Favorable Pharmacodynamic Features and Superior Anti-Leukemic Activity of B43 (Anti-CD 19) Immunotoxins Containing Two Pokeweed Antiviral Protein Molecules Covalently Linked to each Monoclonal Antibody Molecule

Dorothea E. Myers Biotherapy Program, Departments of Therapeutic, Radiology-Radiation Oncology; Childrens Cancer Group Immunotoxin Resource Laboratory, Pharmaceutical Department, University of Minnesota, Minneapolis, Minnesota St. Jude Children's Research Hospital; Departments of Pediatrics, Memphis Department of Chemistry, University of Tennessee, Southwest Texas State University, San Marcos, Texas, USA

Yuri Yanishevski Biotherapy Program, Departments of Therapeutic, Radiology-Radiation Oncology; Childrens Cancer Group Immunotoxin Resource Laboratory, Pharmaceutical Department, University of Minnesota, Minneapolis, Minnesota St. Jude Children's Research Hospital; Departments of Pediatrics, Memphis Department of Chemistry, University of Tennessee, Southwest Texas State University, San Marcos, Texas, USA

Eric Masson Biotherapy Program, Departments of Therapeutic, Radiology-Radiation Oncology; Childrens Cancer Group Immunotoxin Resource Laboratory, Pharmaceutical Department, University of Minnesota, Minneapolis, Minnesota St. Jude Children's Research Hospital; Departments of Pediatrics, Memphis Department of Chemistry, University of Tennessee, Southwest Texas State University, San Marcos, Texas, USA

James D. Irvin Biotherapy Program, Departments of Therapeutic, Radiology-Radiation Oncology; Childrens Cancer Group Immunotoxin Resource Laboratory, Pharmaceutical Department, University of Minnesota, Minneapolis, Minnesota St. Jude Children's Research Hospital; Departments of Pediatrics, Memphis Department of Chemistry, University of Tennessee, Southwest Texas State University, San Marcos, Texas, USA

William E. Evans Biotherapy Program, Departments of Therapeutic, Radiology-Radiation Oncology; Childrens Cancer Group Immunotoxin Resource Laboratory, Pharmaceutical Department, University of Minnesota, Minneapolis, Minnesota St. Jude Children's Research Hospital; Departments of Pediatrics, Memphis Department of Chemistry, University of Tennessee, Southwest Texas State University, San Marcos, Texas, USA

Fatih M. Uckun Biotherapy Program, Departments of Therapeutic, Radiology-Radiation Oncology; Childrens Cancer Group Immunotoxin Resource Laboratory, Pharmaceutical Department, University of Minnesota, Minneapolis, Minnesota St. Jude Children's Research Hospital; Departments of Pediatrics, Memphis Department of Chemistry, University of Tennessee, Southwest Texas State University, San Marcos, Texas, USA; Clinical Pharmacy, Colleges of Pharmacy and MedicineMemphis University of Tennessee, Southwest Texas State University, Department of Chemistry, San Marcos, Texas, USA

Abstract

Standard immunotoxin production procedures using whole IgG as the MoAb moiety yield a heterogeneous mixture of 180 kDa, 210 kDa, and 240 kDa immunotoxin species with 1 to 1, 1 to 2, and 1 to 3 MoAb to toxin ratios. This heterogeneity makes it impossible to precisely deliver a predetermined immunotoxin dose to target cells and impairs the accuracy of pharmacologic studies. In this report, we describe the preparation and characterization of B43(anti-CD19)-pokeweed antiviral protein (PAP) immunotoxins containing either one or two 30 kDa PAP toxin molecules covalently linked to each 150 kDa B43 monoclonal antibody molecule. Compared to the 180 kDa immunotoxin, the 210 kDA immunotoxin displayed greater in vitro chemical stability, resulted in higher systemic exposure levels in vivo, and was a more effective anti-leukemic agent in a SCID mouse model of human B-lineage acute lymphoblastic leukemia. Taken together, the results of this study recommend the clinical evaluation of 210 kDa B43-PAP as a potentially more effective immunotoxin against relapsed B-lineage ALL.

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Favorable Pharmacodynamic Features and Superior Anti-Leukemic Activity of B43 (Anti-CD 19) Immunotoxins Containing Two Pokeweed Antiviral Protein Molecules Covalently Linked to each Monoclonal Antibody Molecule

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Favorable Pharmacodynamic Features and Superior Anti-Leukemic Activity of B43 (Anti-CD 19) Immunotoxins Containing Two Pokeweed Antiviral Protein Molecules Covalently Linked to each Monoclonal Antibody Molecule

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