from5 x 10(-13) M to 2.75 x 10(-11) M, as RIP). In a SCID mouse model of xenografted CD30+ human ALCL, a 3d treatment with non-toxin doses of Ber-H2/MOM (50%LD50), started 24 h 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 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 and 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 (saporin, MOM, PAP-S) should be feasible.
- Subjects :
- Ribosomal Proteins
Ribosome Inactivating Proteins
Ki-1 Antigen
Antineoplastic Agents
Mice, SCID
SCID
Antibodies
Mice
Phytogenic
Ribo
Monoclonal
Tumor Cells, Cultured
Animals
Humans
Antigens
N-Glycosyl Hydrolases
Plant Proteins
Cultured
somal Proteins
Immunotoxins
Antibodies, Monoclonal
Antineoplastic Agents, Phytogenic
Hodgkin Disease
Tumor Cells
Ribosome Inactivating Proteins, Type 2
Animals, Antibodies
Monoclonal, Antigens
CD30, Antineoplastic Agents
Phytogenic, Hodgkin Disease, Humans, Immunotoxins, Mice, Mice
SCID, N-Glycosyl Hydrolases, Plant Proteins, Ribo, Ribosome Inactivating Proteins
Type 1, Ribosome Inactivating Proteins
Type 2, Tumor Cells
Cultured, somal Proteins
CD30
Ribosome Inactivating Proteins, Type 1
Type 2
Type 1
Subjects
Details
- ISSN :
- 00071048
- Volume :
- 92
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- British journal of haematology
- Accession number :
- edsair.pmid.dedup....c2e8163c0d2c185472c0e2a0dd96cfab