Favorable pharmacodynamic features and superior anti-leukemic activity of B43 (anti-CD19) immunotoxins containing two pokeweed antiviral protein molecules covalently linked to each monoclonal antibody molecule.
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.
Myers
D E
DE
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis 55455, USA.
Yanishevski
Y
Y
Masson
E
E
Irvin
J D
JD
Evans
W E
WE
Uckun
F M
FM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology; D018941:Antigens, CD19 / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology*; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D004355:Drug Stability; D005260:Female; D000922:Immunotoxins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009699:N-Glycosyl Hydrolases; D010940:Plant Proteins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D054789:Ribosome Inactivating Proteins, Type 1
D000911:Antibodies, Monoclonal; D018941:Antigens, CD19; D000972:Antineoplastic Agents, Phytogenic; D000998:Antiviral Agents; D000922:Immunotoxins; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D009699:N-Glycosyl Hydrolases; C024275:pokeweed antiviral protein