title: Toxicity profile of the investigational new biotherapeutic agent, B43 (anti-CD19)-pokeweed antiviral protein immunotoxin.
abstract: The investigational biotherapeutic agent, B43(anti-CD19)-pokeweed antiviral protein (PAP) immunotoxin, has shown substantial anti-leukemic activity in SCID mouse models of human B-lineage leukemia and lymphoma. In this report, we describe the results of a comprehensive preclinical toxicity study which determined the toxicity profile of B43-PAP in BALB/c mice. Administration of unconjugated B43 monoclonal antibody was not associated with any toxicity, whereas B43-PAP caused dose-limiting and cardiac and renal toxicities which were fatal. In addition, B43-PAP also caused multifocal skeletal myofiber necrosis, which was associated with abnormal gait and lethargy. Notably, parenteral administrations of methylprednisolone, pentoxyphylline, or dopamine were able to markedly reduce B43-PAP related toxicity. This study provides a basis for further evaluation of the toxicity of B43-PAP in monkeys and humans.
authors.affiliation: University of Minnesota Biotherapy Program, Roseville 55113, USA.
authors.forename: R
authors.initials: R
authors.lastname: Gunther
authors.forename: L M
authors.initials: LM
authors.lastname: Chelstrom
authors.forename: H R
authors.initials: HR
authors.lastname: Wendorf
authors.forename: E A
authors.initials: EA
authors.lastname: Schneider
authors.forename: K
authors.initials: K
authors.lastname: Covalciuc
authors.forename: B
authors.initials: B
authors.lastname: Johnson
authors.forename: D
authors.initials: D
authors.lastname: Clementson
authors.forename: J D
authors.initials: JD
authors.lastname: Irvin
authors.forename: D E
authors.initials: DE
authors.lastname: Myers
authors.forename: F M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000633:toxicity*; D018941:Antigens, CD19 / Q000276:immunology*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000633:toxicity*; D009202:Cardiomyopathies / Q000139:chemically induced / Q000188:drug therapy; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000209:etiology; D004298:Dopamine / Q000627:therapeutic use; D005260:Female; D000922:Immunotoxins / Q000008:administration & dosage / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced; D008775:Methylprednisolone / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D009135:Muscular Diseases / Q000139:chemically induced / Q000188:drug therapy; D009699:N-Glycosyl Hydrolases; D010431:Pentoxifylline / Q000627:therapeutic use; D010940:Plant Proteins / Q000008:administration & dosage / Q000633:toxicity*; D054789:Ribosome Inactivating Proteins, Type 1; D016037:Single-Blind Method
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D018941:Antigens, CD19; D000972:Antineoplastic Agents, Phytogenic; D000922:Immunotoxins; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D009699:N-Glycosyl Hydrolases; C024275:pokeweed antiviral protein; D010431:Pentoxifylline; D004298:Dopamine; D008775:Methylprednisolone