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Title: Preclinical investigation of the antitumour effects of anti-CD19-idarubicin immunoconjugates.
Austin Authors: Rowland, A J;Pietersz, Geoffrey A;McKenzie, Ian F C
Affiliation: Austin Research Institute, Austin Hospital, Heidelberg, Victoria, Australia
Issue Date: 1-Aug-1993
Publication information: Cancer Immunology, Immunotherapy : Cii; 37(3): 195-202
Abstract: Idarubicin (Ida), an analogue of daunomycin, was linked to a mouse monoclonal antibody against the B cell differentiation antigen CD19. Determination of the activity of both the antibody and drug moieties was carried out in vitro using a pre-B cell human acute lymphoblastic leukaemia cell line (NALM-6). A 23% loss in antibody binding and a 20-fold loss in drug activity were observed upon conjugation. Selective cytotoxicity for CD19+ cells, however, was obtained. Measurement of the cytotoxicity, antibody activity and release of the breakdown product, 14-OH-Ida, showed that the conjugates remained stable for more than 100 days after lyophilization and storage at -20 degrees C. In vivo studies were performed in irradiated nu/nu mice bearing NALM-6 tumours. Initial dose response studies with free idarubicin demonstrated that three i.p. doses (every other day) of 10 micrograms resulted in little antitumour activity, but the death of all the animals by day 23. The same treatment regime using 15 micrograms Ida-anti-CD19 conjugate caused the disappearance of four out of five tumours with three complete cures and no evidence of toxicity as assessed by weight loss. Administration of a conjugate of idarubicin with an irrelevant antibody at this dose led to no significant antitumour response. The administration of free drug at a dose of 6 micrograms resulted in a minor antitumour response but high toxicity, whereas injection of Ida-anti-CD19 conjugate at this dose caused no toxicity and a substantial antitumour effect with eradication of two out of five tumours. These results clearly demonstrate that the administration of Ida-anti-CD19 conjugates can result in complete tumour regression in an experimental model. Idarubicin-containing immunoconjugates should be useful for the treatment of patients with non-Hodgkin's lymphoma.
Gov't Doc #: 7687521
Journal: Cancer immunology, immunotherapy : CII
Type: Journal Article
Subjects: Animals
Antibodies, Monoclonal.administration & dosage.pharmacology.therapeutic use
Antibody Affinity
Antigens, CD.immunology
Antigens, CD19
Antigens, Differentiation, B-Lymphocyte.immunology
Burkitt Lymphoma.drug therapy.pathology
Cell Division.drug effects
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Flow Cytometry
Idarubicin.administration & dosage.pharmacology.therapeutic use
Immunotoxins.administration & dosage.pharmacology.therapeutic use
Injections, Intraperitoneal
Mice, Nude
Neoplasm Transplantation
Remission Induction
Time Factors
Tumor Cells, Cultured
Appears in Collections:Journal articles

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